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Fetal anomalies v1.255 PSMF1 Zornitza Stark Marked gene: PSMF1 as ready
Fetal anomalies v1.254 PSMF1 Zornitza Stark gene: PSMF1 was added
gene: PSMF1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PSMF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMF1 were set to https://www.medrxiv.org/content/10.1101/2024.06.19.24308302v1
Phenotypes for gene: PSMF1 were set to Complex neurodevelopmental disorder with motor features, MONDO:0100516, PSMF1-related
Review for gene: PSMF1 was set to GREEN
Added comment: 22 individuals from 15 families reported with a range of neurological phenotypes ranging from early-onset Parkinson's disease; childhood conditions typified by ID and a range of movement disorders; through to perinatal lethal presentations with arthrogryposis multiplex. Genotype-phenotype correlation: biallelic missense variants resulted in the milder phenotypes, while bi-allelic LoF variants in the more severe phenotypes. Supportive functional data.
Sources: Literature
Fetal anomalies v1.252 SERPINA11 Ain Roesley Marked gene: SERPINA11 as ready
Fetal anomalies v1.252 SERPINA11 Ain Roesley gene: SERPINA11 was added
gene: SERPINA11 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SERPINA11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SERPINA11 were set to 38831697
Phenotypes for gene: SERPINA11 were set to pericardial effusion; pleural effusion
Review for gene: SERPINA11 was set to RED
gene: SERPINA11 was marked as current diagnostic
Added comment: 1 family with 2 fetuses.

1st fetus presented with isolated pericardial effusion and a TOP was opted.
post mortem:
mild subcutaneous edema with subtle facial dysmorphic features
small gelatinous glistening cyst on the right pericardium. Bilateral pleural effusion and multiple similar cysts were noted on the lung surfaces

2nd fetus also presented with pleural and pericardial effusion and a TOP was opted
post mortem findings were similar to fetus#1

homozygous nonsense variant in SERPINA11 was found p.(Tyr224*)

Immunofluorescence of lung sections from fetus#1 and a gestation-matched fetus as a control demonstrated undetectable levels of SERPINA11 in the bronchiolar epithelium
Sources: Literature
Fetal anomalies v1.245 LIG4 Santosh Varughese reviewed gene: LIG4: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 15333585, 20133615, 32534991, 11779494, 16088910; Phenotypes: LIG4 SYNDROME, MULTIPLE MYELOMA, RESISTANCE TO; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.245 BCORL1 Zornitza Stark Marked gene: BCORL1 as ready
Fetal anomalies v1.244 BCORL1 Zornitza Stark gene: BCORL1 was added
gene: BCORL1 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: BCORL1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: BCORL1 were set to Congenital anomaly of the kidney and urinary tract, MONDO:0019719, BCORL1-related
Review for gene: BCORL1 was set to AMBER
Added comment: Emerging evidence of disease association.
Sources: Expert Review
Fetal anomalies v1.243 ARMC4 Zornitza Stark Tag new gene name tag was added to gene: ARMC4.
Fetal anomalies v1.243 HOXD12 Zornitza Stark Marked gene: HOXD12 as ready
Fetal anomalies v1.242 HOXD12 Zornitza Stark gene: HOXD12 was added
gene: HOXD12 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: HOXD12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HOXD12 were set to 38663984
Phenotypes for gene: HOXD12 were set to Clubfoot (non-syndromic) MONDO:0007342
Review for gene: HOXD12 was set to AMBER
Added comment: Identified as a candidate gene in a large cohort due to enrichment of rare variants.


PMID: 38663984
Around 9 individuals from 4 unrelated families have been reported with clubfoot and the variants were shown to segregate. Cohort of over 1000 individuals, with several novel candidates identified.

N-terminal region and C-terminal homeobox domain of HOXD12 are known to be clusters for pathogenic variants related to clubfoot.
Loss of function variants are less likely to contribute to clubfoot pathogenesis therefore mechanism of disease is suggested as dominant negative but is not confirmed.
Sources: Literature
Fetal anomalies v1.234 CNOT1 Zornitza Stark edited their review of gene: CNOT1: Added comment: LIMITED by ClinGen for holoprosencephaly 12 with or without pancreatic agenesis, MONDO:0032787

ClinGen curation: CNOT1 was originally reported in cases of holoprosencephaly and/or pancreatic agenesis/insufficiency in 2019 (PMID: 31006513, 31006510). One of the papers included 3 individuals with heterozygous p.Arg535Cys (PMID: 31006513), confirmed to be de novo in 2 individuals. One of these individuals was not scored due to a lack of documentation of holoprosencephaly. The other paper included 2 individuals with de novo p.Arg535Cys, both of whom with holoprosencephaly. A knock-in mouse model of this variant showed neurological and pancreatic abnormalities at E14.5, and this evidence was used to augment the genetic evidence. A mouse brain expression study (PMID: 31006510) was scored as functional evidence. In total, there is Limited evidence to support the gene-disease relationship between CNOT1 and holoprosencephaly with or without pancreatic agenesis. Of note, this gene has also been implicated in Vissers-Bodmer syndrome, which is characterized by global developmental delay and behavioral abnormalities apparent from infancy. As the condition is clinically distinct from holoprosencephaly and/or pancreatic agenesis/insufficiency, lacks specific structural brain anomalies, and likely has different molecular mechanisms, this will be/have been assessed separately.; Changed rating: AMBER; Changed phenotypes: Holoprosencephaly 12 with or without pancreatic agenesis MONDO:0032787
Fetal anomalies v1.234 KDM5C Ain Roesley Phenotypes for gene: KDM5C were changed from Mental retardation, X-linked, syndromic, Claes-Jensen type, MIM# 300534; MONDO:0010355 to Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type MIM# 300534; MONDO:0010355
Fetal anomalies v1.232 PURA Ain Roesley Phenotypes for gene: PURA were changed from Mental retardation, autosomal dominant 31, MIM# 616158 to Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (OMIM 616158)
Fetal anomalies v1.231 FILIP1 Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related to ANeuromuscular disorder, congenital, with dysmorphic facies, MIM# 620775
Fetal anomalies v1.230 FILIP1 Zornitza Stark reviewed gene: FILIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuromuscular disorder, congenital, with dysmorphic facies, MIM# 620775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.225 DISP1 Zornitza Stark edited their review of gene: DISP1: Added comment: PMID: 38529886
25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE).
A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense).
14 heterozygous individuals , 5 compound heterozygous individuals, 6 homozygous individuals (5 of the individuals were from 3 unrelated consanguineous families).

HPE phenotype was also seen prenatally as one of the reported monoallelic individuals was a fetus at 20+6 GW prior to passing due to MTP.; Changed rating: GREEN; Changed publications: 19184110, 26748417, 23542665, 38529886; Changed phenotypes: Holoprosencephaly (MONDO:0016296), DISP1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.225 FRYL Ain Roesley Marked gene: FRYL as ready
Fetal anomalies v1.224 FRYL Ain Roesley gene: FRYL was added
gene: FRYL was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FRYL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FRYL were set to 38479391
Phenotypes for gene: FRYL were set to neurodevelopmental disorder MONDO:0700092, FRYL-related
Review for gene: FRYL was set to AMBER
gene: FRYL was marked as current diagnostic
Added comment: 14 individuals, all de novo except 1x duo testing (not present in tested father)
5x missense + 8x fs/stopgain + 1x canonical splice

7/14 with cardiac anomalies

Of interest to this panel: 1x tetralogy of fallot (TOF) with pulmonary atresia (PA), 2x dextrocardia, 1x hypoplastic left heart syndrome

Other reported features AVSD, VSD, PDA
Sources: Literature
Fetal anomalies v1.223 MAP3K20 Zornitza Stark edited their review of gene: MAP3K20: Added comment: PMID 38451290: five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20.; Changed publications: 38451290; Changed phenotypes: Syndromic disease, MONDO:0002254, MAP3K20-related, Centronuclear myopathy 6 with fiber-type disproportion MIM#617760, Split-foot malformation with mesoaxial polydactyly MIM#616890; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.222 SASS6 Ain Roesley reviewed gene: SASS6: Rating: GREEN; Mode of pathogenicity: None; Publications: 38501757, 36739862; Phenotypes: Microcephaly 14, primary, autosomal recessive, MIM# 616402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v1.217 RBFOX2 Ain Roesley Marked gene: RBFOX2 as ready
Fetal anomalies v1.216 RBFOX2 Ain Roesley gene: RBFOX2 was added
gene: RBFOX2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RBFOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBFOX2 were set to 26785492; 27670201; 27485310; 25205790; 35137168; 26785492; 37165897
Review for gene: RBFOX2 was set to AMBER
gene: RBFOX2 was marked as current diagnostic
Added comment: PMID: 37165897
1x 'splice altering' de novo in in an individual with HLSH + AVSD

- PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (eg. nonsense, frameshift, or canonical splice disruptions). All 3 probands have hypoplastic left heart syndrome (HLHS). No further patient-specific clinical or variant info were available. Same cohort later included in PMID: 32368696, listed 4 de novo variants in this gene, in patients with left ventricular outflow tract obstruction (LVOTO) or conotruncal defects (CTDs).

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.
- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.
Sources: Literature
Fetal anomalies v1.214 KDR Ain Roesley Marked gene: KDR as ready
Fetal anomalies v1.212 KDR Ain Roesley changed review comment from: PMID:30232381
5x families (6 affecteds) with ToF: 2x PTCs + 2x missense + 1x inframe del
noted that all individuals were adults at time of assessment but known to have ToF and/or other CHD

PMID:34113005;
1x family with 2 affecteds, Chet for 2x missense
Sources: Literature; to: GREEN for AD
RED for AR

PMID:30232381
5x families (6 affecteds) with ToF: 2x PTCs + 2x missense + 1x inframe del
noted that all individuals were adults at time of assessment but known to have ToF and/or other CHD

PMID: 34328347;
cohort of ToF, looking into LoF variants
4x identified + 1x classified as VUS (stop gain in penultimate exon)
1x stop gain citing PMID: 28991257

PMID:34113005;
1x family with 2 affecteds, Chet for 2x missense



Sources: Literature
Fetal anomalies v1.211 IRX4 Ain Roesley Marked gene: IRX4 as ready
Fetal anomalies v1.211 IRX4 Ain Roesley gene: IRX4 was added
gene: IRX4 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: IRX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IRX4 were set to 21544582
Phenotypes for gene: IRX4 were set to Ventricular septal defect
Review for gene: IRX4 was set to RED
gene: IRX4 was marked as current diagnostic
Added comment: Two individuals with novel missense variants identified in a large cohort in 2011.

nothing new in punned
Sources: Literature
Fetal anomalies v1.210 HEY2 Ain Roesley Marked gene: HEY2 as ready
Fetal anomalies v1.210 HEY2 Ain Roesley gene: HEY2 was added
gene: HEY2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: HEY2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: HEY2 were set to 32820247
Phenotypes for gene: HEY2 were set to congenital heart defects and thoracic aortic aneurysms
Review for gene: HEY2 was set to RED
gene: HEY2 was marked as current diagnostic
Added comment: A very large family affected by CHD and familial thoracic aortic aneurysms. Trio genome sequencing was carried out in an index patient with critical CHD, and family members had either exome or Sanger sequencing. Identified homozygous loss-of-function variant (c.318_319delAG, p.G108*) in HEY2 in 3 individuals in family with critical CHD, whereas the 20 heterozygous carriers show a spectrum of CVDs (CHD and FTAA, but varying expressivity and incomplete penetrance).

Other studies show that knockout of HEY2 in mice results in cardiovascular defects (CVDs), including septal defects, cardiomyopathy, a thin-walled aorta, and valve anomalies.
Sources: Literature
Fetal anomalies v1.209 DOHH Ain Roesley Marked gene: DOHH as ready
Fetal anomalies v1.208 DOHH Ain Roesley changed review comment from: 4 families - 5 affecteds

1x cardiomyopathy at prenatal examination
4/5 presented with CHD post-natally - VSD, ASD, severe cardiomegaly, Shone syndrome with aortic coarctation; bicuspid aortic valve; tricuspid-valve insufficiency etc

microcephaly was post-natal
Sources: Literature; to: 4 families - 5 affecteds

prenatal examination:
1x cardiomyopathy
1x increased nuchal translucency; chylothorax

post-natal:
4/5 presented with CHD - VSD, ASD, severe cardiomegaly, Shone syndrome with aortic coarctation; bicuspid aortic valve; tricuspid-valve insufficiency etc

5/5 microcephaly
Fetal anomalies v1.208 DOHH Ain Roesley gene: DOHH was added
gene: DOHH was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DOHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOHH were set to 35858628
Phenotypes for gene: DOHH were set to Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, MIM# 620066
Review for gene: DOHH was set to GREEN
gene: DOHH was marked as current diagnostic
Added comment: 4 families - 5 affecteds

1x cardiomyopathy at prenatal examination
4/5 presented with CHD post-natally - VSD, ASD, severe cardiomegaly, Shone syndrome with aortic coarctation; bicuspid aortic valve; tricuspid-valve insufficiency etc

microcephaly was post-natal
Sources: Literature
Fetal anomalies v1.207 AMOTL1 Ain Roesley Marked gene: AMOTL1 as ready
Fetal anomalies v1.206 AMOTL1 Ain Roesley gene: AMOTL1 was added
gene: AMOTL1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: AMOTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMOTL1 were set to 36751037
Phenotypes for gene: AMOTL1 were set to Orofacial clefting syndrome, MONDO:0015335, AMOTL1-related
Review for gene: AMOTL1 was set to GREEN
gene: AMOTL1 was marked as current diagnostic
Added comment: PMID: 36751037- 16 individuals from 12 families with orofacial clefting syndrome and het variants in AMOTL1. Many in 1 hotspot: 5 individuals from 3 families have R157C, 6 individuals from another 4 families have R157H, 1 has P160L, and another has Q161R. Out of this hostpaot- 1 with P368A, 1 with E507K, 1 with E579K. 7 are de novo. All but 2 have clefting, 7 are dysmorphic, 5 have hearing loss, 9 have CHD, 7 have tall stature, 6 have dev delay. Other features include liver disease, myopia, scoliosis and immune involvement.

Another 2 families have been previously reported (described in the panelapp review below) with variants in this hotspot 1 has 2 individuals with R157C, the other has 1 individual with P160L. All hotspot are absent from gnomad v2.
Sources: Literature
Fetal anomalies v1.205 AL117258.1 Ain Roesley Marked gene: AL117258.1 as ready
Fetal anomalies v1.204 AL117258.1 Ain Roesley gene: AL117258.1 was added
gene: AL117258.1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: AL117258.1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AL117258.1 were set to 34903892
Phenotypes for gene: AL117258.1 were set to Heterotaxy; congenital heart defects
Review for gene: AL117258.1 was set to GREEN
gene: AL117258.1 was marked as current diagnostic
Added comment: Gene also known as CIROP and LMLN2

Homozygous or compound heterozygous CIROP variants identified in 12 families with congenital heart defects associated with heterotaxy.

Functional tests performed on Xenopus and zebrafish embryos showed that CIROP was essential for left side symmetry and is expressed in ciliated left–right organisers.
Sources: Literature
Sources: Literature
Fetal anomalies v1.202 CELSR3 Zornitza Stark Marked gene: CELSR3 as ready
Fetal anomalies v1.201 CELSR3 Zornitza Stark gene: CELSR3 was added
gene: CELSR3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CELSR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CELSR3 were set to 38429302
Phenotypes for gene: CELSR3 were set to Neurodevelopmental disorder (MONDO#0700092), CELSR3-related
Added comment: PMID: 38429302:12 affected individuals from 11 families reported with bi-allelic variants. Phenotype ranged from CNS anomalies (7/12), CNS and CAKUT (3/12) and CAKUT only (2/12). 8/12 has ID/DD. Only missense variants reported and 1 inframe variant. Functional studies done in zebrafish demonstrate similar structural anomalies of the developing pronephros and neuronal abnormalities to affected individuals
Sources: Literature
Fetal anomalies v1.200 NARS Zornitza Stark edited their review of gene: NARS: Changed rating: GREEN
Fetal anomalies v1.200 NARS Zornitza Stark changed review comment from: AR disorder: assessed as LIMITED by ClinGen (borderline MODERATE).; to: Both MOIs assessed as MODERATE by ClinGen.
Fetal anomalies v1.200 HSPG2 Ain Roesley Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, MONDO:0009717; Silverman-Handmaker type dyssegmental dysplasia, MONDO:0009140; Schwartz-Jampel syndrome, type 1, OMIM:255800; Dyssegmental dysplasia, Silverman-Handmaker type, OMIM:224410 to Dyssegmental dysplasia, Rolland-Desbuquois type (MONDO:0009139); Schwartz-Jampel syndrome, MONDO:0009717; Silverman-Handmaker type dyssegmental dysplasia, MONDO:0009140; Schwartz-Jampel syndrome, type 1, OMIM:255800; Dyssegmental dysplasia, Silverman-Handmaker type, OMIM:224410
Fetal anomalies v1.198 NARS Zornitza Stark reviewed gene: NARS: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, MIM# 619091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.198 THSD1 Zornitza Stark Marked gene: THSD1 as ready
Fetal anomalies v1.197 THSD1 Zornitza Stark gene: THSD1 was added
gene: THSD1 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: THSD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THSD1 were set to 33569873; 27895300
Phenotypes for gene: THSD1 were set to Lymphatic malformation 13, MIM# 620244
Review for gene: THSD1 was set to GREEN
Added comment: PMID: 33569873 - 1 fetus with a homozygous PTC and nonimmune hydrops fetalis (NIHF), congenital heart disease and hemangiomas. FHx of 1/3 triplets with severe hydrops fetalis, not sequenced.
- Paper reviews previous NIHF cases and reports another homozygous PTC in two families ( and a recurring homozygous missense (p.Cys206Tyr) in three families.


PMID: 27895300- Mouse model has hydrocephaly with poor perfusion.
Sources: Expert Review
Fetal anomalies v1.191 THOC2 Zornitza Stark Phenotypes for gene: THOC2 were changed from Mental retardation, X-linked 12/35 MIM#300957 to Mental retardation, X-linked 12/35 MIM#300957; Arthrogryposis (MONDO:0008779), THOC2-related
Fetal anomalies v1.189 THOC2 Zornitza Stark edited their review of gene: THOC2: Added comment: PMID: 34976470 - arthrogryposis multiplex congenita phenotype (AMC) in two male fetuses in a family, caused by splice deletion c.2482-1_2484delGTCA which was mat inherited. No splice studies conducted, mother was normal. Postulate that amorphic or severe null pathogenic variants (possible complete loss of function) lead to AMC phenotype

PMID: 37945483 - a proband with AMC and the same splice site mutation ^ above, but de novo. Cytoplasmic bodies also detected in muscle; Changed publications: 29851191, 34976470, 37945483; Changed phenotypes: Mental retardation, X-linked 12/35 MIM#300957, Arthrogryposis (MONDO:0008779), THOC2-related
Fetal anomalies v1.188 NARS Zornitza Stark Marked gene: NARS as ready
Fetal anomalies v1.188 NARS Zornitza Stark Gene: nars has been classified as Green List (High Evidence).
Fetal anomalies v1.188 NARS Zornitza Stark Classified gene: NARS as Green List (high evidence)
Fetal anomalies v1.188 NARS Zornitza Stark Gene: nars has been classified as Green List (High Evidence).
Fetal anomalies v1.187 DLG5 Zornitza Stark Marked gene: DLG5 as ready
Fetal anomalies v1.186 DLG5 Zornitza Stark gene: DLG5 was added
gene: DLG5 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: DLG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DLG5 were set to 32631816
Phenotypes for gene: DLG5 were set to Yuksel-Vogel-Bauer syndrome, MIM#620703
Review for gene: DLG5 was set to GREEN
Added comment: Four unrelated families reported, supportive Xenopus animal model data. Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations.
Sources: Expert Review
Fetal anomalies v1.184 MYMK Zornitza Stark edited their review of gene: MYMK: Added comment: Cleft palate, micrognathia, microcephaly, talipes are features detectable on fetal ultrasound.; Changed rating: GREEN
Fetal anomalies v1.184 WDR44 Seb Lunke Marked gene: WDR44 as ready
Fetal anomalies v1.184 WDR44 Seb Lunke Added comment: Comment when marking as ready: GoF mentioned but not well established.
Fetal anomalies v1.182 WDR44 Andrew Fennell gene: WDR44 was added
gene: WDR44 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WDR44 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: WDR44 were set to PMID: 38191484
Phenotypes for gene: WDR44 were set to Ciliopathy, MONDO:0005308, WDR44-related
Review for gene: WDR44 was set to GREEN
Added comment: 11 male patients with 6 missense and 1 nonsense variant in WDR44 displaying a wide range of cognitive impairment and variable congenital anomalies associated with primary cilium dysfunction. All patients had learning difficulties with 8 labelled as intellectually disabled (mild-moderate). Other clinical features included anomalies of craniofacial, musculoskeletal, brain, renal and cardiac development.
WDR44 is a negative regulator of ciliogenesis. Increased binding is hypothesised to underlie the pathogenicity of WDR44 variants identified in this cohort. Functional data supported impaired ciliogenesis initiation in patient fibroblasts and a zebrafish model. A zebrafish model recapitulated the human phenotype when morphants expressed WDR44 L668S, D669N, S764F, G782C, H839R, and R733* variants. Of note, D648G or N840S did not recapitulate the phenotype in the zebrafish model.
The studies supported a GoF mechanism, but the authors could not rule out that LoF of WDR44 contributes to the ciliopathy-like phenotype observed, because protein expression data was only available for a limited number of patients.
Sources: Literature
Fetal anomalies v1.182 MAX Zornitza Stark Marked gene: MAX as ready
Fetal anomalies v1.181 ZRSR2 Zornitza Stark Marked gene: ZRSR2 as ready
Fetal anomalies v1.180 CACHD1 Zornitza Stark Marked gene: CACHD1 as ready
Fetal anomalies v1.179 MAX Rylee Peters gene: MAX was added
gene: MAX was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MAX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAX were set to 38141607
Phenotypes for gene: MAX were set to Syndromic disease (MONDO:0002254), MAX-related
Review for gene: MAX was set to GREEN
Added comment: Three individuals who each share a recurrent de novo germline variant in the MAX gene, resulting in a p.Arg60Gln substitution in the loop of the b-HLH-LZ domain.

Affected individuals have a complex disorder consisting primarily of macrocephaly, polydactyly, and delayed ophthalmic development. Other phenotypes reported include intellectual disability, perianal abscesses, pectus carinatum, hypospadias, renal agenesis, single umbilical artery, flattened thoracic vertebrae.

Functional analysis of the p.Arg60Gln variant shows a significant increase in CCND2 protein and a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc.
Sources: Literature
Fetal anomalies v1.179 ZRSR2 Chris Ciotta gene: ZRSR2 was added
gene: ZRSR2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ZRSR2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ZRSR2 were set to PMID: 38158857
Phenotypes for gene: ZRSR2 were set to Orofacialdigital syndrome MONDO:0015375, ZRSR2-related
Review for gene: ZRSR2 was set to GREEN
Added comment: Oral-facial-digital (OFD) syndrome with brain anomalies ranging from alobar holoprosencephaly to pituitary anomalies.
Six unrelated families with two truncating variants and functional studies:
- p.(Gly404GlufsTer23): detected in one family with 2x affected males
- p.(Arg403GlyfsTer24): 5 unrelated families, both de novo and inherited
Sources: Literature
Fetal anomalies v1.179 CACHD1 Suliman Khan gene: CACHD1 was added
gene: CACHD1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CACHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACHD1 were set to PMID: 38158856
Phenotypes for gene: CACHD1 were set to syndromic complex neurodevelopmental disorder MONDO:0800439
Penetrance for gene: CACHD1 were set to unknown
Review for gene: CACHD1 was set to GREEN
Added comment: PMID: 38158856 - Six affected individuals from four unrelated families with homozygous CACHD1 variants (3 splice, 2 frameshift and 1 nonsense variant). Excluding the two fatal cases, all other were affected by syndromic neurodevelopmental abnormalities, multiple organ systems featuring global impairment of psychomotor development, dysmorphic facial features, genitourinary abnormalities, oculo-auricular and congenital malformation. Seizure was reported in one case. Whole exome sequencing identified bi-allelic loss of function variants in the CACHD1 gene. In vitro human neural models of CACHD1 depletion displayed dysregulated of Wnt signaling in the developing brain.
Sources: Literature
Fetal anomalies v1.179 NUDT2 Zornitza Stark Marked gene: NUDT2 as ready
Fetal anomalies v1.178 NUDT2 Lilian Downie gene: NUDT2 was added
gene: NUDT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NUDT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDT2 were set to PMID: 38141063
Phenotypes for gene: NUDT2 were set to Intellectual developmental disorder with or without peripheral neuropathy MIM#619844
Review for gene: NUDT2 was set to GREEN
Added comment: 9 individuals with partial agenesis or hypoplasia of the corpus callosum
Sources: Literature
Fetal anomalies v1.178 CNOT2 Zornitza Stark Marked gene: CNOT2 as ready
Fetal anomalies v1.177 CNOT2 Zornitza Stark gene: CNOT2 was added
gene: CNOT2 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: CNOT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CNOT2 were set to 31512373; 31145527; 28135719
Phenotypes for gene: CNOT2 were set to Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies 618608
Review for gene: CNOT2 was set to GREEN
Added comment: Congenital heart disease and poor growth may be detectable prenatally.
Sources: Expert Review
Fetal anomalies v1.173 CASP2 Zornitza Stark Phenotypes for gene: CASP2 were changed from neurodevelopmental disorder MONDO:0700092, CASP2-related to Intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, MIM# 620653
Fetal anomalies v1.172 CASP2 Zornitza Stark edited their review of gene: CASP2: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, MIM# 620653
Fetal anomalies v1.170 WBP4 Zornitza Stark Marked gene: WBP4 as ready
Fetal anomalies v1.169 PKP2 Zornitza Stark Marked gene: PKP2 as ready
Fetal anomalies v1.169 PKP2 Zornitza Stark Phenotypes for gene: PKP2 were changed from dilated cardiomyopathy; hypoplastic left heart syndrome; hydrops fetalis; ventricular septal defect; left ventricular non-compaction to Dilated cardiomyopathy, MONDO:0005021, PKP2-related; dilated cardiomyopathy; hypoplastic left heart syndrome; hydrops fetalis; ventricular septal defect; left ventricular non-compaction
Fetal anomalies v1.168 PKP2 Zornitza Stark reviewed gene: PKP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dilated cardiomyopathy, MONDO:0005021, PKP2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.168 PKP2 Seb Lunke Marked gene: PKP2 as ready
Fetal anomalies v1.167 PKP2 Suliman Khan changed review comment from: PMID: 30562116: PMID: 30562116 reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed.
PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD).
PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In case 1, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case 2 had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consistent to Wolff Parkinson-White syndrome.
Sources: Literature; to: PMID: 30562116: reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed.
PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD).
PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In case 1, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case 2 had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consistent to Wolff Parkinson-White syndrome.
Sources: Literature
Fetal anomalies v1.167 PKP2 Suliman Khan changed review comment from: PMID: 30562116: PMID: 30562116 reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed.
PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD).
PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In case 1, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case 2 had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consist to Wolff Parkinson-White syndrome.
Sources: Literature; to: PMID: 30562116: PMID: 30562116 reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed.
PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD).
PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In case 1, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case 2 had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consistent to Wolff Parkinson-White syndrome.
Sources: Literature
Fetal anomalies v1.167 PKP2 Suliman Khan changed review comment from: PMID: 30562116: PMID: 30562116 reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed.
PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD).
PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In cases, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consist to Wolff Parkinson-White syndrome.
Sources: Literature; to: PMID: 30562116: PMID: 30562116 reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed.
PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD).
PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In case 1, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case 2 had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consist to Wolff Parkinson-White syndrome.
Sources: Literature
Fetal anomalies v1.167 PKP2 Suliman Khan gene: PKP2 was added
gene: PKP2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PKP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PKP2 were set to PMID: 30562116; PMID: 35059364; PMID: 38050058
Phenotypes for gene: PKP2 were set to dilated cardiomyopathy; hypoplastic left heart syndrome; hydrops fetalis; ventricular septal defect; left ventricular non-compaction
Penetrance for gene: PKP2 were set to unknown
Review for gene: PKP2 was set to GREEN
Added comment: PMID: 30562116: PMID: 30562116 reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed.
PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD).
PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In cases, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consist to Wolff Parkinson-White syndrome.
Sources: Literature
Fetal anomalies v1.167 EFCAB1 Zornitza Stark Phenotypes for gene: EFCAB1 were changed from Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related to Ciliary dyskinesia, primary, 53, MIM# 620642
Fetal anomalies v1.166 EFCAB1 Zornitza Stark edited their review of gene: EFCAB1: Added comment: HGNC approved name is CLXN; Changed phenotypes: Ciliary dyskinesia, primary, 53, MIM# 620642
Fetal anomalies v1.165 TRIT1 Zornitza Stark Marked gene: TRIT1 as ready
Fetal anomalies v1.163 CASP2 Zornitza Stark Marked gene: CASP2 as ready
Fetal anomalies v1.161 MFN2 Elena Savva Marked gene: MFN2 as ready
Fetal anomalies v1.160 MFN2 Andrew Fennell gene: MFN2 was added
gene: MFN2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MFN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MFN2 were set to PMID: 37804319
Phenotypes for gene: MFN2 were set to Mitochondrial disease, MONDO:0044970, MFN2-related
Review for gene: MFN2 was set to AMBER
Added comment: A single report of fetus with severe antenatal encephalopathy with lissencephaly, polymicrogyria, and cerebellar atrophy. The authors identified a homozygous in-frame deletion leading to exon 16 skipping and in-frame loss of 50 amino acids 13 (p.Gln574_Val624del). Functional evidence of mitochondrial dysfunction (clumping) and respiratory chain complex deficiencies.
Sources: Literature
Fetal anomalies v1.160 HAND2 Zornitza Stark Phenotypes for gene: HAND2 were changed from Congenital heart defects to Congenital heart disease, MONDO:0005453, HAND2-related
Fetal anomalies v1.159 ADAMTS15 Zornitza Stark Phenotypes for gene: ADAMTS15 were changed from Arthrogryposis (MONDO:0008779), ADMATS15-related to Arthrogryposis, distal, type 12, MIM# 620545
Fetal anomalies v1.158 ADAMTS15 Zornitza Stark edited their review of gene: ADAMTS15: Changed phenotypes: Arthrogryposis, distal, type 12, MIM# 620545
Fetal anomalies v1.151 MYCN Elena Savva Added comment: Comment on phenotypes: Three individuals now reported with gain-of-function missense variants (identical variant in two individuals). Clinical presentation includes megalencephaly, hypoplastic corpus callosum, postaxial polydactyly, intellectual disability and motor delay. Knock-in mouse model showed morphological manifestations in multiple tissues including digits, female reproductive system and kidney.
Fetal anomalies v1.149 ATRX Zornitza Stark Phenotypes for gene: ATRX were changed from Alpha-thalassemia/mental retardation syndrome, MIM# 301040 to ATR-X-related syndrome MONDO:0016980
Fetal anomalies v1.148 PPP1R13L Zornitza Stark Phenotypes for gene: PPP1R13L were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 - PPP1R13L-related; Dilated cardiomyopathy, onset in infancy; Cleft lip and palate to Arrhythmogenic cardiomyopathy with or without ectodermal abnormalities, MIM#620519
Fetal anomalies v1.147 GNPNAT1 Zornitza Stark Marked gene: GNPNAT1 as ready
Fetal anomalies v1.146 GNPNAT1 Zornitza Stark gene: GNPNAT1 was added
gene: GNPNAT1 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: GNPNAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNPNAT1 were set to 36097642; 35427807; 32591345
Phenotypes for gene: GNPNAT1 were set to Rhizomelic dysplasia, Ain-Naz type, MIM#619598
Review for gene: GNPNAT1 was set to AMBER
Added comment: 3 unrelated families reported with a skeletal dysplasia characterised by severe short stature and rhizomelic shortening. No antenatal features reported. The parents in PMID 36097642 had a medical termination of pregnancy at 4 months gestation for a fetus with skeletal anomalies - not genotyped.
Sources: Expert Review
Fetal anomalies v1.145 ARHGAP29 Zornitza Stark Phenotypes for gene: ARHGAP29 were changed from Cleft palate; cleft lip with or without cleft palate to Clefting disorder, MONDO:0000358, ARHGAP29-related
Fetal anomalies v1.143 DBR1 Seb Lunke Marked gene: DBR1 as ready
Fetal anomalies v1.143 DBR1 Seb Lunke Phenotypes for gene: DBR1 were changed from Prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation, and death before the first year of life to Ichthyosis (MONDO#0019269), DBR1-related
Fetal anomalies v1.142 DBR1 Chern Lim edited their review of gene: DBR1: Added comment: PMID: 37656279:
- A homozygous missense as a founder recessive DBR1 variant in four consanguineous families.
- Total of 7 affected children. WES done for one proband from each family.
- Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life.
- RNA and protein studies using fibroblasts derived from a patient are supportive of pathogenicity: RNA-seq, rt-qPCR and western blotting, showing marked reduction of DBR1 level and intronic RNA lariat accumulation in the patient sample.
- Haplotype analysis revealed that the four families all share a haplotype extending at least 2.27 Mb around the c.200A>G p.(Tyr67Cys) DBR1 founder variant.
- Authors proposed this is a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility, and highlighted the apparent lack of correlation with the degree of DBR1 deficiency.; Changed phenotypes: Ichthyosis (MONDO#0019269), DBR1-related
Fetal anomalies v1.142 LNPK Zornitza Stark Marked gene: LNPK as ready
Fetal anomalies v1.140 LNPK Lilian Downie gene: LNPK was added
gene: LNPK was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: LNPK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LNPK were set to PMID: 30032983, PMID:35599435, https://academic.oup.com/braincomms/advance-article/doi/10.1093/braincomms/fcad222/7243438?login=true
Phenotypes for gene: LNPK were set to Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum MIM#618090
Review for gene: LNPK was set to GREEN
Added comment: Moderate to severe ID, majority of patients 10/15 have period of regression
Epilepsy (myoclonic frequently)
Structural brain anomalies 'ear of the lynx sign', callosal hypoplasia, mild brain including cerebellar atrophy.
Microcephaly, macrocephaly and normal head circumference described.
Sources: Literature
Fetal anomalies v1.140 DBR1 Chern Lim gene: DBR1 was added
gene: DBR1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DBR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DBR1 were set to 37656279
Phenotypes for gene: DBR1 were set to Prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation, and death before the first year of life
Review for gene: DBR1 was set to AMBER
gene: DBR1 was marked as current diagnostic
Added comment: PMID: 37656279:
- A homozygous missense as a founder recessive DBR1 variant in four consanguineous families.
- Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life.
- RNA and protein studies using fibroblasts derived from a patient are supportive of pathogenicity: RNA-seq, rt-qPCR and western blotting, showing marked reduction of DBR1 level and intronic RNA lariat accumulation in the patient sample.
- Haplotype analysis revealed that the four families all share a haplotype extending at least 2.27 Mb around the c.200A>G p.(Tyr67Cys) DBR1 founder variant.
- Authors proposed this is a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility, and highlighted the apparent lack of correlation with the degree of DBR1 deficiency.
Sources: Literature
Fetal anomalies v1.140 CUL3 Zornitza Stark Marked gene: CUL3 as ready
Fetal anomalies v1.139 CUL3 Lucy Spencer gene: CUL3 was added
gene: CUL3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CUL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CUL3 were set to 37665043
Phenotypes for gene: CUL3 were set to Neurodevelopmental disorder with or without autism or seizures (MIM#619239); Pseudohypoaldosteronism, type IIE (MIM#614496)
Review for gene: CUL3 was set to GREEN
Added comment: PMID: 37665043
1 case study and a review of the literature. 5 patients with de novo variants (PTCs and missense) in CUL3 who have various cardiac phenotypes: atrial septal defects, left ventricular outflow tract obstruction. Hypertrophic right ventricle pulmonary atresia, and other congenital heart defects. 2 of these patients have a neurological phenotype as well, while the other three are not reported to have one (but at least one was a terminated pregnancy).
Sources: Literature
Fetal anomalies v1.139 SOX11 Zornitza Stark reviewed gene: SOX11: Rating: GREEN; Mode of pathogenicity: None; Publications: 29459093, 24886874, 33086258, 33785884, 35642566, 35341651; Phenotypes: Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, MIM# 615866; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.139 ATP5O Zornitza Stark Marked gene: ATP5O as ready
Fetal anomalies v1.138 ATP5O Zornitza Stark gene: ATP5O was added
gene: ATP5O was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: ATP5O was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP5O were set to 35621276; 34954817
Phenotypes for gene: ATP5O were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, MIM# 620359
Review for gene: ATP5O was set to GREEN
Added comment: Prenatal phenotypes reported (IUGR, CHD, oligohydramnios)
Sources: Expert list
Fetal anomalies v1.136 PLCB4 Zornitza Stark Phenotypes for gene: PLCB4 were changed from Auriculocondylar syndrome 2, MIM# 614669 to Auriculocondylar syndrome 2A, MIM# 614669; Auriculocondylar syndrome 2B, MIM# 620458
Fetal anomalies v1.135 PLCB4 Zornitza Stark reviewed gene: PLCB4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Auriculocondylar syndrome 2A, MIM# 614669, Auriculocondylar syndrome 2B, MIM# 620458; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.135 PHF5A Zornitza Stark Marked gene: PHF5A as ready
Fetal anomalies v1.132 PHF5A Daniel Flanagan gene: PHF5A was added
gene: PHF5A was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: PHF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PHF5A were set to PMID: 37422718
Review for gene: PHF5A was set to GREEN
Added comment: Nine subjects with congenital malformations, including hypospadias, growth abnormalities, and developmental delay who had de novo PHF5A variants. Prenatally, six subjects had intrauterine growth retardation. All subjects had motor and speech delay and developmental delay. Congenital abnormalities comprised hypospadias in three of four male subjects and heart defects, inguinal hernia, and sacral dimple in three subjects. Six of the nine subjects had short stature. Craniofacial dysmorphism is variable in the nine subjects, high forehead and preauricular skin tag(s) in five subjects.
Sources: Expert list
Fetal anomalies v1.132 SENP7 Elena Savva Marked gene: SENP7 as ready
Fetal anomalies v1.131 SENP7 Elena Savva gene: SENP7 was added
gene: SENP7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SENP7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SENP7 were set to PMID: 37460201
Phenotypes for gene: SENP7 were set to Arthrogryposis multiplex congenita, MONDO:0015168, SENP7-related
Review for gene: SENP7 was set to AMBER
Added comment: PMID: 37460201
- 1 family (4 affecteds, sibling pair and 1st cousin) with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia. Fetus could not be tested, so 3 confirmed genetically.
- Homozygous for a PTC, decreased mRNA from one sample supports an NMD outcome.
- Additional studies performed supporting downstream proteins expression being affected
- Neutropenia observed in 2/3 patients
Sources: Literature
Fetal anomalies v1.130 STX5 Ain Roesley Marked gene: STX5 as ready
Fetal anomalies v1.129 STX5 Ain Roesley gene: STX5 was added
gene: STX5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: STX5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STX5 were set to 34711829
Phenotypes for gene: STX5 were set to congenital disorder of glycosylation MONDO#0015286, STX5-related
Review for gene: STX5 was set to AMBER
gene: STX5 was marked as current diagnostic
Added comment: 1x family with 3x deceased shortly after death + 3x spontaneous abortions + 2x abortions due to abnormal fatal ultrasound (US).
Hom for NM_003164.4:c.163 A > G p.(Met55Val), which results in complete loss of short isoform (which uses Met55 as the start)

phenotype: short long bones on US, dysmorphism, skeletal dysplasia, profound hypotonia, hepatomegaly elevated cholesterol.
Post-natally they died of progressive liver failure with cholestasis and hyperinsulinemic hypoglycemias

Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking
Sources: Literature
Fetal anomalies v1.128 INTS13 Zornitza Stark Marked gene: INTS13 as ready
Fetal anomalies v1.126 DCAF15 Zornitza Stark Marked gene: DCAF15 as ready
Fetal anomalies v1.124 INTS13 Chirag Patel gene: INTS13 was added
gene: INTS13 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: INTS13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS13 were set to PMID: 36229431
Phenotypes for gene: INTS13 were set to Oral-facial-digital syndrome
Review for gene: INTS13 was set to GREEN
gene: INTS13 was marked as current diagnostic
Added comment: 2 families with 4 affected individuals with Oral-facial-digital (OFD) phenotype. Homozygosity mapping and WES found 2 homozygous variants in INTS13 gene. This is a subunit of the Integrator complex, which associates with RNA Polymerase II and cleaves nascent RNA to modulate gene expression. Variants segregated with disease. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Knockdown in Xenopus embryos leads to motile cilia anomalies.
Sources: Literature
Fetal anomalies v1.122 DCAF15 Chirag Patel gene: DCAF15 was added
gene: DCAF15 was added to Fetal anomalies. Sources: Other
Mode of inheritance for gene: DCAF15 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DCAF15 were set to Cornelia de Lange syndrome
Review for gene: DCAF15 was set to AMBER
Added comment: ESHG 2023:
3 unrelated cases with CdLS (1 x TOP with MCA, 1 x death @20mths, 1 x living child)
Features suggestive of CdLS - DD, microcephaly, CHD, dysmorphism, visual/hearing impairment.

WES identified recurrent de novo variant (p.Ser470Phe) in DCAF15 gene. This mediates ubiquitination and degradation of target proteins, and interacts with cohesin complex members (SMC1/SMC3).

Protein analysis from individuals showed increased accumulation of ubiquitination-modified proteins and SM3 (GOF mechanism). EpiSign analysis showed same DNA methylation pattern as other CdLS cases/genes. Zebrafish model showed reduced body length, reduced head size, reduced oligodendrocytes, heart defect, aberrant motor neurons, and abnormal response to visual/auditory stimuli.
Sources: Other
Fetal anomalies v1.121 ERI1 Zornitza Stark Marked gene: ERI1 as ready
Fetal anomalies v1.120 ERI1 Zornitza Stark gene: ERI1 was added
gene: ERI1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ERI1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: ERI1 were set to 37352860
Phenotypes for gene: ERI1 were set to Spondyloepimetaphyseal dysplasia (MONDO#0100510)
Review for gene: ERI1 was set to GREEN
Added comment: PMID: 37352860 - 8 individuals from 7 unrelated families
- Patients with biallelic missense show a MORE severe spondyloepimetaphyseal dysplasia, syndactyly, brachydactyly/clinodactyly/camptodactyly
- Patients with biallelic null/whole gene deletion had mild ID and digit anomalies including brachydactyly/clinodactyly/camptodactyly
- Patient chet for a missense and PTC variant has a blended phenotype with short stature, syndactyly, brachydactyly/clinodactyly/camptodactyly, mild ID and failure to thrive

- Missense variants were functionally shown to not be able to rescue 5.8S rRNA processing in KO HeLa cells
- K/O mice had neonatal lethality with growth defects, brachydactyly. Skeletal-specific K/O had mild platyspondyly, had more in keeping with patients with null variants than missense

More severe phenotype hypothesised due to "exonuclease-dead proteins may compete for the target RNA molecules with other exonucleases that have functional redundancy
with ERI1, staying bound to those RNA molecules"
Sources: Literature
Fetal anomalies v1.119 NUDCD2 Seb Lunke Marked gene: NUDCD2 as ready
Fetal anomalies v1.118 NUDCD2 Ee Ming Wong gene: NUDCD2 was added
gene: NUDCD2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NUDCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDCD2 were set to 37272762
Phenotypes for gene: NUDCD2 were set to Multiple congenital anomalies (MONDO:0019042), NUDCD2-related
Penetrance for gene: NUDCD2 were set to unknown
Review for gene: NUDCD2 was set to AMBER
gene: NUDCD2 was marked as current diagnostic
Added comment: - Two unrelated probands, each biallelic for two variants in NUDCD2 (total 3x LoF variants, 1x missense variant)
- Immunoblotting of proteins extracted from the primary fibroblasts of one proband with 2x LoF variants demonstrated markedly reduced NUDCD2 levels compared to healthy individuals
Sources: Literature
Fetal anomalies v1.118 RAB34 Elena Savva Marked gene: RAB34 as ready
Fetal anomalies v1.118 RAB34 Elena Savva Phenotypes for gene: RAB34 were changed from Clefting; corpus callosum; short bones; hypertelorism; polydactyly; cardiac defects; anorectal anomalies to Multiple congenital anomalies, (MONDO:0019042), RAB34-related
Fetal anomalies v1.116 DRG1 Krithika Murali Marked gene: DRG1 as ready
Fetal anomalies v1.114 DRG1 Dean Phelan gene: DRG1 was added
gene: DRG1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DRG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DRG1 were set to PMID: 37179472
Phenotypes for gene: DRG1 were set to Neurodevelopmental disorder (MONDO:0700092), DRG1-related
Review for gene: DRG1 was set to GREEN
Added comment: PMID: 37179472
- Biallelic variants were identified in four affected individuals from three distinct families with neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature and craniofacial anomalies. Functional studies show the variants result in a loss of function.
Sources: Literature
Fetal anomalies v1.114 RAB34 Sarah Pantaleo gene: RAB34 was added
gene: RAB34 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RAB34 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAB34 were set to PMID: 37384395
Phenotypes for gene: RAB34 were set to Clefting; corpus callosum; short bones; hypertelorism; polydactyly; cardiac defects; anorectal anomalies
Penetrance for gene: RAB34 were set to Complete
Review for gene: RAB34 was set to GREEN
Added comment: Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogenous disorders characterised by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in >20 genes encoding ciliary proteins have been found to cause OFDS.

Identified by WES biallelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families (aided by GeneMatcher).

Affected individuals presented a novel form of OFDS accompanied by cardiac, cerebral, skeletal (eg. Shortening of long bones), and anorectal defects.

RAB34 encodes a member of the Lab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Protein products of pathogenic variants clustered near the RAB34 C-terminus exhibit a strong loss of function.

Onset is prenatal (multiple developmental defects including short femur, polydactyly, heart malformations, kidney malformations, brain malformations), resulting in medical termination for three probands.

In the fourth, the only one alive at birth, proband born at 39+5 weeks, normal growth parameters after pregnancy with polyhydramnios, corpus callosum agenesis and polydactyly. Respiratory distress at birth.

All four probands presented typical features of ciliopathy disorders, overlapping with oral, facial and digital abnormalities.

All with homozygous missense variants. All absent in gnomAD (in homozygous state). Sanger sequencing confirmed mode of inheritance.
Sources: Literature
Fetal anomalies v1.114 BRWD1 Zornitza Stark Phenotypes for gene: BRWD1 were changed from Situs inversus; primary ciliary dyskinesia like to Situs inversus; Ciliary dyskinesia, primary, 51, MIM# 620438
Fetal anomalies v1.113 KIF26A Zornitza Stark Marked gene: KIF26A as ready
Fetal anomalies v1.112 KIF26A Zornitza Stark gene: KIF26A was added
gene: KIF26A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF26A were set to 36564622
Phenotypes for gene: KIF26A were set to Cortical dysplasia, complex, with other brain malformations 11, MIM# 620156
Review for gene: KIF26A was set to GREEN
Added comment: Five individuals from two families each with a different homozygous truncating variant in KIF26A segregating with profound ENS dysfunction that manifested clinically like Hirschsprung’s disease despite normal ganglionosis. Moreover, they all have neurological involvement with brain malformations ranging from ventriculomegaly to severe congenital hydrocephalus in two siblings who died early in life. Clinically, they displayed developmental delay and, in the longest surviving individual, spastic paraplegia.

Brain abnormalities may be detectable antenatally.
Sources: Literature
Fetal anomalies v1.111 MAP4K4 Zornitza Stark Marked gene: MAP4K4 as ready
Fetal anomalies v1.106 GATAD2A Zornitza Stark Marked gene: GATAD2A as ready
Fetal anomalies v1.105 GATAD2A Zornitza Stark gene: GATAD2A was added
gene: GATAD2A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GATAD2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372
Phenotypes for gene: GATAD2A were set to Neurodevelopmental disorder, MONDO:0700092, GATAD2A-related
Review for gene: GATAD2A was set to AMBER
Added comment: Inconsistent pattern of congenital abnormalities.

https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature
Fetal anomalies v1.103 MED11 Zornitza Stark Phenotypes for gene: MED11 were changed from neurodevelopmental disorder MONDO#0700092, MED11-related to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327
Fetal anomalies v1.101 KIF21A Chirag Patel gene: KIF21A was added
gene: KIF21A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: KIF21A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF21A were set to PMID: 34740919
Phenotypes for gene: KIF21A were set to Severe fetal akinesia with arthrogryposis multiplex
Review for gene: KIF21A was set to AMBER
Added comment: 2 unrelated consanguineous Turkish families with 5 affected fetuses with severe fetal akinesia with arthrogryposis multiplex. WES identified different homozygous LOF variants in KIF21A gene (p.Leu449* and p.Arg791Glufs*8). Parents and a healthy sibling were heterozygous carriers. No functional studies.
Sources: Literature
Fetal anomalies v1.99 FILIP1 Zornitza Stark Marked gene: FILIP1 as ready
Fetal anomalies v1.98 FILIP1 Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168 to Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Fetal anomalies v1.97 ESAM Seb Lunke Marked gene: ESAM as ready
Fetal anomalies v1.93 ACTC1 Lilian Downie reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36945405; Phenotypes: Atrial septal defect 5 MIM#612794, Cardiomyopathy, dilated, 1R MIM#613424, Cardiomyopathy, hypertrophic, 11 MIM#612098, ACTC1 related distal arthrogryposis MONDO:0019942; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.93 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Fetal anomalies v1.93 FILIP1 Paul De Fazio edited their review of gene: FILIP1: Changed phenotypes: Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Fetal anomalies v1.93 FILIP1 Paul De Fazio gene: FILIP1 was added
gene: FILIP1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452
Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Penetrance for gene: FILIP1 were set to unknown
Review for gene: FILIP1 was set to GREEN
gene: FILIP1 was marked as current diagnostic
Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings.

Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism.
Sources: Literature
Fetal anomalies v1.92 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Congenital heart disease, MONDO:0005453, PLXND1-related to Congenital heart defects, multiple types, 9, MIM# 620294
Fetal anomalies v1.91 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Congenital heart defects, multiple types, 9, MIM# 620294
Fetal anomalies v1.91 PLXND1 Zornitza Stark Marked gene: PLXND1 as ready
Fetal anomalies v1.90 PLXND1 Zornitza Stark gene: PLXND1 was added
gene: PLXND1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLXND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXND1 were set to 35396997
Phenotypes for gene: PLXND1 were set to Congenital heart disease, MONDO:0005453, PLXND1-related
Review for gene: PLXND1 was set to GREEN
Added comment: 10 individuals including four fetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT)/truncus arteriosus.
Sources: Literature
Fetal anomalies v1.88 EFCAB1 Zornitza Stark Marked gene: EFCAB1 as ready
Fetal anomalies v1.87 EFCAB1 Zornitza Stark gene: EFCAB1 was added
gene: EFCAB1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to 36727596
Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related
Review for gene: EFCAB1 was set to GREEN
Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility.
Sources: Literature
Fetal anomalies v1.85 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from neuromuscular disease, GOLGA2-related MONDO#0019056 to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Fetal anomalies v1.84 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Fetal anomalies v1.83 SLC31A1 Zornitza Stark Marked gene: SLC31A1 as ready
Fetal anomalies v1.82 SLC31A1 Daniel Flanagan gene: SLC31A1 was added
gene: SLC31A1 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC31A1 were set to PMID: 35913762; 36562171
Phenotypes for gene: SLC31A1 were set to Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092)
Review for gene: SLC31A1 was set to AMBER
Added comment: PMID:36562171
Homozygous c.236T>C; p.(Leu79Pro) identified in a newborn of consanguineous parents. Variant absent from gnomAD. Prenatal ultrasound showed a male fetus with short femoral bones, an apparently enlarged heart-to-thorax ratio, and a wide cisterna magna. The infant was born with pulmonary hypoplasia. At 2 weeks of age, multifocal brain hemorrhages were diagnosed and the infant developed seizures. The infant died at 1 month of age. The Mother had three healthy children while nine pregnancies had been extrauterine gravidities or ended in first or mid-trimester spontaneous abortions.

PMID: 35913762
SLC31A1 is also referred to as CTR1.
Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality.
Sources: Expert list
Fetal anomalies v1.79 CDK5 Zornitza Stark reviewed gene: CDK5: Rating: AMBER; Mode of pathogenicity: None; Publications: 25560765, 32273484, 32097629, 28854363, 7490100; Phenotypes: Lissencephaly 7 with cerebellar hypoplasia, MIM# 616342; Mode of inheritance: None
Fetal anomalies v1.79 KDM2B Ain Roesley Marked gene: KDM2B as ready
Fetal anomalies v1.78 KDM2B Ain Roesley gene: KDM2B was added
gene: KDM2B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2B were set to 36322151
Phenotypes for gene: KDM2B were set to neurodevelopmental disorder MONDO#070009, KDM2B-related
Review for gene: KDM2B was set to GREEN
gene: KDM2B was marked as current diagnostic
Added comment: 27 individuals from 22 families were recruited
13 SNV classified LP/P, all de novo except 2 familial cases
5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function)

14 families with SNVs and a variety of cardiac anomalies including ASD, VSD, MR, PDA, PFO, Atrial septal aneurysm and Mild mitral insufficiency
Sources: Literature
Fetal anomalies v1.76 SHROOM4 Alison Yeung reviewed gene: SHROOM4: Rating: GREEN; Mode of pathogenicity: None; Publications: 36379543; Phenotypes: Congenital anomaly of the kidney and urinary tracy (CAKUT), SHROOM4-related, MONDO:0019719; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v1.76 FRA10AC1 Zornitza Stark Phenotypes for gene: FRA10AC1 were changed from Neurodevelopmental disorder, MONDO:0700092, FRA10AC1-related to Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, MIM# 620113
Fetal anomalies v1.75 FRA10AC1 Zornitza Stark reviewed gene: FRA10AC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, MIM# 620113; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.75 KCNK3 Zornitza Stark Marked gene: KCNK3 as ready
Fetal anomalies v1.74 MED11 Ain Roesley Marked gene: MED11 as ready
Fetal anomalies v1.73 MED11 Ain Roesley gene: MED11 was added
gene: MED11 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED11 were set to 36001086
Phenotypes for gene: MED11 were set to neurodevelopmental disorder MONDO#0700092, MED11-related
Review for gene: MED11 was set to AMBER
gene: MED11 was marked as current diagnostic
Added comment: 7 affected from 5 families (3x consang) with the same recurrent variant of p.(Arg109*).

Protein truncating, NOT NMD as proven by RT-PCR and western blot. Zebrafish knockout model recapitulates key clinical phenotypes

NO evidence of founder effect from haplotype analysis

7/7 cerebral dysgyria, cortical atrophy
5/7 limb contracture
4/7 epilepsy
3/7 families with IUGR
3/7 GDD
3/7 hearing loss
3/7 undescended testis
2/7 nystagmus
1/7 congenital cataract
Sources: Literature
Fetal anomalies v1.72 FOSL2 Zornitza Stark Marked gene: FOSL2 as ready
Fetal anomalies v1.71 FOSL2 Krithika Murali gene: FOSL2 was added
gene: FOSL2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FOSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOSL2 were set to 36197437
Phenotypes for gene: FOSL2 were set to Neurodevelopmental disorder, MONDO:0700092, FOSL2-related
Review for gene: FOSL2 was set to GREEN
Added comment: PMID 36197437 Cospain et al 2022 report 11 individuals from 10 families with heterozygous PTC variants in exon 4/4 of the FOSL2 gene. All variants were predicted to escape NMD resulting in a truncated protein, with the truncation occurring proximal to the C-terminal domain (supportive functional studies).

In 10/11 families the variant occurred de novo in a single affected proband. In one family with 2 affected siblings, the variant was present in the siblings but absent in the unaffected parent likely due to gonadal mosaicism.

Clinical features included:
- Cutis aplasia congenital of the scalp (10/11)
- Tooth enamel hypoplasia and discolouration (8/9)
- Multiple other ectodermal features also noted e.g. small brittle nails, hypotrichosis/hypertrichosis, lichen sclerosis
- 5 individuals had cataracts (mostly bilateral, congenital/early childhood onset)
- 6/9 IUGR
- 5/9 postnatal growth restriction
- 7/9 developmental delay/ID
- 5/7 ADHD/ASD
- 2/9 seizures
Sources: Literature
Fetal anomalies v1.71 KCNK3 Krithika Murali gene: KCNK3 was added
gene: KCNK3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: KCNK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNK3 were set to 36195757
Phenotypes for gene: KCNK3 were set to Neurodevelopmental disorder, MONDO:0700092, KCNK3-related; developmental delay with sleep apnoea (DDSA)
Review for gene: KCNK3 was set to GREEN
Added comment: PMID 36195757 Sörmann et al 2022 report 9 unrelated individuals with de novo heterozygous KCNK3 missense variants (21 weeks to 25 years old). All 8 living probands (3-25 years) had hypotonia, global developmental delay, central and/or obstructive sleep apnoea and feeding difficulties. 7/9 probands had additional anomalies including microcephaly (at least 3/9), arthrogryposis/flexion contractures/foot deformities (7/9), scoliosis, cleft palate (2/9), and ambiguous genitalia/undescended testes (5/6) and dysmorphism. IUGR reported in 3/9 probands and polyhdramnios in 2/9.

KCNK3 encodes the TASK-1 K2P channel expressed throughout the central nervous system. All identified variants clustered near the X-gate and are involved in inter- or intra-subunit interaction likely to hold the X-gate closed. Individuals with variants located in the M2 transmembrane helix had a more severe phenotype than those with variants in the M4 helix. Functional studies support a gain of function disease mechanism with increased channel activation. TASK-1 K+ channel inhibitors (some in clinical use) have been raised as a possible therapeutic strategy.

----

Heterozygous LoF variants associated with a different disorder - primary pulmonary arterial hypertension
Sources: Literature
Fetal anomalies v1.71 ADAMTS19 Zornitza Stark Phenotypes for gene: ADAMTS19 were changed from Heart valve disorder, MONDO:0002869 to Cardiac valvular dysplasia 2, MIM# 620067
Fetal anomalies v1.70 ADAMTS19 Zornitza Stark reviewed gene: ADAMTS19: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiac valvular dysplasia 2, MIM# 620067; Mode of inheritance: None
Fetal anomalies v1.70 ATP7A Zornitza Stark changed review comment from: Well established gene-disease association, IUGR is a feature.; to: Well established gene-disease association, IUGR is a feature.

Treatment: subcutaneous injections of copper histidine or copper chloride

ClinGen has assessed as moderate evidence for actionability.

Neonatal treatment with subcutaneous copper-histidine (initiated before 30 days of life) is recommended for asymptomatic males with a diagnosis of MD, but is not recommended for symptomatic boys or after 30 days of life. Treatment should be continued indefinitely. In an open-label clinical trial, 12 patients with MD treated with copper-histidine within 22 days of life had 92% survival after a mean follow-up of 4.6 years compared to 13% in a historical control group of 15 patients treated after a late diagnosis (mean age at diagnosis: 163 ± 113 days, range: 42 to 390). Two of the 12 patients with earlier treatment had normal neurological development. A second open-label trial of 35 presymptomatic patients receiving copper-histidine at less than a month of age reported significant improvement of four major neurodevelopmental (gross motor, fine motor/adaptive, personal/social, and language) domains and a non-significant lower mortality (28.5% vs 50%) at age of 3 years (or age of death) compared to 22 patients treated later and after onset of symptoms.
Fetal anomalies v1.70 PDCD6IP Zornitza Stark Phenotypes for gene: PDCD6IP were changed from Primary microcephaly to Microcephaly 29, primary, autosomal recessive, MIM# 620047
Fetal anomalies v1.69 PDCD6IP Zornitza Stark reviewed gene: PDCD6IP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Microcephaly 29, primary, autosomal recessive, MIM# 620047; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.69 USP9X Krithika Murali reviewed gene: USP9X: Rating: GREEN; Mode of pathogenicity: None; Publications: 31443933, 26833328; Phenotypes: Mental retardation, X-linked 99, XLR (MIM#300919) and XLD (MIM#300968); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Fetal anomalies v1.67 NODAL Zornitza Stark edited their review of gene: NODAL: Added comment: NODAL is a good biological candidate for heterotaxy disorders, and this is supported by animal models. The gene is depleted for LoF variants in gnomad.

The missense variants reported in PMIDs 9354794 and 19064609 are present at a high population frequency in gnomad, including some in homozygous case: their association with disease is DISPUTED.

A total of at least 7 families reported with severe CHD and high impact variants (stop gain, frameshift and canonical splice site). However, almost invariably these were inherited from unaffected or questionably affected parents (e.g. self reports of heart murmur in childhood), raising questions about whether these variants contribute to disease under a monogenic or polygenic model and/or about penetrance.

Discussed at GenCC on 13/9/2022 and agreed on MODERATE assessment.; Changed rating: AMBER; Changed publications: 9354794, 19064609, 29368431, 19933292, 11311163, 30293987
Fetal anomalies v1.67 ALDH1A2 Zornitza Stark Phenotypes for gene: ALDH1A2 were changed from Multiple congenital anomalies, ALDH1A2-related, MONDO:0019042 to Diaphragmatic hernia 4, with cardiovascular defects, MIM# 620025
Fetal anomalies v1.66 ALDH1A2 Zornitza Stark reviewed gene: ALDH1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diaphragmatic hernia 4, with cardiovascular defects, MIM# 620025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.65 ADAMTS15 Zornitza Stark Marked gene: ADAMTS15 as ready
Fetal anomalies v1.64 ADAMTS15 Zornitza Stark gene: ADAMTS15 was added
gene: ADAMTS15 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ADAMTS15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS15 were set to 35962790
Phenotypes for gene: ADAMTS15 were set to Arthrogryposis (MONDO:0008779), ADMATS15-related
Review for gene: ADAMTS15 was set to GREEN
Added comment: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: contractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5).
Sources: Literature
Fetal anomalies v1.63 NPNT Zornitza Stark Marked gene: NPNT as ready
Fetal anomalies v1.60 NPNT Chirag Patel gene: NPNT was added
gene: NPNT was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NPNT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPNT were set to PMID: 35246978, 34049960, 17537792
Phenotypes for gene: NPNT were set to Renal agenesis, no OMIM #
Review for gene: NPNT was set to GREEN
Added comment: 3 consanguineous families with multiple affecteds with bilateral renal agenesis. Whole-exome sequencing (WES)-based homozygosity mapping identified 2 homozygous truncating variants. Reverse transcription polymerase chain reaction data showing complete nonsense-mediated decay of the NPNT transcript. Loss of nephronectin (NPNT) is known to lead to failure of metanephric kidney development with resulting renal agenesis in murine models.
Sources: Literature
Fetal anomalies v1.58 KIF5B Chirag Patel gene: KIF5B was added
gene: KIF5B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: KIF5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF5B were set to PMID: 35342932
Phenotypes for gene: KIF5B were set to Kyphomelic dysplasia, no OMIM #
Review for gene: KIF5B was set to GREEN
Added comment: 4 individuals with Kyphomelic dysplasia (severe bowing of the limbs, sharp angulation of the femora and humeri, short stature, narrow thorax, distinctive facial features, and neonatal respiratory distress. WES found de novo heterozygous missense variants in KIF5B encoding kinesin-1 heavy chain. All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. No functional studies of variants.

Previously 2 animal model experiments showed that loss of function of KIF5B can cause kyphomelic dysplasia. First, chondrocyte-specific knockout of Kif5b in mice was shown to produce a disorganized growth plate, leading to bone deformity. Second, double mutants disrupting the two zebrafish kif5b caused abnormal skeletal morphogenesis and the curvature of Meckel's and ceratohyal cartilages.
Sources: Literature
Fetal anomalies v1.55 ZMYND8 Zornitza Stark Marked gene: ZMYND8 as ready
Fetal anomalies v1.54 ZMYND8 Zornitza Stark gene: ZMYND8 was added
gene: ZMYND8 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYND8 were set to 35916866; 32530565
Phenotypes for gene: ZMYND8 were set to Neurodevelopmental disorder, MONDO:0700092, ZMYND8-related; Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Review for gene: ZMYND8 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Expert Review
Fetal anomalies v1.53 PRIM1 Zornitza Stark Phenotypes for gene: PRIM1 were changed from Microcephalic primordial dwarfism, MONDO:0017950 to Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, MIM# 620005
Fetal anomalies v1.52 PRIM1 Zornitza Stark reviewed gene: PRIM1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, MIM# 620005; Mode of inheritance: None
Fetal anomalies v1.52 BMP3 Seb Lunke Marked gene: BMP3 as ready
Fetal anomalies v1.51 BMP3 Seb Lunke gene: BMP3 was added
gene: BMP3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: BMP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP3 were set to 35089417
Phenotypes for gene: BMP3 were set to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129
Added comment: Single missense variant identified segregating with disease following WES screen in a family with coloboma and/or microphthalmia in BMP3. Two additional unrelated patients identified with different missense in BMP3. Pathogenicity however largely on in-silicos, with one of the 3 missense having 29 hets in gnomAD. Additional functional work in bmp3 -/- zebra fish and some supporting evidence but not conclusive.
Sources: Literature
Fetal anomalies v1.50 SPTA1 Zornitza Stark Marked gene: SPTA1 as ready
Fetal anomalies v1.48 PPP1R13L Zornitza Stark Phenotypes for gene: PPP1R13L were changed from Dilated cardiomyopathy, onset in infancy; Cleft lip and palate to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 - PPP1R13L-related; Dilated cardiomyopathy, onset in infancy; Cleft lip and palate
Fetal anomalies v1.47 PPP1R13L Krithika Murali edited their review of gene: PPP1R13L: Changed phenotypes: Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 - PPP1R13L-related disorder, Dilated cardiomyopathy, onset in infancy, Cleft lip and palate
Fetal anomalies v1.47 GINS3 Zornitza Stark gene: GINS3 was added
gene: GINS3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GINS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS3 were set to 35603789
Phenotypes for gene: GINS3 were set to Meier-Gorlin syndrome, MONDO:0016817, GINS3-related
Review for gene: GINS3 was set to GREEN
Added comment: 7 individuals from 5 families reported, presenting with prenatal and postnatal growth deficiency as well as other features. Three unique missense variants identified, two affecting p.Asp24. These variants are thought to be hypomorphic. Supportive mouse model.
Sources: Literature
Fetal anomalies v1.42 WNT7B Zornitza Stark Marked gene: WNT7B as ready
Fetal anomalies v1.41 WNT7B Zornitza Stark gene: WNT7B was added
gene: WNT7B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WNT7B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WNT7B were set to 35790350
Phenotypes for gene: WNT7B were set to Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects syndrome; Multiple congenital anomalies/dysmorphic features syndrome MONDO:0043005, WNT7B-related
Review for gene: WNT7B was set to GREEN
Added comment: Three families reported with fetuses with multiple congenital anomalies and bi-allelic LoF variants. Two of the families had at the same variant. Supportive zebrafish model.
Sources: Literature
Fetal anomalies v1.40 PAN2 Zornitza Stark Marked gene: PAN2 as ready
Fetal anomalies v1.39 PAN2 Naomi Baker gene: PAN2 was added
gene: PAN2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PAN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAN2 were set to PMID:35304602; 29620724
Phenotypes for gene: PAN2 were set to Syndromic disease MONDO:0002254
Added comment: PMID:35304602 reports five individuals from 3 families with biallelic (homozygous) loss-of-function variants. Clinical presentation incudes mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck.

PMID:29620724 reports one individual with biallelic (homozygous) loss-of-function variant who presented with global developmental delay, mild hypotonia, craniosynostosis, severe early-onset scoliosis, imperforate anus, and double urinary collecting system.
Sources: Literature
Fetal anomalies v1.38 ETV2 Zornitza Stark Marked gene: ETV2 as ready
Fetal anomalies v1.38 ETV2 Zornitza Stark gene: ETV2 was added
gene: ETV2 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: ETV2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ETV2 were set to 33359164
Phenotypes for gene: ETV2 were set to multiple fetal anomalies; congenital heart disease MONDO:000545, ETV2-related; vertebral malformations
Review for gene: ETV2 was set to RED
Added comment: 1 family with 4 fetus-es all cHet for a fs (NMD-predicted) and a missense

3/4 vertebral malformations
2/4 Tetralogy of Fallot
1/4 arterial septal defect
1/4 ventricular septal defect, aortic dilatation
1/4 pre-axial polydactyly
Sources: Expert Review
Fetal anomalies v1.37 ADD1 Zornitza Stark Marked gene: ADD1 as ready
Fetal anomalies v1.36 ADD1 Zornitza Stark gene: ADD1 was added
gene: ADD1 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: ADD1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: ADD1 were set to 34906466
Phenotypes for gene: ADD1 were set to Neurodevelopmental disorder MONDO:0700092, ADD1-related
Review for gene: ADD1 was set to GREEN
Added comment: 4 unrelated individuals affected by ID and/or complete or partial agenesis of corpus callosum, and enlarged lateral ventricles. WES found loss-of-function variants - 1 recessive missense variant and 3 de novo variants. The recessive variant is associated with ACC and enlarged lateral ventricles, and the de novo variants were associated with complete or partial agenesis of corpus callosum, mild ID and attention deficit. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes. Three adducin genes (ADD1, ADD2, and ADD3) encode cytoskeleton proteins that are critical for osmotic rigidity and cell shape. ADD1, ADD2, and ADD3 form heterodimers (ADD1/ADD2, ADD1/ADD3), which further form heterotetramers. Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown
Sources: Expert Review
Fetal anomalies v1.32 MYO9A Zornitza Stark changed review comment from: This gene-disease association has been reviewed as part of GenCC discordance resolution: note at least two of the variants reported have homozygotes with gnomad, which would be out of keeping for a severe paediatric disorder.; to: This gene-disease association has been reviewed as part of GenCC discordance resolution: note at least two of the variants reported have homozygotes with gnomad, which would be out of keeping for a severe paediatric disorder.

However, also note reports of fetal akinesia and hydrocephalus, which are pertinent to this panel.
Fetal anomalies v1.32 MYO9A Zornitza Stark edited their review of gene: MYO9A: Added comment: This gene-disease association has been reviewed as part of GenCC discordance resolution: note at least two of the variants reported have homozygotes with gnomad, which would be out of keeping for a severe paediatric disorder.; Changed rating: AMBER
Fetal anomalies v1.31 USP14 Zornitza Stark Marked gene: USP14 as ready
Fetal anomalies v1.31 USP14 Zornitza Stark Phenotypes for gene: USP14 were changed from Distal arthrogryposis, corpus callosum anomalies, and dysmorphic features; no OMIM # to Syndromic disease MONDO:0002254, USP14-related; Distal arthrogryposis, corpus callosum anomalies, and dysmorphic features
Fetal anomalies v1.30 ZNF526 Zornitza Stark Phenotypes for gene: ZNF526 were changed from Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia to Dentici-Novelli neurodevelopmental syndrome, MIM# 619877
Fetal anomalies v1.29 USP14 Chirag Patel gene: USP14 was added
gene: USP14 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: USP14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP14 were set to PMID: 35066879
Phenotypes for gene: USP14 were set to Distal arthrogryposis, corpus callosum anomalies, and dysmorphic features; no OMIM #
Review for gene: USP14 was set to RED
Added comment: 3 fetuses from 2 different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233_236delTTCC; p.Leu78Glnfs*11) in USP14, and sequencing of family members showed segregation with the phenotype. Ubiquitin-specific protease 14 (USP14) encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human multiple congenital contractures phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay.
Sources: Literature
Fetal anomalies v1.25 FTO Bryony Thompson reviewed gene: FTO: Rating: GREEN; Mode of pathogenicity: None; Publications: 19234441, 19559399, 26378117, 26697951, 26378117, 26740239; Phenotypes: Growth retardation, developmental delay, facial dysmorphism MIM#612938; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.25 ODC1 Lucy Spencer gene: ODC1 was added
gene: ODC1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ODC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ODC1 were set to 30475435; 30239107
Phenotypes for gene: ODC1 were set to Bachmann-Bupp syndrome (MIM#619075)
Review for gene: ODC1 was set to GREEN
Added comment: Polyhydraminos are a common prenatal finding in individuals with ODC1 variants. Malformations of cortical development and intracranial calcification have also been reported.
Sources: Literature
Fetal anomalies v1.25 MAPKAPK5 Zornitza Stark Phenotypes for gene: MAPKAPK5 were changed from Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic to Neurocardiofaciodigital syndrome, MIM# 619869
Fetal anomalies v1.24 MAPKAPK5 Zornitza Stark edited their review of gene: MAPKAPK5: Changed phenotypes: Neurocardiofaciodigital syndrome, MIM# 619869
Fetal anomalies v1.22 COASY Ain Roesley reviewed gene: COASY: Rating: ; Mode of pathogenicity: None; Publications: 35499143; Phenotypes: Pontocerebellar hypoplasia, type 12, MIM#618266; Mode of inheritance: None; Current diagnostic: yes
Fetal anomalies v1.21 PIDD1 Zornitza Stark Phenotypes for gene: PIDD1 were changed from Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum to Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, MIM# 619827; Pachygyria; Lissencephaly; Abnormality of the corpus callosum
Fetal anomalies v1.20 PIDD1 Zornitza Stark edited their review of gene: PIDD1: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, MIM# 619827, Pachygyria, Lissencephaly, Abnormality of the corpus callosum
Fetal anomalies v1.20 CDK10 Ain Roesley Marked gene: CDK10 as ready
Fetal anomalies v1.19 CDK10 Ain Roesley gene: CDK10 was added
gene: CDK10 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CDK10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK10 were set to 28886341; 34974531
Phenotypes for gene: CDK10 were set to Al Kaissi syndrome MIM#617694
Review for gene: CDK10 was set to GREEN
gene: CDK10 was marked as current diagnostic
Added comment: 6 families reported

1x with IUGR, 1x hydrocephalus and 1x with fetal hydrops, hydrocephalus, multicystic, dysplastic kidneys, lung hypoplasia, cardiomyopathy, retrognathia

Small birth weight/sizes reported in all
Sources: Literature
Fetal anomalies v1.18 RSPO2 Zornitza Stark Marked gene: RSPO2 as ready
Fetal anomalies v1.17 RSPO2 Zornitza Stark gene: RSPO2 was added
gene: RSPO2 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: RSPO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSPO2 were set to 29769720; 32457899
Phenotypes for gene: RSPO2 were set to Tetraamelia syndrome 2, MIM# 618021
Review for gene: RSPO2 was set to GREEN
Added comment: Tetraamelia syndrome-2 (TETAMS2) is characterized by rudimentary appendages or complete absence of the limbs, usually symmetric, as well as bilateral agenesis of the lungs. There are abnormalities of the pulmonary vasculature and dysmorphic features, including bilateral cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, and labioscrotal fold aplasia. Four unrelated families and functional data including animal model.
Sources: Expert Review
Fetal anomalies v1.16 MDFIC Zornitza Stark Marked gene: MDFIC as ready
Fetal anomalies v1.15 MDFIC Belinda Chong gene: MDFIC was added
gene: MDFIC was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MDFIC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDFIC were set to 35235341
Phenotypes for gene: MDFIC were set to Hydrops fetalis MONDO:0015193
Review for gene: MDFIC was set to GREEN
Added comment: Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, and presenting as chylothorax, pleural effusions, chylous ascites, and lymphedema, is a severe disorder often resulting in fetal or perinatal demise.

Seven individuals with CCLA from six independent families. Clinical manifestations of affected fetuses and children included nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema. Generation of a mouse model of human MDFIC truncation variants revealed that homozygous mutant mice died perinatally exhibiting chylothorax.
Sources: Literature
Fetal anomalies v1.15 TNNI1 Zornitza Stark Marked gene: TNNI1 as ready
Fetal anomalies v1.14 TNNI1 Zornitza Stark Phenotypes for gene: TNNI1 were changed from arthrogryposis; joint contractures to Arthrogryposis MONDO:0008779, TNNI1-related
Fetal anomalies v1.13 TNNI1 Krithika Murali gene: TNNI1 was added
gene: TNNI1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TNNI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNNI1 were set to 34934811
Phenotypes for gene: TNNI1 were set to arthrogryposis; joint contractures
Review for gene: TNNI1 was set to AMBER
Added comment: No OMIM gene disease association reported

PMID 34934811 Nishimori et al report 2 individuals from a Japanese family with joint contractures, elevated CK and a novel heterozygous TNNI1 variant.

The proband was born with clasped thumbs (gestational age not stated) requiring surgical correction at 5 months of age. At age 14 was diagnosed with contractures of the neck, trunk, hip and knee with elevated serum CK (1689 IU/L). No muscle weakness noted. Muscle biopsy showed moth-eaten appearance of type I fibres and electron microscopy showed type 1 fibre Z disk streaming.

Trio exome sequencing identified a paternally heterozygous nonsense TNNI1 variant (c.523A>T p.K175*). The proband's father and paternal grandfather (not genotyped) also have a history of joint contractures with elevated CK.

The affected amino acid residue is in the tropomyosin binding site near the C-terminus and is highly conserved. The variant is absent from gnomAD. rt-PCR products of mRNA from the patient's muscle biopsy showed presence of both mutated and normal transcripts.
Sources: Literature
Fetal anomalies v1.12 NEXN Zornitza Stark Marked gene: NEXN as ready
Fetal anomalies v1.11 NEXN Krithika Murali gene: NEXN was added
gene: NEXN was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NEXN was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: NEXN were set to 33947203; 33949776; 35166435; 32058062
Phenotypes for gene: NEXN were set to Lethal fetal cardiomyopathy; Hydrops fetalis; Cardiomyopathy, dilated 1CC - MIM#613122
Review for gene: NEXN was set to GREEN
Added comment: NEXN encodes cardiac Z-disc protein. Monoallelic variants associated with both paediatric and adult-onset dilated cardiomyopathy. 3 unrelated families reported with biallelic variants associated with lethal fetal cardiomyopathy.

PMID 35166435 - 3 consecutive affected pregnancies with intrauterine fetal death, dilated cardiomyopathy +/- fetal hydrops/IUGR. Autopsy findings of DCM, endomyocardial fibroelastosis. Non-consanguineous Swedish family. Homozygous variant identified - (NM_144573:c.1302del;p.(Ile435Serfs*3)). Heterozygous carriers enriched in Swedish population.


PMID: 33949776 - Report a 11 year old with mild DCM on cardiac MRI with a heterozygous paternally inherited variant (1949_1951del), father also had mild DCM. Also report a 2nd patient who presented with fetal Hydrops at 33 weeks gestation requiring emergency C-section. Homozygous c.1174C > T,p.(R392*) variants identified. Microscopic investigation showed endomyocardial fibroelastosis.

PMID: 32058062 - male fetus, compound het, DCM, MTOP; previous pregnancy with the same history.
Sources: Literature
Fetal anomalies v1.11 NDUFS4 Krithika Murali reviewed gene: NDUFS4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11181577, 11165261, 16478720, 10944442, 24295889, 22326555; Phenotypes: Mitochondrial complex I deficiency, nuclear type 1 - MIM#252010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.11 SCAF4 Zornitza Stark Marked gene: SCAF4 as ready
Fetal anomalies v1.9 SCAF4 Lucy Spencer gene: SCAF4 was added
gene: SCAF4 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SCAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAF4 were set to PMID: 32730804
Phenotypes for gene: SCAF4 were set to Neurodevelopmental disorder, SCAF4-related MONDO#0700092
Review for gene: SCAF4 was set to GREEN
Added comment: PMID: 32730804- 11 individuals with SCAF4 variants, 9 are de novo. Present with mild to severe ID/Dev delay, most have seizures, 4 have cardiac defects, 4 have renal anomalies, 3 have urogenital anomalies, 6 have skeletal anomalies, 2 have GI anomalies.
Sources: Literature
Fetal anomalies v1.9 UNC80 Zornitza Stark Phenotypes for gene: UNC80 were changed from Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, MIM# 616801; MONDO:0014777
Fetal anomalies v1.7 UNC80 Ain Roesley reviewed gene: UNC80: Rating: AMBER; Mode of pathogenicity: None; Publications: 26545877; Phenotypes: Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, MIM# 616801, MONDO:0014777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v1.5 NAA15 Zornitza Stark changed review comment from: Typically presents post-natally.; to: Congenital heart defects in 4 of 19 individuals reported with the neurodevelopmental syndrome.

PMID 33557580 - WES of 4511 patients with CHD identified 4 subjects with a rare LoF variant (allele frequency <0.00005) in the NAA15 gene, resulting in NAA15 haploinsufficiency. Parental analyses indicated that 3 of these LoF variants (p.Ser761*, p.Lys336Lys fs*6, and p.Arg470*) arose de novo in the probands. The inheritance of the p.Ala718fs variant is uncertain, as parental samples were unavailable. The authors also reference their previous studies identifying 2 other patients with CHD and LoF NAA15 heterozygous variants.
Fetal anomalies v1.4 NARS Krithika Murali gene: NARS was added
gene: NARS was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225; 32788587
Phenotypes for gene: NARS were set to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive - MIM#619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant - MIM#619092
Review for gene: NARS was set to GREEN
Added comment: HGNC approved gene symbol - NARS1

Both mono allelic and biallelic variants associated with a progressive neurological disorder with onset in infancy. Antenatal features reported.

PMID 32738225 - reports roband with de novo heterozygous variant - IUGR and oligohydramnios noted prenatally. At birth noted to have low weight and OFC for gestational age. Proband with homozygous variant diagnosed with microcephaly, seizures and FTT in the neonatal period. Proband with compound het variants born with a low weight (-2.38 SD) and height (-3.76 SD) for gestational age. Review of supplementary material table - microcephaly at birth reported in 17 unrelated families.
Sources: Literature
Fetal anomalies v1.3 IRX5 Zornitza Stark edited their review of gene: IRX5: Added comment: Third family with Hamamy syndrome and homozygous missense variant reported, p.Arg168His. Two cousins, >4 meioses, good segregation data.; Changed rating: GREEN; Changed publications: 22581230, 27453922, 34899143
Fetal anomalies v1.3 ZNF335 Zornitza Stark Marked gene: ZNF335 as ready
Fetal anomalies v1.2 ZNF335 Zornitza Stark gene: ZNF335 was added
gene: ZNF335 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: ZNF335 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF335 were set to 23178126; 27540107; 29652087; 34982360
Phenotypes for gene: ZNF335 were set to Microcephaly 10, primary, autosomal recessive (MIM#615095)
Review for gene: ZNF335 was set to GREEN
Added comment: Microcephaly is generally primary, including reports of -9SD at birth.
Sources: Expert Review
Fetal anomalies v0.4732 OXR1 Zornitza Stark Marked gene: OXR1 as ready
Fetal anomalies v0.4731 OXR1 Zornitza Stark reviewed gene: OXR1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay - MIM#213000; Mode of inheritance: None
Fetal anomalies v0.4731 MED27 Zornitza Stark Marked gene: MED27 as ready
Fetal anomalies v0.4730 EXOSC9 Zornitza Stark Marked gene: EXOSC9 as ready
Fetal anomalies v0.4729 OXR1 Krithika Murali gene: OXR1 was added
gene: OXR1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: OXR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OXR1 were set to PMID: 31785787
Phenotypes for gene: OXR1 were set to Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay - MIM#213000
Review for gene: OXR1 was set to GREEN
Added comment: Early-onset condition associated with cerebellar atrophy and severe global developmental delay. Limited antenatal information provided but affected individuals were much older at the time of formal diagnosis PMID: 31785787, antenatal detection may be possible.

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5 individuals from 3 unrelated families reported with bi-allelic variants in this gene. Presentation was in early childhood with hypotonia, global developmental delay, delayed walking at about age 3 years, and severely impaired intellectual development with profound speech delay or even absent language. All also developed epilepsy between 7 and 10 years of age, but the seizures were controlled by medication in most. Subtle nonspecific dysmorphic features included poor overall growth, large forehead, tall face, mild hypertelorism, joint hyperlaxity, and long fingers and toes. Brain imaging in all 5 individuals showed cerebellar atrophy and dysplasia. Additional cerebellar features, such as tremor, ataxia, and nystagmus, were not noted in these individuals.
Sources: Literature
Fetal anomalies v0.4729 MED27 Krithika Murali gene: MED27 was added
gene: MED27 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia - MIM#619286
Review for gene: MED27 was set to GREEN
Added comment: Severe neurodevelopmental disorder with onset in infancy associated with multiple, significant brain anomalies which may be detectable antenatally (although antenatal phenotype not reported in published cases)
Sources: Literature
Fetal anomalies v0.4729 EXOSC9 Krithika Murali gene: EXOSC9 was added
gene: EXOSC9 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: EXOSC9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC9 were set to 33040083; 30690203; 29727687
Phenotypes for gene: EXOSC9 were set to Pontocerebellar hypoplasia, type 1D - MIM#618065
Review for gene: EXOSC9 was set to GREEN
Added comment: Multiple antenatal features reported including IUGR, reduced fetal movements, oligohydramnios, congenital fractures and contractures.
Sources: Literature
Fetal anomalies v0.4729 EXOSC8 Zornitza Stark Marked gene: EXOSC8 as ready
Fetal anomalies v0.4728 EXOSC5 Zornitza Stark Marked gene: EXOSC5 as ready
Fetal anomalies v0.4727 CWF19L1 Zornitza Stark Marked gene: CWF19L1 as ready
Fetal anomalies v0.4726 RBP4 Zornitza Stark Marked gene: RBP4 as ready
Fetal anomalies v0.4725 RBP4 Zornitza Stark gene: RBP4 was added
gene: RBP4 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: RBP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBP4 were set to 25910211; 29178648
Phenotypes for gene: RBP4 were set to Microphthalmia, isolated, with coloboma 10 MIM#616428
Review for gene: RBP4 was set to GREEN
Added comment: At least 3 unrelated microphthalmia, anophthalmia and coloboma families and supporting functional assays. Study established an uncharacterized mode of maternal inheritance, distinct from imprinting and oocyte-derived mRNA.
Sources: Expert Review
Fetal anomalies v0.4724 PRR12 Zornitza Stark Marked gene: PRR12 as ready
Fetal anomalies v0.4723 PRR12 Zornitza Stark gene: PRR12 was added
gene: PRR12 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: PRR12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRR12 were set to 33314030; 29556724
Phenotypes for gene: PRR12 were set to Neuroocular syndrome, MIM#619539; Complex microphthalmia
Review for gene: PRR12 was set to GREEN
Added comment: PMID 33314030: Four unrelated families reported with unilateral or bilateral microphthalmia +/- Peters anomaly. In addition, 3 unrelated families reported with more complex phenotype including ID in PMID 29556724.
Sources: Expert Review
Fetal anomalies v0.4722 EXOSC8 Krithika Murali changed review comment from: Severe autosomal recessive neurodegenerative disorder. PMID 24989451 report polyhydramnios, vermis hypoplasia, mega cisterna magna and corpus callosum anomalies in affectd individuals
Sources: Literature; to: Severe autosomal recessive neurodegenerative disorder. PMID 24989451 (more info in supplementary material) report polyhydramnios, vermis hypoplasia, mega cisterna magna and corpus callosum anomalies in affectd individuals
Sources: Literature
Fetal anomalies v0.4722 EXOSC8 Krithika Murali gene: EXOSC8 was added
gene: EXOSC8 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: EXOSC8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC8 were set to 34210538; 24989451
Phenotypes for gene: EXOSC8 were set to Pontocerebellar hypoplasia, type 1C - MIM#616081
Review for gene: EXOSC8 was set to GREEN
Added comment: Severe autosomal recessive neurodegenerative disorder. PMID 24989451 report polyhydramnios, vermis hypoplasia, mega cisterna magna and corpus callosum anomalies in affectd individuals
Sources: Literature
Fetal anomalies v0.4722 MAB21L1 Zornitza Stark Marked gene: MAB21L1 as ready
Fetal anomalies v0.4721 MAB21L1 Zornitza Stark gene: MAB21L1 was added
gene: MAB21L1 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: MAB21L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAB21L1 were set to 30487245
Phenotypes for gene: MAB21L1 were set to Cerebellar, ocular, craniofacial, and genital syndrome OMIM#618479
Review for gene: MAB21L1 was set to GREEN
Added comment: Pontocerebellar hypoplasia, Dandy-Walker malformation, microcephaly reported.
Sources: Expert Review
Fetal anomalies v0.4720 FBXW11 Zornitza Stark Marked gene: FBXW11 as ready
Fetal anomalies v0.4718 EXOSC5 Krithika Murali gene: EXOSC5 was added
gene: EXOSC5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: EXOSC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC5 were set to 32504085; 29302074
Phenotypes for gene: EXOSC5 were set to Cerebellar ataxia, brain abnormalities, and cardiac conduction defects - MIM#619576
Review for gene: EXOSC5 was set to GREEN
Added comment: Associated with congenital anomalies
Sources: Literature
Fetal anomalies v0.4718 CAPN15 Zornitza Stark Marked gene: CAPN15 as ready
Fetal anomalies v0.4717 CAPN15 Zornitza Stark gene: CAPN15 was added
gene: CAPN15 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPN15 were set to 32885237
Phenotypes for gene: CAPN15 were set to Oculogastrointestinal neurodevelopmental syndrome, MIM# 619318; microphthalmia HP:0000568; coloboma HP:0000589
Review for gene: CAPN15 was set to GREEN
Added comment: PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families). Capn15 knockout mice showed similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth.
Sources: Expert Review
Fetal anomalies v0.4716 C16orf62 Zornitza Stark Marked gene: C16orf62 as ready
Fetal anomalies v0.4715 C16orf62 Zornitza Stark changed review comment from: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475;31712251).

Microphthalmia and multiple other anomalies.
Sources: Expert Review; to: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impaired autophagy and VPS35L knockout mouse resulted in early embryonic lethality (PMID 25434475;31712251).

Microphthalmia and multiple other anomalies.
Sources: Expert Review
Fetal anomalies v0.4715 C16orf62 Zornitza Stark gene: C16orf62 was added
gene: C16orf62 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C16orf62 were set to 25434475; 31712251
Phenotypes for gene: C16orf62 were set to Ritscher-Schinzel syndrome-3 (RTSC3), MIM#619135
Review for gene: C16orf62 was set to AMBER
Added comment: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475;31712251).

Microphthalmia and multiple other anomalies.
Sources: Expert Review
Fetal anomalies v0.4714 CWF19L1 Krithika Murali gene: CWF19L1 was added
gene: CWF19L1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CWF19L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CWF19L1 were set to 27016154
Phenotypes for gene: CWF19L1 were set to Spinocerebellar ataxia, autosomal recessive 17 - MIM#616127
Review for gene: CWF19L1 was set to GREEN
Added comment: Fetal phenotype also described by 27016154 - MTOP at 22 weeks of gestation of an affected fetus due to small cerebellum and agenesis of corpus callosum. Postmortem examination showed unilateral hexadactyly and vertebral malformations.
Sources: Literature
Fetal anomalies v0.4714 TMEM218 Zornitza Stark Marked gene: TMEM218 as ready
Fetal anomalies v0.4713 NID1 Zornitza Stark Marked gene: NID1 as ready
Fetal anomalies v0.4712 MTX2 Zornitza Stark Marked gene: MTX2 as ready
Fetal anomalies v0.4711 KIAA0556 Zornitza Stark Marked gene: KIAA0556 as ready
Fetal anomalies v0.4710 BRF1 Zornitza Stark Marked gene: BRF1 as ready
Fetal anomalies v0.4709 IFT74 Zornitza Stark Marked gene: IFT74 as ready
Fetal anomalies v0.4709 IFT74 Zornitza Stark Phenotypes for gene: IFT74 were changed from ?Bardet-Biedl syndrome 22 - MIM#617119; Joubert syndrome 40 - MIM#619582 to Bardet-Biedl syndrome 22 - MIM#617119; Joubert syndrome 40 - MIM#619582
Fetal anomalies v0.4707 BRF1 Krithika Murali gene: BRF1 was added
gene: BRF1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: BRF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRF1 were set to 25561519; 25561519; 27748960
Phenotypes for gene: BRF1 were set to Cerebellofaciodental syndrome - MIM#616202
Review for gene: BRF1 was set to GREEN
Added comment: Cerebellofaciodental syndrome is an autosomal recessive neurodevelopmental disorder characterized by delayed development, intellectual disability, abnormal facial and dental findings, and cerebellar hypoplasia.

At least 5 unrelated families and a zebrafish model.
Sources: Literature
Fetal anomalies v0.4707 FAM149B1 Zornitza Stark Marked gene: FAM149B1 as ready
Fetal anomalies v0.4706 CCDC28B Zornitza Stark Marked gene: CCDC28B as ready
Fetal anomalies v0.4704 ARL3 Zornitza Stark Marked gene: ARL3 as ready
Fetal anomalies v0.4704 ARL3 Zornitza Stark Gene: arl3 has been classified as Green List (High Evidence).
Fetal anomalies v0.4704 ARL3 Zornitza Stark Classified gene: ARL3 as Green List (high evidence)
Fetal anomalies v0.4704 ARL3 Zornitza Stark Gene: arl3 has been classified as Green List (High Evidence).
Fetal anomalies v0.4703 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Fetal anomalies v0.4702 MTX2 Krithika Murali gene: MTX2 was added
gene: MTX2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MTX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTX2 were set to 32917887
Phenotypes for gene: MTX2 were set to Mandibuloacral dysplasia progeroid syndrome - MIM#619127
Review for gene: MTX2 was set to GREEN
Added comment: Biallelic variants associated with severe progeroid form of MAD
Sources: Literature
Fetal anomalies v0.4702 NID1 Krithika Murali gene: NID1 was added
gene: NID1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NID1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NID1 were set to 23674478; 25558065; 12480912; 30773799
Phenotypes for gene: NID1 were set to Dandy-Walker malformation and occipital cephalocele; Hydrocephalus with or without seizures
Review for gene: NID1 was set to GREEN
Added comment: No OMIM gene disease association. Monoallelic variants associated with brain anomalies including hydrocephalus, Dandy Walker malformation and occipital cephalocele.
-
Sources: Literature
Fetal anomalies v0.4702 IFT74 Krithika Murali gene: IFT74 was added
gene: IFT74 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: IFT74 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT74 were set to 33531668; 27486776; 32144365
Phenotypes for gene: IFT74 were set to ?Bardet-Biedl syndrome 22 - MIM#617119; Joubert syndrome 40 - MIM#619582
Review for gene: IFT74 was set to GREEN
Added comment: Biallelic variants associated with both Joubert and Bardet-Biedl syndrome phenotype - multiple congenital anomalies reported.
Sources: Literature
Fetal anomalies v0.4702 FAM149B1 Krithika Murali gene: FAM149B1 was added
gene: FAM149B1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM149B1 were set to 30905400
Phenotypes for gene: FAM149B1 were set to Joubert syndrome 36 - MIM#618763
Review for gene: FAM149B1 was set to GREEN
Added comment: Biallelic variants associated with Joubert syndrome in 4 unrelated families. Reported characteristics in published cases includes macrocephaly, mesoaxial polydactyly and cleft lip
Sources: Literature
Fetal anomalies v0.4702 CCDC28B Krithika Murali gene: CCDC28B was added
gene: CCDC28B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CCDC28B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC28B were set to 32139166
Phenotypes for gene: CCDC28B were set to Joubert syndrome
Review for gene: CCDC28B was set to AMBER
Added comment: No new publications since last PanelApp review May 2020

---

PMID: 32139166 - Single family with Joubert syndrome. Patient was homozygous for a missense, with polydactyly, severe ID, and the molar tooth sign observed in MRI. Sibling fetus MRI showed vermis hypoplasia, and was also homozygous for the variant. Parents confirmed unaffected carriers. Knockdown of CCDC28B in human TERT retinal pigment epithelial cells reduced both the number and length of cilia 430C-T variant is postulated to be a modifier of BBS.
Sources: Literature
Fetal anomalies v0.4702 ARL3 Krithika Murali gene: ARL3 was added
gene: ARL3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ARL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL3 were set to 30269812; 16565502
Phenotypes for gene: ARL3 were set to Joubert syndrome 35- MIM#618161
Review for gene: ARL3 was set to GREEN
Added comment: Associated with Joubert syndrome with antenatally detectable features including renal and brain anomalies
Sources: Literature
Fetal anomalies v0.4702 MORC2 Zornitza Stark Marked gene: MORC2 as ready
Fetal anomalies v0.4701 MINPP1 Zornitza Stark Marked gene: MINPP1 as ready
Fetal anomalies v0.4700 MORC2 Krithika Murali gene: MORC2 was added
gene: MORC2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MORC2 were set to 32693025
Phenotypes for gene: MORC2 were set to Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy - MIM#619090
Review for gene: MORC2 was set to RED
Added comment: No new publications since last PanelApp review Dec 2020. No antenatal features reported.

---

MORC2 variants have commonly been associated with CMT, presenting axonal neuropathy with progressive weakness, muscle cramps and sensory impairment. However, Sacoto et al (2020) (PMID: 32693025) present a cohort of 20 individuals (19 kindreds) with a neurodevelopmental disorder characterised by DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. Hearing loss was observed in 11/19 subjects, primarily SNHL.
Sources: Literature
Fetal anomalies v0.4700 NCAPD2 Zornitza Stark Marked gene: NCAPD2 as ready
Fetal anomalies v0.4699 MINPP1 Krithika Murali gene: MINPP1 was added
gene: MINPP1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696; 33168985
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia, type 16 - MIM#619527
Review for gene: MINPP1 was set to GREEN
Added comment: Biallelic LoF variants associated with pontocerebellar hypoplasia. Early-onset progressive microcephaly is a phenotypic feature with one affected individual reported to have prenatal evidence of microcephaly associated with increased thalami echogenicity (PMID 33257696)
Sources: Literature
Fetal anomalies v0.4699 NCAPD2 Zornitza Stark gene: NCAPD2 was added
gene: NCAPD2 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: NCAPD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPD2 were set to 31056748; 27737959; 28097321
Phenotypes for gene: NCAPD2 were set to Microcephaly 21, primary, autosomal recessive; OMIM #617983
Review for gene: NCAPD2 was set to GREEN
Added comment: Three families reported: 1 family with 2 sibs with microcephaly and ID, and homozygous NCAPD2 mutation, which segregated with disease. No functional evidence. 1 family with 1 affected and homozygous NCAPD2 mutation, which segregated with disease. Patient fibroblasts showed impaired chromosome segregation and abnormal recovery from mitotic condensation compared to controls. 1 family with 2 sibs with microcephaly, growth retardation, and ID, and homozygous NCAPD2 mutation, which segregated with disease. Functional studies of the variants and studies of patient cells were not performed.

IUGR reported.
Sources: Expert Review
Fetal anomalies v0.4698 NSRP1 Zornitza Stark Marked gene: NSRP1 as ready
Fetal anomalies v0.4697 NSRP1 Zornitza Stark gene: NSRP1 was added
gene: NSRP1 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to Neurodevelopmental disorder, MONDO:0700092, NSRP1-related; Epilepsy; Cerebral palsy; microcephaly; Intellectual disability
Review for gene: NSRP1 was set to GREEN
Added comment: Novel gene regulating splicing. Biallelic LoF pathogenic variants reported in 6 individuals from 3 unrelated families associated with a phenotype characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.

Structural brain abnormalities.
Sources: Expert Review
Fetal anomalies v0.4696 NUF2 Zornitza Stark Marked gene: NUF2 as ready
Fetal anomalies v0.4696 NUF2 Zornitza Stark gene: NUF2 was added
gene: NUF2 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: NUF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NUF2 were set to 33721060
Phenotypes for gene: NUF2 were set to Syndromic disease, MONDO:0002254; microcephaly; short stature; bilateral vocal cord paralysis; micrognathia; atrial septal defect
Review for gene: NUF2 was set to RED
Added comment: PMID: 33721060 - de novo missense variant identified in one male patient with microcephaly and short stature, with additional features, such as bilateral vocal cord paralysis, micrognathia and atrial septal defect.
Sources: Expert Review
Fetal anomalies v0.4695 NUP188 Zornitza Stark Marked gene: NUP188 as ready
Fetal anomalies v0.4694 NUP188 Zornitza Stark gene: NUP188 was added
gene: NUP188 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: NUP188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP188 were set to 32021605; 28726809; 32275884
Phenotypes for gene: NUP188 were set to Sandestig-Stefanova syndrome, 618804; microcephaly; ID; cataract; structural brain abnormalities
Review for gene: NUP188 was set to GREEN
Added comment: 8 unrelated individuals reported.
Sources: Expert Review
Fetal anomalies v0.4693 NUP85 Zornitza Stark Marked gene: NUP85 as ready
Fetal anomalies v0.4692 NUP85 Zornitza Stark gene: NUP85 was added
gene: NUP85 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: NUP85 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP85 were set to 34170319
Phenotypes for gene: NUP85 were set to Microcephaly, MONDO:0001149, NUP85-related
Review for gene: NUP85 was set to AMBER
Added comment: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction. In the second family, compound heterozygous missense variants in NUP85 were detected (c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

Variants in this gene are also associated with nephrotic syndrome.
Sources: Expert Review
Fetal anomalies v0.4691 PUS7 Zornitza Stark Marked gene: PUS7 as ready
Fetal anomalies v0.4690 PTPN23 Zornitza Stark Marked gene: PTPN23 as ready
Fetal anomalies v0.4689 PUS7 Belinda Chong gene: PUS7 was added
gene: PUS7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PUS7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PUS7 were set to 30526862; 30778726; 31583274
Phenotypes for gene: PUS7 were set to Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature; OMIM #618342
Review for gene: PUS7 was set to RED
gene: PUS7 was marked as current diagnostic
Added comment: Onset at infancy

11 patients from 6 families with ID, speech delay, short stature, microcephaly, and aggressive behavior, with homozygous PUS7 mutations, which segregated with disease.
Sources: Literature
Fetal anomalies v0.4689 PRIM1 Zornitza Stark Marked gene: PRIM1 as ready
Fetal anomalies v0.4688 PPP1R15B Zornitza Stark Marked gene: PPP1R15B as ready
Fetal anomalies v0.4687 PPIL1 Zornitza Stark Marked gene: PPIL1 as ready
Fetal anomalies v0.4686 PTPN23 Belinda Chong gene: PTPN23 was added
gene: PTPN23 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PTPN23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPN23 were set to 31395947; 29899372; 29090338; 27848944; 25558065
Phenotypes for gene: PTPN23 were set to Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, MIM# 618890
Review for gene: PTPN23 was set to GREEN
gene: PTPN23 was marked as current diagnostic
Added comment: Onset at birth or early infancy.

Over 10 families reported with an autosomal recessive neurologic disorder characterised by global developmental delay apparent from early infancy, poor overall growth often with microcephaly (6/10), impaired intellectual development with delayed or absent speech, axial hypotonia, and peripheral spasticity. Additional common but variable features include early-onset seizures, optic atrophy with poor visual fixation, and dysmorphic facial features. Brain imaging shows cerebral atrophy, poor or absent myelination with loss of white matter volume, and often hypoplasia of the corpus callosum and/or cerebellum.
Sources: Literature
Fetal anomalies v0.4686 PRIM1 Belinda Chong gene: PRIM1 was added
gene: PRIM1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRIM1 were set to 33060134
Phenotypes for gene: PRIM1 were set to Microcephalic primordial dwarfism, MONDO:0017950
Review for gene: PRIM1 was set to AMBER
gene: PRIM1 was marked as current diagnostic
Added comment: - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant.
Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD).

Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinaemia, and lymphopaenia accompanied by intermittent anaemia/thrombocytopaenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections.

Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype.
Sources: Literature
Fetal anomalies v0.4686 PPP1R15B Belinda Chong gene: PPP1R15B was added
gene: PPP1R15B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PPP1R15B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP1R15B were set to 26159176; 26307080; 27640355
Phenotypes for gene: PPP1R15B were set to Microcephaly, short stature, and impaired glucose metabolism 2, MIM# 616817
Review for gene: PPP1R15B was set to AMBER
gene: PPP1R15B was marked as current diagnostic
Added comment: Three unrelated families reported, two with the same variant. Phenotype in family reported in PMID 27640355 included infantile cirrhosis requiring transplantation.
Sources: Literature
Fetal anomalies v0.4686 PPIL1 Belinda Chong gene: PPIL1 was added
gene: PPIL1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to Pontocerebellar hypoplasia, type 14, MIM# 619301; microcephaly; seizures
Review for gene: PPIL1 was set to GREEN
gene: PPIL1 was marked as current diagnostic
Added comment: The patients presented at birth with severe microcephaly (-2 to -6 SD), which progressed postnatally (-4 to -8 SD)

17 individuals from 9 unrelated families reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID. Mouse models support gene-disease association.
Sources: Literature
Fetal anomalies v0.4686 SYNCRIP Zornitza Stark Marked gene: SYNCRIP as ready
Fetal anomalies v0.4686 SYNCRIP Zornitza Stark gene: SYNCRIP was added
gene: SYNCRIP was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SYNCRIP were set to 34157790
Phenotypes for gene: SYNCRIP were set to SYNCRIP-related neurodevelopmental disorder
Review for gene: SYNCRIP was set to RED
Added comment: One of 8 individuals reported so far had PVNH. Other features present post-natally.
Sources: Expert Review
Fetal anomalies v0.4683 DEPDC5 Zornitza Stark reviewed gene: DEPDC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 31444548; Phenotypes: Epilepsy, familial focal, with variable foci 1 MIM#604364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.4683 AR Alison Yeung Phenotypes for gene: AR were changed from Androgen insensitivity, MIM# 300068 to Androgen insensitivity, MIM# 300068; Androgen insensitivity syndrome, MONDO:0019154
Fetal anomalies v0.4682 AR Alison Yeung reviewed gene: AR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Androgen insensitivity, MIM# 300068, Androgen insensitivity syndrome, MONDO:0019154; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v0.4682 AP4B1 Alison Yeung reviewed gene: AP4B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 47, autosomal recessive, MIM# 614066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.4681 ALDH1A2 Alison Yeung Phenotypes for gene: ALDH1A2 were changed from Congenital heart defects; diaphragmatic eventration; pulmonary hypoplasia; thymus aplasia to Multiple congenital anomalies, ALDH1A2-related, MONDO:0019042
Fetal anomalies v0.4677 ADAMTS19 Alison Yeung Phenotypes for gene: ADAMTS19 were changed from Heart valve disease (HVD) to Heart valve disorder, MONDO:0002869
Fetal anomalies v0.4676 PLK1 Zornitza Stark Marked gene: PLK1 as ready
Fetal anomalies v0.4674 PIGH Zornitza Stark Marked gene: PIGH as ready
Fetal anomalies v0.4673 PHC1 Zornitza Stark Marked gene: PHC1 as ready
Fetal anomalies v0.4672 ADAMTS17 Alison Yeung Phenotypes for gene: ADAMTS17 were changed from Weill-Marchesani 4 syndrome, recessive, 613195 to Weill-Marchesani 4 syndrome, recessive, MIM# 613195
Fetal anomalies v0.4671 PDCD6IP Zornitza Stark Marked gene: PDCD6IP as ready
Fetal anomalies v0.4670 PCYT2 Zornitza Stark Marked gene: PCYT2 as ready
Fetal anomalies v0.4669 ACTC1 Alison Yeung Phenotypes for gene: ACTC1 were changed from Atrial septal defect 5 612794; Cardiomyopathy, hypertrophic, 11 612098 to Atrial septal defect 5, MIM# 612794; Cardiomyopathy, hypertrophic, 11 MIM# 612098
Fetal anomalies v0.4668 PCDH12 Zornitza Stark Marked gene: PCDH12 as ready
Fetal anomalies v0.4667 PARP6 Zornitza Stark Marked gene: PARP6 as ready
Fetal anomalies v0.4667 PARP6 Zornitza Stark Gene: parp6 has been classified as Green List (High Evidence).
Fetal anomalies v0.4667 PARP6 Zornitza Stark Classified gene: PARP6 as Green List (high evidence)
Fetal anomalies v0.4667 PARP6 Zornitza Stark Gene: parp6 has been classified as Green List (High Evidence).
Fetal anomalies v0.4666 NKX2-5 Zornitza Stark Marked gene: NKX2-5 as ready
Fetal anomalies v0.4666 NKX2-5 Alison Yeung Marked gene: NKX2-5 as ready
Fetal anomalies v0.4666 NKX2-5 Alison Yeung Phenotypes for gene: NKX2-5 were changed from CONGENITAL HYPOTHYROIDISM NON-GOITROUS TYPE 5; TETRALOGY OF FALLOT; ATRIAL SEPTAL DEFECT WITH ATRIOVENTRICULAR CONDUCTION DEFECTS to Atrial septal defect 7, with or without AV conduction defects, MIM# 108900; Hypoplastic left heart syndrome 2, MIM# 614435; Tetralogy of Fallot, MIM# 187500; Ventricular septal defect 3, MIM# 614432; Hypothyroidism, congenital nongoitrous, 5, MIM# 225250
Fetal anomalies v0.4665 NPC2 Zornitza Stark Marked gene: NPC2 as ready
Fetal anomalies v0.4662 NPHP1 Zornitza Stark Marked gene: NPHP1 as ready
Fetal anomalies v0.4658 NPHP3 Zornitza Stark Marked gene: NPHP3 as ready
Fetal anomalies v0.4656 NIPBL Alison Yeung Marked gene: NIPBL as ready
Fetal anomalies v0.4654 NPHP4 Zornitza Stark Marked gene: NPHP4 as ready
Fetal anomalies v0.4652 NRAS Zornitza Stark Marked gene: NRAS as ready
Fetal anomalies v0.4650 NRAS Zornitza Stark Mode of pathogenicity for gene: NRAS was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.4648 NSD1 Zornitza Stark Marked gene: NSD1 as ready
Fetal anomalies v0.4645 NSDHL Zornitza Stark Marked gene: NSDHL as ready
Fetal anomalies v0.4642 NUP107 Zornitza Stark Marked gene: NUP107 as ready
Fetal anomalies v0.4642 NUP107 Zornitza Stark Phenotypes for gene: NUP107 were changed from EARLY-CHILDHOOD-ONSET STEROID-RESISTANT NEPHROTIC SYNDROME to Galloway-Mowat syndrome 7, MIM# 618348
Fetal anomalies v0.4640 OCRL Zornitza Stark Marked gene: OCRL as ready
Fetal anomalies v0.4640 OFD1 Zornitza Stark Marked gene: OFD1 as ready
Fetal anomalies v0.4639 OFD1 Zornitza Stark changed review comment from: XLD. Polydactyly is a rare feature. Primarily facial/neurological features.; to: Well established gene-disease associations, multiple congenital anomalies.
Fetal anomalies v0.4639 PCGF2 Zornitza Stark Marked gene: PCGF2 as ready
Fetal anomalies v0.4639 PCGF2 Zornitza Stark Phenotypes for gene: PCGF2 were changed from Craniofacial Neurological Cardiovascular and Skeletal Features; Intellectual disability; INTELLECTUAL DUSBILITY to Turnpenny-Fry syndrome, MIM# 618371
Fetal anomalies v0.4636 PCNT Zornitza Stark Marked gene: PCNT as ready
Fetal anomalies v0.4636 PCNT Zornitza Stark Phenotypes for gene: PCNT were changed from MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE II to Microcephalic osteodysplastic primordial dwarfism, type II, MIM# 210720; MONDO:0008872
Fetal anomalies v0.4634 PDHA1 Zornitza Stark Marked gene: PDHA1 as ready
Fetal anomalies v0.4632 PDHA1 Zornitza Stark changed review comment from: Variants in this gene can cause congenital anomalies.
Sources: Literature; to: Variants in this gene can cause congenital anomalies, primarily affecting the brain. One report of CDH.
Sources: Literature
Fetal anomalies v0.4632 PDHA1 Zornitza Stark changed review comment from: Single individual reported as part of a cohort. Note variants in this gene can cause congenital anomalies.
Sources: Literature; to: Variants in this gene can cause congenital anomalies.
Sources: Literature
Fetal anomalies v0.4632 PEX1 Zornitza Stark Marked gene: PEX1 as ready
Fetal anomalies v0.4630 PEX10 Zornitza Stark Marked gene: PEX10 as ready
Fetal anomalies v0.4628 PEX11B Zornitza Stark Marked gene: PEX11B as ready
Fetal anomalies v0.4626 PEX11B Zornitza Stark changed review comment from: Congenital cataracts.; to: Congenital cataracts. Three families altogether, two published, and one internal.
Fetal anomalies v0.4626 PEX11B Zornitza Stark edited their review of gene: PEX11B: Added comment: Congenital cataracts.; Changed rating: GREEN; Changed phenotypes: Peroxisome biogenesis disorder 14B, MIM# 614920; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.4626 PEX12 Zornitza Stark Marked gene: PEX12 as ready
Fetal anomalies v0.4624 PEX13 Zornitza Stark Marked gene: PEX13 as ready
Fetal anomalies v0.4622 PEX14 Zornitza Stark Marked gene: PEX14 as ready
Fetal anomalies v0.4620 PEX16 Zornitza Stark Marked gene: PEX16 as ready
Fetal anomalies v0.4618 POMGNT1 Zornitza Stark Marked gene: POMGNT1 as ready
Fetal anomalies v0.4618 POMGNT1 Zornitza Stark Phenotypes for gene: POMGNT1 were changed from MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY LIMB-GIRDLE TYPE C3; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY CONGENITAL WITH MENTAL RETARDATION TYPE B3; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY CONGENITAL WITH BRAIN AND EYE ANOMALIES TYPE A3 (MDDGA3 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3, 253280
Fetal anomalies v0.4617 PEX19 Zornitza Stark Marked gene: PEX19 as ready
Fetal anomalies v0.4615 PEX2 Zornitza Stark Marked gene: PEX2 as ready
Fetal anomalies v0.4613 PEX26 Zornitza Stark Marked gene: PEX26 as ready
Fetal anomalies v0.4611 PEX3 Zornitza Stark Marked gene: PEX3 as ready
Fetal anomalies v0.4609 PEX5 Zornitza Stark Marked gene: PEX5 as ready
Fetal anomalies v0.4607 NR2F2 Zornitza Stark Marked gene: NR2F2 as ready
Fetal anomalies v0.4607 NR2F2 Zornitza Stark Phenotypes for gene: NR2F2 were changed from CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 4 to Congenital heart defects, multiple types, 4, MIM# 615779
Fetal anomalies v0.4604 PEX6 Zornitza Stark Marked gene: PEX6 as ready
Fetal anomalies v0.4602 PGAP2 Zornitza Stark Marked gene: PGAP2 as ready
Fetal anomalies v0.4602 PGAP2 Zornitza Stark Phenotypes for gene: PGAP2 were changed from INTELLECTUAL DISABILITY to Hyperphosphatasia with mental retardation syndrome 3, MIM# 614207, MONDO:0013628
Fetal anomalies v0.4600 PGAP2 Zornitza Stark changed review comment from: Bi-allelic variants in this gene are typically associated with severe DD/ID, hypotonia with very poor motor development, poor speech, and increased serum alkaline phosphatase, although presentations with milder ID have also been reported. More than 10 unrelated families reported.; to: Bi-allelic variants in this gene are typically associated with severe DD/ID, hypotonia with very poor motor development, poor speech, and increased serum alkaline phosphatase, although presentations with milder ID have also been reported. More than 10 unrelated families reported.

Microcephaly is a feature.
Fetal anomalies v0.4600 PGAP3 Zornitza Stark Marked gene: PGAP3 as ready
Fetal anomalies v0.4600 PGAP3 Zornitza Stark Phenotypes for gene: PGAP3 were changed from HYPERPHOSPHATASIA WITH MENTAL RETARDATION SYNDROME 4 to Hyperphosphatasia with mental retardation syndrome 4, MIM# 615716, MONDO:0014318
Fetal anomalies v0.4598 PGAP3 Zornitza Stark changed review comment from: Bi-allelic variants in this gene are associated with severe DD/ID, lack of speech acquisition, seizures, and dysmorphic facial features. Laboratory studies show increased serum alkaline phosphatase. More than 15 unrelated families reported.; to: Bi-allelic variants in this gene are associated with severe DD/ID, lack of speech acquisition, seizures, and dysmorphic facial features. Laboratory studies show increased serum alkaline phosphatase. More than 15 unrelated families reported.

Microcephaly, CC abnormalities reported.
Fetal anomalies v0.4598 PGM1 Zornitza Stark Marked gene: PGM1 as ready
Fetal anomalies v0.4596 PGM1 Zornitza Stark changed review comment from: The most common features include cleft lip and bifid uvula, apparent at birth, followed by hepatopathy, intermittent hypoglycemia, short stature, and exercise intolerance, often accompanied by increased serum creatine kinase. Less common features include rhabdomyolysis, dilated cardiomyopathy, and hypogonadotropic hypogonadism; to: Over 50 individuals reported. The most common features include cleft lip and bifid uvula, apparent at birth, followed by hepatopathy, intermittent hypoglycemia, short stature, and exercise intolerance, often accompanied by increased serum creatine kinase. Less common features include rhabdomyolysis, dilated cardiomyopathy, and hypogonadotropic hypogonadism
Fetal anomalies v0.4596 PGM1 Zornitza Stark commented on gene: PGM1: The most common features include cleft lip and bifid uvula, apparent at birth, followed by hepatopathy, intermittent hypoglycemia, short stature, and exercise intolerance, often accompanied by increased serum creatine kinase. Less common features include rhabdomyolysis, dilated cardiomyopathy, and hypogonadotropic hypogonadism
Fetal anomalies v0.4596 PHF8 Zornitza Stark Marked gene: PHF8 as ready
Fetal anomalies v0.4596 PHF8 Zornitza Stark Phenotypes for gene: PHF8 were changed from MENTAL RETARDATION SYNDROMIC X-LINKED SIDERIUS TYPE to Intellectual developmental disorder, X-linked, syndromic, Siderius type, MIM# 300263
Fetal anomalies v0.4594 PHGDH Zornitza Stark Marked gene: PHGDH as ready
Fetal anomalies v0.4592 PHIP Zornitza Stark Marked gene: PHIP as ready
Fetal anomalies v0.4588 PHIP Zornitza Stark changed review comment from: Recent large case series describing 20 individuals; variable expressivity, some inherited from mildly affected parents, most de novo.
Sources: Expert list; to: Recent large case series describing 20 individuals; variable expressivity, some inherited from mildly affected parents, most de novo. ID, dysmorphism and obesity are the key features. Clinical presentation is typically post-natal.
Sources: Expert list
Fetal anomalies v0.4588 PIEZO2 Zornitza Stark Marked gene: PIEZO2 as ready
Fetal anomalies v0.4588 PIEZO2 Zornitza Stark Phenotypes for gene: PIEZO2 were changed from Ataxia, dysmetria, contractures & scoliosis with normal cognition but loss of discriminative touch perception; ARTHROGRYPOSIS, DISTAL, TYPE 3 to Marden-Walker syndrome, MIM# 248700; Arthrogryposis, distal, type 3, MIM# 114300
Fetal anomalies v0.4585 PIEZO2 Zornitza Stark changed review comment from: Gene is associated with several phenotypes. The other two DA phenotypes do not have ID as a feature. Mild ID is part of the phenotype of some individuals with DA type 3. ID is part of the phenotype of Marden-Walker, however only one individual with PIEZO2 variant has been reported to date.; to: Gene is associated with several phenotypes, contractures are a key feature.
Fetal anomalies v0.4585 PIGA Zornitza Stark Marked gene: PIGA as ready
Fetal anomalies v0.4583 PIGL Zornitza Stark Marked gene: PIGL as ready
Fetal anomalies v0.4581 PIGO Zornitza Stark Marked gene: PIGO as ready
Fetal anomalies v0.4581 PIGO Zornitza Stark Phenotypes for gene: PIGO were changed from HYPERPHOSPHATASIA WITH MENTAL RETARDATION SYNDROME 2 to Hyperphosphatasia with mental retardation syndrome 2, MIM# 614749, MONDO:0013882
Fetal anomalies v0.4579 PIGT Zornitza Stark Marked gene: PIGT as ready
Fetal anomalies v0.4577 PIGV Zornitza Stark Marked gene: PIGV as ready
Fetal anomalies v0.4577 PIGV Zornitza Stark Phenotypes for gene: PIGV were changed from HYPERPHOSPHATASIA WITH MENTAL RETARDATION to Hyperphosphatasia with mental retardation syndrome 1, MIM# 239300, MONDO:0009398
Fetal anomalies v0.4575 PIK3CA Zornitza Stark Marked gene: PIK3CA as ready
Fetal anomalies v0.4575 PIK3CA Zornitza Stark Phenotypes for gene: PIK3CA were changed from CLOVES: CONGENITAL LIPOMATOUS OVERGROWTH, VASCULAR MALFORMATIONS, AND EPIDERMAL NEVI; HEMIMEGALENCEPHALY PIK3CA; MEGALENCEPHALY-CAPILLARY MALFORMATION-POLYMICROGYRIA SYNDROME, SOMATIC 3 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, MIM# 615937
Fetal anomalies v0.4572 PIK3CA Zornitza Stark changed review comment from: Single case report of MCAP with fetal hydrops presentation, PIK3CA variant identified.
Sources: Expert list; to: Multiple congenital anomalies.
Sources: Expert list
Fetal anomalies v0.4572 PIK3R1 Zornitza Stark Marked gene: PIK3R1 as ready
Fetal anomalies v0.4571 PIK3R1 Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: IUGR.
Fetal anomalies v0.4571 PIK3R2 Zornitza Stark Marked gene: PIK3R2 as ready
Fetal anomalies v0.4568 PITX3 Zornitza Stark Marked gene: PITX3 as ready
Fetal anomalies v0.4568 PITX3 Zornitza Stark Phenotypes for gene: PITX3 were changed from CATARACT AUTOSOMAL DOMINANT; ANTERIOR SEGMENT MESENCHYMAL DYSGENESIS; CATARACT POSTERIOR POLAR TYPE 4 to Anterior segment dysgenesis 1, multiple subtypes, MIM# 107250; Cataract 11, multiple types, MIM# 610623; Microphthalmia
Fetal anomalies v0.4565 PKD1L1 Zornitza Stark Marked gene: PKD1L1 as ready
Fetal anomalies v0.4563 PKHD1 Zornitza Stark Marked gene: PKHD1 as ready
Fetal anomalies v0.4562 PKLR Zornitza Stark Marked gene: PKLR as ready
Fetal anomalies v0.4561 PMM2 Zornitza Stark Marked gene: PMM2 as ready
Fetal anomalies v0.4559 PNKP Zornitza Stark Marked gene: PNKP as ready
Fetal anomalies v0.4559 PNKP Zornitza Stark Phenotypes for gene: PNKP were changed from ATAXIA-OCULOMOTOR APRAXIA 4; EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 10 to Microcephaly, seizures, and developmental delay, MIM#613402
Fetal anomalies v0.4557 POC1A Zornitza Stark Marked gene: POC1A as ready
Fetal anomalies v0.4557 POC1A Zornitza Stark Phenotypes for gene: POC1A were changed from PRIMORDIAL DWARFISM; SHORT STATURE, ONYCHODYSPLASIA, FACIAL DYSMORPHISM, AND HYPOTRICHOSIS SYNDROME to Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis, MIM#614813
Fetal anomalies v0.4556 POGZ Zornitza Stark Marked gene: POGZ as ready
Fetal anomalies v0.4554 PLK1 Belinda Chong gene: PLK1 was added
gene: PLK1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK1 were set to 33875846
Phenotypes for gene: PLK1 were set to Epilepsy; microcephaly; intellectual disability
Review for gene: PLK1 was set to AMBER
gene: PLK1 was marked as current diagnostic
Added comment: Five individuals reported with microcephaly. However, unclear if microcephaly is pre or post natal.
Sources: Literature
Fetal anomalies v0.4553 POGZ Zornitza Stark changed review comment from: White-Sutton syndrome is a neurodevelopmental disorder characterized by delayed psychomotor development apparent in infancy and a characteristic constellation of dysmorphic facial features. Additional features may include hypotonia, sensorineural hearing impairment, visual defects, joint laxity, and gastrointestinal difficulties, such as poor feeding.

More than 40 individuals reported.; to: White-Sutton syndrome is a neurodevelopmental disorder characterized by delayed psychomotor development apparent in infancy and a characteristic constellation of dysmorphic facial features. Additional features may include hypotonia, sensorineural hearing impairment, visual defects, joint laxity, and gastrointestinal difficulties, such as poor feeding.

More than 40 individuals reported.

Microcephaly is a feature, congenital heart disease rarely reported.
Fetal anomalies v0.4553 POLR1C Zornitza Stark Marked gene: POLR1C as ready
Fetal anomalies v0.4551 POLR1C Zornitza Stark changed review comment from: 8 unrelated individuals reported, ID is part of the phenotype.
Sources: Expert list; to: Treacher Collins more likely to be detected antenatally.

Sources: Expert list
Fetal anomalies v0.4551 POMGNT2 Zornitza Stark Marked gene: POMGNT2 as ready
Fetal anomalies v0.4551 POMGNT2 Zornitza Stark Phenotypes for gene: POMGNT2 were changed from WALKER WARBERG SYNDROME to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8, MIM# 614830
Fetal anomalies v0.4550 POMGNT2 Zornitza Stark edited their review of gene: POMGNT2: Changed phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8 614830
Fetal anomalies v0.4550 POMK Zornitza Stark Marked gene: POMK as ready
Fetal anomalies v0.4550 POMT1 Zornitza Stark Marked gene: POMT1 as ready
Fetal anomalies v0.4550 POMT1 Zornitza Stark Phenotypes for gene: POMT1 were changed from MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY LIMB-GIRDLE TYPE C1; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY CONGENITAL WITH MENTAL RETARDATION TYPE B1; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY CONGENITAL WITH BRAIN AND EYE ANOMALIES TYPE A1 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 236670; Walker-Walburg syndrome
Fetal anomalies v0.4548 POMT2 Zornitza Stark Marked gene: POMT2 as ready
Fetal anomalies v0.4548 POMT2 Zornitza Stark Phenotypes for gene: POMT2 were changed from MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY CONGENITAL WITH BRAIN AND EYE ANOMALIES TYPE A2; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY CONGENITAL WITH MENTAL RETARDATION TYPE B2; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY LIMB-GIRDLE TYPE C2 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 2 613150
Fetal anomalies v0.4546 POMT2 Zornitza Stark edited their review of gene: POMT2: Changed phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 2 613150
Fetal anomalies v0.4546 PIGH Belinda Chong gene: PIGH was added
gene: PIGH was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PIGH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGH were set to 29573052; 33156547; 29603516
Phenotypes for gene: PIGH were set to Glycosylphosphatidylinositol biosynthesis defect 17, MIM# 618010
Review for gene: PIGH was set to AMBER
gene: PIGH was marked as current diagnostic
Added comment: Microcephaly appears to present at postnatal in these individuals.

Three further families reported, including two sibs with microcephaly.
Sources: Literature
Fetal anomalies v0.4546 PHC1 Belinda Chong gene: PHC1 was added
gene: PHC1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PHC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PHC1 were set to 23418308
Phenotypes for gene: PHC1 were set to Microcephaly 11, primary, autosomal recessive, MIM#615414
Review for gene: PHC1 was set to RED
gene: PHC1 was marked as current diagnostic
Added comment: Short stature and microcephaly, currently not enough information.

Single family reported with functional data.
Sources: Literature
Fetal anomalies v0.4546 POR Zornitza Stark Marked gene: POR as ready
Fetal anomalies v0.4546 PORCN Zornitza Stark Marked gene: PORCN as ready
Fetal anomalies v0.4544 POU1F1 Zornitza Stark Marked gene: POU1F1 as ready
Fetal anomalies v0.4544 POU1F1 Zornitza Stark Phenotypes for gene: POU1F1 were changed from POU1F1-RELATED COMBINED PITUITARY HORMONE DEFICIENCY to Pituitary hormone deficiency, combined, 1, MIM# 613038
Fetal anomalies v0.4542 PPP2R1A Zornitza Stark Marked gene: PPP2R1A as ready
Fetal anomalies v0.4542 PPP2R1A Zornitza Stark Phenotypes for gene: PPP2R1A were changed from INTELLECTUAL DISABILITY to Mental retardation, autosomal dominant 36, MIM#616362; Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome, MONDO:0014605
Fetal anomalies v0.4538 PPP2R5D Zornitza Stark Marked gene: PPP2R5D as ready
Fetal anomalies v0.4538 PPP2R5D Zornitza Stark Phenotypes for gene: PPP2R5D were changed from INTELLECTUAL DISABILITY to Mental retardation, autosomal dominant 35, MIM#616355
Fetal anomalies v0.4535 PPP2R5D Zornitza Stark changed review comment from: (P/LP in ClinVar): >15 missense, 1 PTC DN missense mechanism suspected: Functional studies showed defective holoenzyme assembly in transfected HEK293 cells and mutant subunits hindering dephosphorylation of B56δ-anchored substrates. Moreover,. p.P53S was the only variant to not show defective binding - authors speculate an alternative mechanism. Unknown mechanism for PTCs: pLI = 1 and very few in gnomAD. Missense variants cluster p.198-207 (Decipher).; to: (P/LP in ClinVar): >15 missense, 1 PTC DN missense mechanism suspected: Functional studies showed defective holoenzyme assembly in transfected HEK293 cells and mutant subunits hindering dephosphorylation of B56δ-anchored substrates. Moreover,. p.P53S was the only variant to not show defective binding - authors speculate an alternative mechanism. Unknown mechanism for PTCs: pLI = 1 and very few in gnomAD. Missense variants cluster p.198-207 (Decipher).

Hydrocephalus reported in some.
Fetal anomalies v0.4535 PPP1CB Zornitza Stark Marked gene: PPP1CB as ready
Fetal anomalies v0.4535 PPP1CB Zornitza Stark Phenotypes for gene: PPP1CB were changed from Rasopathy with developmental delay, short stature and sparse slow-growing hair to Noonan syndrome-like disorder with loose anlagen hair 2, OMIM # 617506
Fetal anomalies v0.4532 PDCD6IP Belinda Chong gene: PDCD6IP was added
gene: PDCD6IP was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PDCD6IP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD6IP were set to 32286682
Phenotypes for gene: PDCD6IP were set to Primary microcephaly
Review for gene: PDCD6IP was set to AMBER
gene: PDCD6IP was marked as current diagnostic
Added comment: Primary microcephaly was noticed at birth and their occipital-frontal circumference (OFC) was ≤−2 standard deviations (SD), may be relevant for this panel however, currently not enough information.

One consanguineous family with 2 affected sibs with primary microcephaly (-4SD), intellectual disability and short stature (-5/6SD), and homozygous frameshift variant in PDCD6IP. The homozygous variant was confirmed in both affected sibs, while the four healthy siblings and parents were heterozygous. The clinical features observed in the patients were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies.
Sources: Literature
Fetal anomalies v0.4532 PCYT2 Belinda Chong gene: PCYT2 was added
gene: PCYT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Spastic paraplegia 82, autosomal recessive MIM#618770
Review for gene: PCYT2 was set to RED
gene: PCYT2 was marked as current diagnostic
Added comment: Brain imaging shows progressive cerebral and cerebellar atrophy however, normal initially.

5 individuals from 4 families reported with progressive neurologic disorder characterized by global developmental delay apparent from infancy, significant motor impairment, and progressive spasticity mainly affecting the lower limbs. Some never achieved walking, whereas others lost the ability to walk or walk with an unsteady gait. Additional features included variably impaired intellectual development with language difficulties, ocular anomalies, such as nystagmus and visual impairment, and seizures. Brain imaging shows progressive cerebral and cerebellar atrophy, as well as white matter hyperintensities. Overall poor growth, but only one individual reported with microcephaly -3SD, and head size appears relatively spared against other reported growth parameters.
Sources: Literature
Fetal anomalies v0.4532 PCDH12 Belinda Chong gene: PCDH12 was added
gene: PCDH12 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PCDH12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDH12 were set to 27164683; 30178464
Phenotypes for gene: PCDH12 were set to Diencephalic-mesencephalic junction dysplasia syndrome 1, MIM# 251280
Review for gene: PCDH12 was set to GREEN
gene: PCDH12 was marked as current diagnostic
Added comment: Brain malformations were detectable antenatally.

Diencephalic-mesencephalic junction dysplasia syndrome-1 (DMJDS1) is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, severely delayed or even absent psychomotor development with profound intellectual disability, and spasticity or dystonia. Some patients may have seizures and/or visual impairment. Brain imaging shows a characteristic developmental malformation of the midbrain; subtle intracranial calcifications may also be present. At least 12 families reported.
Sources: Literature
Fetal anomalies v0.4532 PARP6 Belinda Chong gene: PARP6 was added
gene: PARP6 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PARP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PARP6 were set to 34067418
Phenotypes for gene: PARP6 were set to Intellectual disability; Epilepsy; Microcephaly
Review for gene: PARP6 was set to GREEN
gene: PARP6 was marked as current diagnostic
Added comment: IUGR and partial agenesis of the corpus callosum has been observed.

Four unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype. Supportive functional data. One pair of siblings with a homozygous missense: limited evidence for bi-allelic variants causing disease.
Sources: Literature
Fetal anomalies v0.4531 TBC1D7 Zornitza Stark Marked gene: TBC1D7 as ready
Fetal anomalies v0.4530 TAOK1 Zornitza Stark Marked gene: TAOK1 as ready
Fetal anomalies v0.4529 STT3A Zornitza Stark Marked gene: STT3A as ready
Fetal anomalies v0.4528 RHEB Zornitza Stark Marked gene: RHEB as ready
Fetal anomalies v0.4527 PPP2R5C Zornitza Stark Marked gene: PPP2R5C as ready
Fetal anomalies v0.4526 LMNB2 Zornitza Stark Marked gene: LMNB2 as ready
Fetal anomalies v0.4525 MCM7 Zornitza Stark Marked gene: MCM7 as ready
Fetal anomalies v0.4524 LMNB1 Zornitza Stark Marked gene: LMNB1 as ready
Fetal anomalies v0.4523 LINGO1 Zornitza Stark Marked gene: LINGO1 as ready
Fetal anomalies v0.4522 LAGE3 Zornitza Stark Marked gene: LAGE3 as ready
Fetal anomalies v0.4521 KIF21B Zornitza Stark Marked gene: KIF21B as ready
Fetal anomalies v0.4519 PQBP1 Zornitza Stark Marked gene: PQBP1 as ready
Fetal anomalies v0.4517 PRKAR1A Zornitza Stark Marked gene: PRKAR1A as ready
Fetal anomalies v0.4517 PRKAR1A Zornitza Stark Gene: prkar1a has been classified as Green List (High Evidence).
Fetal anomalies v0.4517 PRKAR1A Zornitza Stark Phenotypes for gene: PRKAR1A were changed from ACRODYSOSTOSIS to Acrodysostosis 1, with or without hormone resistance, MIM#101800
Fetal anomalies v0.4516 PRKAR1A Zornitza Stark Mode of inheritance for gene: PRKAR1A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.4515 PRKAR1A Zornitza Stark changed review comment from: Multiple phenotypes associated with this gene, but this particular OMIM condition has ID as part of the phenotype.; to: Multiple phenotypes associated with this gene, but this particular OMIM condition has prenatal growth retardation as part of the phenotype.
Fetal anomalies v0.4515 PRKD1 Zornitza Stark Marked gene: PRKD1 as ready
Fetal anomalies v0.4515 PRKD1 Zornitza Stark Phenotypes for gene: PRKD1 were changed from Syndromic congenital heart defects to Congenital heart defects and ectodermal dysplasia, MIM#617364
Fetal anomalies v0.4513 PRKD1 Zornitza Stark edited their review of gene: PRKD1: Added comment: PMID: 27479907 (2016): three individuals reported, two with the c.1774G>A variant and one with the c.896T>G variant. All had congenital heart disease, two had some developmental delay, and two had variable features of ectodermal dysplasia, including sparse hair, dry skin, thin skin, fragile nails, premature loss of primary teeth, and small widely spaced teeth; the third individuals had a 'disorganized eyebrow.'

PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.

c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.; Changed publications: 27479907, 32817298; Changed phenotypes: Congenital heart defects and ectodermal dysplasia, MIM#617364; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.4513 PRSS56 Zornitza Stark Marked gene: PRSS56 as ready
Fetal anomalies v0.4511 RAB18 Zornitza Stark Marked gene: RAB18 as ready
Fetal anomalies v0.4511 RAB18 Zornitza Stark Phenotypes for gene: RAB18 were changed from WARBURG MICRO SYNDROME TYPE 3 to Warburg micro syndrome 3, MIM# 614222
Fetal anomalies v0.4509 RAB3GAP1 Zornitza Stark Marked gene: RAB3GAP1 as ready
Fetal anomalies v0.4509 RAB3GAP1 Zornitza Stark Phenotypes for gene: RAB3GAP1 were changed from WARBURG MICRO SYNDROME TYPE 1 to Warburg micro syndrome 1, MIM# 600118; Martsolf syndrome 2, MIM# 619420
Fetal anomalies v0.4507 RAB3GAP2 Zornitza Stark Marked gene: RAB3GAP2 as ready
Fetal anomalies v0.4507 RAB3GAP2 Zornitza Stark Phenotypes for gene: RAB3GAP2 were changed from MARTSOLF SYNDROME to Warburg micro syndrome 2, MIM# 614225
Fetal anomalies v0.4505 RAC1 Zornitza Stark Marked gene: RAC1 as ready
Fetal anomalies v0.4505 RAC1 Zornitza Stark Phenotypes for gene: RAC1 were changed from Developmental Disorders with Diverse Phenotypes to Mental retardation, autosomal dominant 48, MIM# 617751
Fetal anomalies v0.4501 RAD21 Zornitza Stark Marked gene: RAD21 as ready
Fetal anomalies v0.4498 RAF1 Zornitza Stark Marked gene: RAF1 as ready
Fetal anomalies v0.4496 RAF1 Zornitza Stark Mode of pathogenicity for gene: RAF1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.4494 RAI1 Zornitza Stark Marked gene: RAI1 as ready
Fetal anomalies v0.4491 RAPSN Zornitza Stark Marked gene: RAPSN as ready
Fetal anomalies v0.4490 RAPSN Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: Fetal akinesia, contractures.
Fetal anomalies v0.4490 RARB Zornitza Stark Marked gene: RARB as ready
Fetal anomalies v0.4490 RARB Zornitza Stark Gene: rarb has been classified as Green List (High Evidence).
Fetal anomalies v0.4490 RARB Zornitza Stark Phenotypes for gene: RARB were changed from MICROPHTHALMIA AND DIAPHRAGMATIC HERNIA to Microphthalmia, syndromic 12, MIM# 615524
Fetal anomalies v0.4489 RARB Zornitza Stark Publications for gene: RARB were set to
Fetal anomalies v0.4488 RARS2 Zornitza Stark Marked gene: RARS2 as ready
Fetal anomalies v0.4488 RARS2 Zornitza Stark Gene: rars2 has been classified as Green List (High Evidence).
Fetal anomalies v0.4488 RARS2 Zornitza Stark Phenotypes for gene: RARS2 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 6 to Pontocerebellar hypoplasia, type 6, MIM# 611523
Fetal anomalies v0.4487 RARS2 Zornitza Stark Publications for gene: RARS2 were set to 26083569
Fetal anomalies v0.4486 RARS2 Zornitza Stark changed review comment from: Progressive microcephaly is part of the phenotype. At least three unrelated families reported.; to: Progressive microcephaly, PCH. At least three unrelated families reported.
Fetal anomalies v0.4486 RASA1 Zornitza Stark Marked gene: RASA1 as ready
Fetal anomalies v0.4486 RASA1 Zornitza Stark Phenotypes for gene: RASA1 were changed from PARKES WEBER SYNDROME; CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION to Capillary malformation-arteriovenous malformation 1, MIM# 608354
Fetal anomalies v0.4483 RASA1 Zornitza Stark changed review comment from: Single individual reported as part of a cohort.
Sources: Literature; to: AV malformations/fistulas, which can be large.
Sources: Literature
Fetal anomalies v0.4483 RASA1 Zornitza Stark edited their review of gene: RASA1: Changed rating: GREEN; Changed phenotypes: Capillary malformation-arteriovenous malformation 1, MIM# 608354
Fetal anomalies v0.4483 RAX Zornitza Stark Marked gene: RAX as ready
Fetal anomalies v0.4481 RBM8A Zornitza Stark Marked gene: RBM8A as ready
Fetal anomalies v0.4480 RBPJ Zornitza Stark Marked gene: RBPJ as ready
Fetal anomalies v0.4478 RECQL4 Zornitza Stark Marked gene: RECQL4 as ready
Fetal anomalies v0.4478 MCM7 Krithika Murali gene: MCM7 was added
gene: MCM7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MCM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM7 were set to 33654309; 34059554
Phenotypes for gene: MCM7 were set to Meier-Gorlin syndrome; Microcephaly; Intellectual disability; Lipodystrophy; Adrenal insufficiency
Review for gene: MCM7 was set to AMBER
Added comment: Association with congenital microcephaly. No new publications since last PanelApp review

---

MCM7 is a component of the MCM complex, a DNA helicase which is essential for DNA replication. Other components have been linked to disease with phenotypes including microcephaly and ID. MCM7 is not associated with any phenotype in OMIM or G2P at present. ------ Currently there are 3 unrelated pedigrees in literature with different biallelic MCM7 variants associated with disease (see below). Although there is some functional data in support of variant-level deleteriousness or gene-level pathogenicity, the clinical gestalt is very different between the 3 families.

- PMID: 33654309 (2021) - Two unrelated individuals with different compound het variants in MCM7 but disparate clinical features. One patient had typical Meier-Gorlin syndrome (including growth retardation, microcephaly, congenital lung emphysema, absent breast development, microtia, facial dysmorphism) whereas the second case had a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. While small at birth, the second patient did not demonstrate reduced stature or microcephaly at age 14.5 years. Both individuals had normal neurodevelopment. Functional studies using patient-derived fibroblasts demonstrate that the identified MCM7 variants were deleterious at either transcript or protein levels and through interfering with MCM complex formation, impact efficiency of S phase progression.

- PMID: 34059554 (2021) - Homozygous missense variant identified in three affected individuals from a consanguineous family with severe primary microcephaly, severe ID and behavioural abnormalities. Knockdown of Mcm7 in mouse neuroblastoma cells lead to reduced cell viability and proliferation with increased apoptosis, which were rescued by overexpression of wild-type but not mutant MCM7.
Sources: Literature
Fetal anomalies v0.4478 LMNB2 Krithika Murali gene: LMNB2 was added
gene: LMNB2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: LMNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMNB2 were set to 33033404
Phenotypes for gene: LMNB2 were set to Microcephaly 27, primary, autosomal dominant - MIM#619180
Review for gene: LMNB2 was set to GREEN
Added comment: Almost all reported individuals had congenital microcephaly.
Sources: Literature
Fetal anomalies v0.4478 LMNB1 Krithika Murali gene: LMNB1 was added
gene: LMNB1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMNB1 were set to 32910914
Phenotypes for gene: LMNB1 were set to Microcephaly 26, primary, autosomal dominant - MIM#619179
Review for gene: LMNB1 was set to GREEN
Added comment: Monoallelic variants associated with profound microcephaly - this was noted antenatally in 5 unrelated individuals (total of 8 individuals from 5 families reported)
Sources: Literature
Fetal anomalies v0.4478 LINGO1 Krithika Murali gene: LINGO1 was added
gene: LINGO1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: LINGO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LINGO1 were set to 28837161; 31668702
Phenotypes for gene: LINGO1 were set to Mental retardation, autosomal recessive 64 - MIM#618103
Review for gene: LINGO1 was set to AMBER
Added comment: 5 individuals reported from 2 families. 4 out of the 5 individuals had microcephaly. ID, developmentatl delay, spasticity, hypertonia, feeding problems also reported features. No antenatal information or birth growth parameters provided, but it is possible that microcephaly was antenatal/congenital in onset based on other phenotypic features reported.
Sources: Literature
Fetal anomalies v0.4478 KIF21B Krithika Murali gene: KIF21B was added
gene: KIF21B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: KIF21B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF21B were set to 32415109
Phenotypes for gene: KIF21B were set to Global developmental delay; Intellectual disability; Abnormality of brain morphology; Microcephaly
Review for gene: KIF21B was set to GREEN
Added comment: Monoallelic variants associated with a neurodevelopmental disorder. Phenotypic features include ID, corpus callosum anomalies and microcephaly. PMID 32415109 report 4 unrelated individuals, 2 had IUGR +/- oligohydramnios.
Sources: Literature
Fetal anomalies v0.4478 PSAP Seb Lunke Marked gene: PSAP as ready
Fetal anomalies v0.4476 PTCH1 Seb Lunke Marked gene: PTCH1 as ready
Fetal anomalies v0.4473 PTPN11 Seb Lunke Marked gene: PTPN11 as ready
Fetal anomalies v0.4473 PTPN11 Seb Lunke Phenotypes for gene: PTPN11 were changed from LEOPARD SYNDROME TYPE 1; NOONAN SYNDROME 1 to LEOPARD syndrome 1, AD, MIM#151100 AD; Noonan syndrome 1, AD, MIM#163950
Fetal anomalies v0.4470 PUF60 Seb Lunke Marked gene: PUF60 as ready
Fetal anomalies v0.4466 RERE Seb Lunke Marked gene: RERE as ready
Fetal anomalies v0.4466 RERE Seb Lunke Phenotypes for gene: RERE were changed from Phenocopy of Proximal 1p36 Deletions to Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart, MIM# 616975
Fetal anomalies v0.4463 RET Zornitza Stark Marked gene: RET as ready
Fetal anomalies v0.4461 SNORD118 Zornitza Stark Marked gene: SNORD118 as ready
Fetal anomalies v0.4459 SNORD118 Zornitza Stark changed review comment from: Many reported individuals have ID; however overall this is a progressive neurological disorder with variable onset, including in late adulthood.; to: Variable onset, including in infancy with brain abnormalities detectable by imaging.
Fetal anomalies v0.4459 RET Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: Megacolon is a feature.
Fetal anomalies v0.4459 RFX6 Zornitza Stark Marked gene: RFX6 as ready
Fetal anomalies v0.4459 RFX6 Zornitza Stark Phenotypes for gene: RFX6 were changed from MARTINEZ-FRIAS SYNDROME to Mitchell-Riley syndrome, MIM#615710
Fetal anomalies v0.4457 RFX6 Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: Intestinal atresia.
Fetal anomalies v0.4457 RIPK4 Zornitza Stark Marked gene: RIPK4 as ready
Fetal anomalies v0.4457 RIPK4 Zornitza Stark Phenotypes for gene: RIPK4 were changed from POPLITEAL PTERYGIUM SYNDROME, LETHAL TYPE to Popliteal pterygium syndrome, Bartsocas-Papas type, MIM# 263650
Fetal anomalies v0.4455 RIT1 Zornitza Stark Marked gene: RIT1 as ready
Fetal anomalies v0.4453 RIT1 Zornitza Stark Mode of pathogenicity for gene: RIT1 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.4453 RIT1 Zornitza Stark Mode of pathogenicity for gene: RIT1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.4451 RMRP Zornitza Stark Marked gene: RMRP as ready
Fetal anomalies v0.4451 RMRP Zornitza Stark Phenotypes for gene: RMRP were changed from CARTILAGE-HAIR HYPOPLASIA to Anauxetic dysplasia 1, MIM#607095
Fetal anomalies v0.4450 RMRP Zornitza Stark changed review comment from: Affected individuals are described as having mild ID; note gene is associated with two milder phenotypes, cartilage-hair hypoplasia and metaphyseal dysplasia without hypotrichosis, which are not associated with ID.; to: Skeletal abnormalities; note gene is associated with two milder phenotypes, cartilage-hair hypoplasia and metaphyseal dysplasia without hypotrichosis, which are more subtle.
Fetal anomalies v0.4450 RNU4ATAC Zornitza Stark changed review comment from: ID is reported as part of the phenotype. NOTE this gene codes for snRNA, not protein.; to: IUGR. NOTE this gene codes for snRNA, not protein.
Fetal anomalies v0.4450 RNU4ATAC Zornitza Stark Marked gene: RNU4ATAC as ready
Fetal anomalies v0.4450 RNU4ATAC Zornitza Stark Phenotypes for gene: RNU4ATAC were changed from MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE I to Microcephalic osteodysplastic primordial dwarfism, type I, MIM#210710; Roifman syndrome, MIM#616651
Fetal anomalies v0.4448 ROBO1 Zornitza Stark Marked gene: ROBO1 as ready
Fetal anomalies v0.4448 ROBO1 Zornitza Stark Phenotypes for gene: ROBO1 were changed from Tetralogy of Fallot and septal defects to Tetralogy of Fallot and septal defects; Congenital heart disease, MONDO:0005453
Fetal anomalies v0.4445 ROGDI Zornitza Stark Marked gene: ROGDI as ready
Fetal anomalies v0.4443 ROGDI Zornitza Stark changed review comment from: Kohlschutter-Tonz syndrome (KTZS) is an autosomal recessive disorder characterized by severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting both primary and secondary teeth and causing yellow or brown discolouration of the teeth. More than 10 families reported.; to: Kohlschutter-Tonz syndrome (KTZS) is an autosomal recessive disorder characterized by severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting both primary and secondary teeth and causing yellow or brown discolouration of the teeth. More than 10 families reported.

Cerebellar hypoplasia and ventriculomegaly described.
Fetal anomalies v0.4443 RPGRIP1L Zornitza Stark Marked gene: RPGRIP1L as ready
Fetal anomalies v0.4441 RPL11 Zornitza Stark Marked gene: RPL11 as ready
Fetal anomalies v0.4438 RPL5 Zornitza Stark Marked gene: RPL5 as ready
Fetal anomalies v0.4435 RPS10 Zornitza Stark Marked gene: RPS10 as ready
Fetal anomalies v0.4433 RPS17 Zornitza Stark Marked gene: RPS17 as ready
Fetal anomalies v0.4430 RPS19 Zornitza Stark Marked gene: RPS19 as ready
Fetal anomalies v0.4427 RPS26 Zornitza Stark Marked gene: RPS26 as ready
Fetal anomalies v0.4424 RTTN Zornitza Stark Marked gene: RTTN as ready
Fetal anomalies v0.4424 RTTN Zornitza Stark Phenotypes for gene: RTTN were changed from BILATERAL DIFFUSE POLYMICROGYRIA to Microcephaly, short stature, and polymicrogyria with seizures, MIM# 614833; Microcephalic primordial dwarfism due to RTTN deficiency MONDO:0018764
Fetal anomalies v0.4422 RYR1 Zornitza Stark Marked gene: RYR1 as ready
Fetal anomalies v0.4420 SALL1 Zornitza Stark Marked gene: SALL1 as ready
Fetal anomalies v0.4418 SALL4 Zornitza Stark Marked gene: SALL4 as ready
Fetal anomalies v0.4418 SALL4 Zornitza Stark Phenotypes for gene: SALL4 were changed from ACRO-RENAL-OCULAR SYNDROME; DUANE-RADIAL RAY SYNDROME to Duane-radial ray syndrome, MIM# 607323; MONDO:0011812; IVIC syndrome, MIM# 147750; MONDO:0007836
Fetal anomalies v0.4416 SATB2 Zornitza Stark Marked gene: SATB2 as ready
Fetal anomalies v0.4413 SBDS Zornitza Stark Marked gene: SBDS as ready
Fetal anomalies v0.4411 SBDS Zornitza Stark changed review comment from: Some cognitive involvement but ID rare, see reference.; to: Multiple skeletal abnormalities.
Fetal anomalies v0.4411 SCARF2 Zornitza Stark Marked gene: SCARF2 as ready
Fetal anomalies v0.4411 SCARF2 Zornitza Stark Gene: scarf2 has been classified as Green List (High Evidence).
Fetal anomalies v0.4411 SCARF2 Zornitza Stark Phenotypes for gene: SCARF2 were changed from VAN DEN ENDE-GUPTA SYNDROME to Van den Ende-Gupta syndrome, MIM# 600920
Fetal anomalies v0.4410 SCARF2 Zornitza Stark Publications for gene: SCARF2 were set to
Fetal anomalies v0.4409 SDCCAG8 Zornitza Stark Marked gene: SDCCAG8 as ready
Fetal anomalies v0.4409 SDCCAG8 Zornitza Stark Phenotypes for gene: SDCCAG8 were changed from SENIOR-LOKEN SYNDROME 7 to Bardet-Biedl syndrome 16, MIM# 615993; MONDO:0014444; Senior-Loken syndrome 7, MIM# 613615; MONDO:0013326; Nephronophthisis
Fetal anomalies v0.4407 SEC23B Zornitza Stark Marked gene: SEC23B as ready
Fetal anomalies v0.4404 SEMA3A Zornitza Stark Marked gene: SEMA3A as ready
Fetal anomalies v0.4404 TBC1D7 Krithika Murali gene: TBC1D7 was added
gene: TBC1D7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TBC1D7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D7 were set to 23687350; 24515783
Phenotypes for gene: TBC1D7 were set to Macrocephaly/megalencephaly syndrome, autosomal recessive - MIM#248000
Review for gene: TBC1D7 was set to AMBER
Added comment: PMID: 24515783 report 2 siblings with biallelic variants. One noted to be macrosomic at birth and parents reported macrocephaly.

PMID: 23687350 report 2 affected siblings. One was noted to be macrocephalic at birth.
Sources: Literature
Fetal anomalies v0.4404 TAOK1 Krithika Murali gene: TAOK1 was added
gene: TAOK1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TAOK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAOK1 were set to 35091509; 31230721; 33565190
Phenotypes for gene: TAOK1 were set to Developmental delay with or without intellectual impairment or behavioral abnormalities - MIM#619575
Review for gene: TAOK1 was set to GREEN
Added comment: Heterozygous TAOK1 variants associated with developmental delay

PMID 35091509 - complication of polyhydramnios noted in 2 pregnancies in unrelated families

PMID 33565190:
- 1 patient with ventriculomegaly detected 28 week USS and polyhydramnios with secondary complication of multi-suture craniosynostosis
- 1 infant with low birth weight.
- 1 individual - antenatal history includes polyhydramnios at 5 months gestation

PMID 31230721 - report one individual noted to be macrocephalic at birth with cleft palate
Sources: Literature
Fetal anomalies v0.4404 STT3A Krithika Murali gene: STT3A was added
gene: STT3A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: STT3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: STT3A were set to 34653363; 23842455; 30701557; 28424003
Phenotypes for gene: STT3A were set to Congenital disorder of glycosylation, type Iw, autosomal dominant - MIM#619714; Congenital disorder of glycosylation, type Iw, autosomal recessive - MIM#615596
Review for gene: STT3A was set to GREEN
Added comment: Biallelic variants associated with an earlier onset of symptoms. PMID: 23842455 report IUGR in one infant. PMID: 28424003 - report 5 affected individuals from one family, birth growth parameters of 4/5 individuals suggestive of growth restriction/relative microcephaly.
---
ID/DD reported in all cases (at least 7 individuals from 3 unrelated families, with 2 different homozygous variants in STT3A)

PMID: 34653363 - 16 patients from 9 families with new AD mode of inheritance (both de novo and inherited). All variants were missense within/around acritical active/catalytic sites. Patients aged 3-55yo, with children noted to be "healthy" until reaching young adulthood
Clinical features include dysmorphic features, macrocephaly (6/16), mild-moderate ID/DD (10/16), short stature (8/16), skeletal abnormalities (10/16), muscle cramps (7/16).
Functional studies verifies AR disease is caused by LOF variants, whereas the AD variants cause DN proven by cotransfection in WT yeast resulting in impaired glycosylation (protein levels unchanged).
Sources: Literature
Fetal anomalies v0.4404 RHEB Krithika Murali gene: RHEB was added
gene: RHEB was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RHEB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RHEB were set to 29051493; 31337748
Phenotypes for gene: RHEB were set to Intellectual disability; Macrocephaly; Focal cortical dysplasia
Review for gene: RHEB was set to GREEN
Added comment: No new publications since last PanelApp review. Reviewed PMID: 29051493 supplementary information - three individuals with short stature and macrocephaly. Limited antenatal information provided/birth HC parameters, but one of the affected individuals was noted to have a large head circumference from 20 weeks gestation. PMID 31337748: Somatic variant in this gene found in one individual with focal cortical dysplasia.

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3 individuals from two families with heterozygous RHEB variants. Two siblings carried the c.110 C > T (p.Pro37Leu) variant, and a sporadic individual carried the c.202 T>C (p.Ser68Pro) allele. All 3 individuals had short stature (−2 to −3 SD) and early brain overgrowth with pronounced macrocephaly during childhood (+2.5/+3 SD). They had severe to profound ID with hypotonia, as well as autism spectrum disorder. 2 of 3 individuals were reported to have epilepsy. In a zebrafish model, overexpression of RHEB produced megalencephaly, supporting a hyperactivating effect. This is supported in mice where loss of RHEB activity does not cause an overt neurological phenotype
Single individual with somatic variants in this gene and focal cortical dysplasia also reported.
Sources: Literature
Fetal anomalies v0.4404 SEPSECS Zornitza Stark Marked gene: SEPSECS as ready
Fetal anomalies v0.4404 SEPSECS Zornitza Stark Phenotypes for gene: SEPSECS were changed from Pontocerebellar hypoplasia type 2D to Pontocerebellar hypoplasia type 2D, MIM#613811
Fetal anomalies v0.4402 SETD5 Zornitza Stark Marked gene: SETD5 as ready
Fetal anomalies v0.4402 SETD5 Zornitza Stark Phenotypes for gene: SETD5 were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT 23 to Intellectual disability, autosomal dominant 23 (MIM # 615761)
Fetal anomalies v0.4400 SHH Zornitza Stark Marked gene: SHH as ready
Fetal anomalies v0.4400 SHH Zornitza Stark Phenotypes for gene: SHH were changed from MICROPHTHALMIA ISOLATED WITH COLOBOMA TYPE 5; TRIPHALANGEAL THUMB-POLYSYNDACTYLY SYNDROME; HOLOPROSENCEPHALY TYPE 3; SOLITARY MEDIAN MAXILLARY CENTRAL INCISOR to 1. Holoprosencephaly 3 (MIM#142945), AD; 2. Microphthalmia with coloboma 5 (MIM#611638), AD; 3. Schizencephaly (MIM#269160); 4. Single median maxillary central incisor (MIM#147250) AD
Fetal anomalies v0.4397 SHOC2 Zornitza Stark Marked gene: SHOC2 as ready
Fetal anomalies v0.4395 SHOC2 Zornitza Stark Mode of pathogenicity for gene: SHOC2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.4393 SHOX Zornitza Stark Marked gene: SHOX as ready
Fetal anomalies v0.4392 PPP2R5C Krithika Murali gene: PPP2R5C was added
gene: PPP2R5C was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PPP2R5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP2R5C were set to 25972378
Phenotypes for gene: PPP2R5C were set to macrocephaly; overgrowth
Review for gene: PPP2R5C was set to AMBER
Added comment: x1 case only in the literature with relative macrocephaly noted at birth.

PMID: 25972378 - Loveday et al 2015 undertook trio exome sequencing in children with an overgrowth syndrome phenotype with unaffected parents. One individual with a de novo PPP2R5C c.468_470delAAC p.Thr157del variant identified. The proband had moderate ID, was born at 37 weeks gestation weighing 3100g (0.8SD) with a head circumference of 36cm (2.4SD).
Sources: Literature
Fetal anomalies v0.4392 SIL1 Zornitza Stark Marked gene: SIL1 as ready
Fetal anomalies v0.4391 SIL1 Zornitza Stark reviewed gene: SIL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Marinesco-Sjogren syndrome (MIM#248800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.4389 SIX3 Zornitza Stark Marked gene: SIX3 as ready
Fetal anomalies v0.4386 SLC10A7 Zornitza Stark Marked gene: SLC10A7 as ready
Fetal anomalies v0.4384 SLC12A1 Zornitza Stark Marked gene: SLC12A1 as ready
Fetal anomalies v0.4384 SLC12A1 Zornitza Stark Phenotypes for gene: SLC12A1 were changed from Bartter syndrome, type 1 601678 to Bartter syndrome, type 1, MIM#601678
Fetal anomalies v0.4383 SLC13A5 Zornitza Stark Marked gene: SLC13A5 as ready
Fetal anomalies v0.4381 SLC16A2 Zornitza Stark Marked gene: SLC16A2 as ready
Fetal anomalies v0.4378 SLC2A10 Zornitza Stark Marked gene: SLC2A10 as ready
Fetal anomalies v0.4378 SLC2A10 Zornitza Stark Phenotypes for gene: SLC2A10 were changed from ARTERIAL TORTUOSITY SYNDROME to Arterial tortuosity syndrome, MIM# 208050
Fetal anomalies v0.4377 SLC2A10 Zornitza Stark reviewed gene: SLC2A10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Arterial tortuosity syndrome, MIM# 208050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.4377 SLC35A2 Zornitza Stark Marked gene: SLC35A2 as ready
Fetal anomalies v0.4375 SLC35C1 Zornitza Stark Marked gene: SLC35C1 as ready
Fetal anomalies v0.4372 SLC35C1 Zornitza Stark changed review comment from: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe DD/ID, mild dysmorphism, and impaired neutrophil motility. More than 5 unrelated families reported, note immune dysfunction is not always present.

Microcephaly is a feature.; to: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe DD/ID, mild dysmorphism, and impaired neutrophil motility. More than 5 unrelated families reported, note immune dysfunction is not always present.

Microcephaly is a feature. Variable severity, some present in childhood.
Fetal anomalies v0.4372 SLC35C1 Zornitza Stark changed review comment from: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe DD/ID, mild dysmorphism, and impaired neutrophil motility. More than 5 unrelated families reported, note immune dysfunction is not always present.; to: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe DD/ID, mild dysmorphism, and impaired neutrophil motility. More than 5 unrelated families reported, note immune dysfunction is not always present.

Microcephaly is a feature.
Fetal anomalies v0.4372 SLC35D1 Zornitza Stark Marked gene: SLC35D1 as ready
Fetal anomalies v0.4370 SLC39A8 Zornitza Stark Marked gene: SLC39A8 as ready
Fetal anomalies v0.4370 SLC39A8 Zornitza Stark Phenotypes for gene: SLC39A8 were changed from Intellectual Disability with Cerebellar Atrophy to Congenital disorder of glycosylation, type IIn , MIM#16721
Fetal anomalies v0.4368 SLX4 Zornitza Stark Marked gene: SLX4 as ready
Fetal anomalies v0.4367 SMARCA2 Zornitza Stark Marked gene: SMARCA2 as ready
Fetal anomalies v0.4367 SMARCA2 Zornitza Stark Gene: smarca2 has been classified as Green List (High Evidence).
Fetal anomalies v0.4367 SMARCA2 Zornitza Stark Phenotypes for gene: SMARCA2 were changed from COFFIN SIRIS; NICOLAIDES-BARAITSER SYNDROME to Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome
Fetal anomalies v0.4366 SMARCA2 Zornitza Stark Publications for gene: SMARCA2 were set to
Fetal anomalies v0.4365 SMARCA2 Zornitza Stark Mode of pathogenicity for gene: SMARCA2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.4364 SMARCA2 Zornitza Stark Mode of inheritance for gene: SMARCA2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.4363 SMARCA4 Zornitza Stark Marked gene: SMARCA4 as ready
Fetal anomalies v0.4363 SMARCA4 Zornitza Stark Gene: smarca4 has been classified as Green List (High Evidence).
Fetal anomalies v0.4363 SMARCA4 Zornitza Stark Phenotypes for gene: SMARCA4 were changed from COFFIN SIRIS; RHABDOID TUMOR PREDISPOSITION SYNDROME 2 to Coffin-Siris syndrome 4, MIM# 614609
Fetal anomalies v0.4362 SMARCA4 Zornitza Stark Publications for gene: SMARCA4 were set to
Fetal anomalies v0.4361 SMARCA4 Zornitza Stark Mode of inheritance for gene: SMARCA4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.4360 SMARCA4 Zornitza Stark changed review comment from: Single individual reported as part of a CDH cohort.
Sources: Literature; to: IUGR and multiple congenital anomalies.
Sources: Literature
Fetal anomalies v0.4360 SMARCA4 Zornitza Stark edited their review of gene: SMARCA4: Changed rating: GREEN; Changed phenotypes: Coffin-Siris syndrome 4, MIM# 614609
Fetal anomalies v0.4360 SMC1A Zornitza Stark Marked gene: SMC1A as ready
Fetal anomalies v0.4359 SMC1A Zornitza Stark changed review comment from: CDH is a feature of CdL, but cannot find a report specifically with SMC1A variant.; to: Multiple congenital anomalies syndrome.
Fetal anomalies v0.4359 SMC3 Zornitza Stark Marked gene: SMC3 as ready
Fetal anomalies v0.4357 SMC3 Zornitza Stark changed review comment from: CDH is a feature of CdL but cannot find specific reports of SMC3 variants.; to: Multiple congenital anomalies syndrome.
Fetal anomalies v0.4357 SMN1 Zornitza Stark Marked gene: SMN1 as ready
Fetal anomalies v0.4357 SMN1 Zornitza Stark Phenotypes for gene: SMN1 were changed from Spinal muscular atrophy 253400; Spinal muscular atrophy 271150; Spinal muscular atrophy 253550; Spinal muscular atrophy 253300 to Spinal muscular atrophy 253400; Spinal muscular atrophy 271150; Spinal muscular atrophy 253550; Spinal muscular atrophy 253300
Fetal anomalies v0.4356 SMO Zornitza Stark Marked gene: SMO as ready
Fetal anomalies v0.4355 SMO Zornitza Stark edited their review of gene: SMO: Added comment: Bi-allelic loss-of-function variations in SMO reported in seven individuals from five independent families. Wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis).
Somatic recurrent missense variant, L412F causes Curry-Jones syndrome.; Changed publications: 32413283, 27236920; Changed phenotypes: Microcephaly, congenital heart disease, polydactyly, aganglionosis, Pallister-Hall-like syndrome, MIM# 241800; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.4353 SMO Zornitza Stark Mode of pathogenicity for gene: SMO was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.4351 SMOC1 Zornitza Stark Marked gene: SMOC1 as ready
Fetal anomalies v0.4349 SMPD1 Zornitza Stark Marked gene: SMPD1 as ready
Fetal anomalies v0.4347 ZNHIT3 Zornitza Stark Marked gene: ZNHIT3 as ready
Fetal anomalies v0.4347 ZNF668 Zornitza Stark Marked gene: ZNF668 as ready
Fetal anomalies v0.4346 PIDD1 Zornitza Stark Marked gene: PIDD1 as ready
Fetal anomalies v0.4345 ZNF526 Zornitza Stark Marked gene: ZNF526 as ready
Fetal anomalies v0.4345 YRDC Zornitza Stark Marked gene: YRDC as ready
Fetal anomalies v0.4344 NFIB Zornitza Stark Marked gene: NFIB as ready
Fetal anomalies v0.4343 YIF1B Zornitza Stark Marked gene: YIF1B as ready
Fetal anomalies v0.4343 YIPF5 Zornitza Stark Marked gene: YIPF5 as ready
Fetal anomalies v0.4343 WDR4 Zornitza Stark Marked gene: WDR4 as ready
Fetal anomalies v0.4343 WDR37 Zornitza Stark Marked gene: WDR37 as ready
Fetal anomalies v0.4343 VPS51 Zornitza Stark Marked gene: VPS51 as ready
Fetal anomalies v0.4343 VPS50 Zornitza Stark Marked gene: VPS50 as ready
Fetal anomalies v0.4343 VPS4A Zornitza Stark Marked gene: VPS4A as ready
Fetal anomalies v0.4343 TUBGCP2 Zornitza Stark Marked gene: TUBGCP2 as ready
Fetal anomalies v0.4343 HEXB Zornitza Stark Marked gene: HEXB as ready
Fetal anomalies v0.4342 GTPBP2 Zornitza Stark Marked gene: GTPBP2 as ready
Fetal anomalies v0.4341 MCF2 Zornitza Stark Marked gene: MCF2 as ready
Fetal anomalies v0.4340 MAN2C1 Zornitza Stark Marked gene: MAN2C1 as ready
Fetal anomalies v0.4339 INTS8 Zornitza Stark Marked gene: INTS8 as ready
Fetal anomalies v0.4338 GRM7 Zornitza Stark Marked gene: GRM7 as ready
Fetal anomalies v0.4337 ERMARD Zornitza Stark Marked gene: ERMARD as ready
Fetal anomalies v0.4337 ERMARD Zornitza Stark Gene: ermard has been classified as Red List (Low Evidence).
Fetal anomalies v0.4337 ERMARD Zornitza Stark Classified gene: ERMARD as Red List (low evidence)
Fetal anomalies v0.4337 ERMARD Zornitza Stark Gene: ermard has been classified as Red List (Low Evidence).
Fetal anomalies v0.4336 GPT2 Zornitza Stark Marked gene: GPT2 as ready
Fetal anomalies v0.4335 GON7 Zornitza Stark Marked gene: GON7 as ready
Fetal anomalies v0.4334 EOMES Zornitza Stark Marked gene: EOMES as ready
Fetal anomalies v0.4333 GOLGA2 Zornitza Stark Marked gene: GOLGA2 as ready
Fetal anomalies v0.4333 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from to neuromuscular disease, GOLGA2-related MONDO#0019056
Fetal anomalies v0.4331 GOLGA2 Zornitza Stark reviewed gene: GOLGA2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: neuromuscular disease, GOLGA2-related MONDO#0019056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.4331 ENO1 Zornitza Stark Marked gene: ENO1 as ready
Fetal anomalies v0.4330 CEP85L Zornitza Stark Marked gene: CEP85L as ready
Fetal anomalies v0.4329 HEXA Zornitza Stark Marked gene: HEXA as ready
Fetal anomalies v0.4328 FOXR1 Zornitza Stark Marked gene: FOXR1 as ready
Fetal anomalies v0.4327 HERC1 Zornitza Stark Marked gene: HERC1 as ready
Fetal anomalies v0.4326 FDXR Zornitza Stark Marked gene: FDXR as ready
Fetal anomalies v0.4325 CDK5 Zornitza Stark Marked gene: CDK5 as ready
Fetal anomalies v0.4324 EXOC7 Zornitza Stark Marked gene: EXOC7 as ready
Fetal anomalies v0.4322 DYNC1I2 Zornitza Stark Marked gene: DYNC1I2 as ready
Fetal anomalies v0.4321 FIBP Zornitza Stark Marked gene: FIBP as ready
Fetal anomalies v0.4320 B3GNT2 Zornitza Stark Marked gene: B3GNT2 as ready
Fetal anomalies v0.4319 CTNNA2 Zornitza Stark Marked gene: CTNNA2 as ready
Fetal anomalies v0.4317 DICER1 Zornitza Stark Marked gene: DICER1 as ready
Fetal anomalies v0.4317 TUBGCP2 Chirag Patel gene: TUBGCP2 was added
gene: TUBGCP2 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to PMID: 31630790
Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, OMIM # 618737
Review for gene: TUBGCP2 was set to GREEN
Added comment: Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures (PAMDDFS) is an autosomal recessive neurologic disorder characterized by progressive microcephaly associated with abnormal facial features, hypotonia, and variable global developmental delay with impaired intellectual development. Brain imaging shows variable malformation of cortical development on the lissencephaly spectrum, mainly pachygyria and thin corpus callosum.

4 unrelated patients with homozygous or compound heterozygous mutations in the TUBGCP2 gene, found by WES and segregated with the disorder in all families. Functional studies of the variants were not performed, but analysis of patient fibroblasts derived from the patient with a splice site mutation demonstrated the production of several abnormal transcripts that were predicted to result in a loss of function.
Sources: Expert list
Fetal anomalies v0.4315 COPB2 Zornitza Stark Marked gene: COPB2 as ready
Fetal anomalies v0.4314 ARF1 Zornitza Stark Marked gene: ARF1 as ready
Fetal anomalies v0.4314 ARF1 Zornitza Stark Gene: arf1 has been classified as Green List (High Evidence).
Fetal anomalies v0.4314 ARF1 Zornitza Stark Classified gene: ARF1 as Green List (high evidence)
Fetal anomalies v0.4314 ARF1 Zornitza Stark Gene: arf1 has been classified as Green List (High Evidence).
Fetal anomalies v0.4313 ARF1 Zornitza Stark reviewed gene: ARF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Periventricular nodular heterotopia 8 (MIM#618185); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.4313 ATXN2L Zornitza Stark Marked gene: ATXN2L as ready
Fetal anomalies v0.4311 COPB1 Zornitza Stark Marked gene: COPB1 as ready
Fetal anomalies v0.4311 VPS4A Chirag Patel gene: VPS4A was added
gene: VPS4A was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS4A were set to PMID: 33186543; 33186545
Phenotypes for gene: VPS4A were set to CIMDAG syndrome MIM# 619273
Review for gene: VPS4A was set to GREEN
Added comment: CIMDAG syndrome is a multisystemic disorder characterized by severely impaired psychomotor development and hematologic abnormalities apparent from early infancy. Affected individuals show poor overall growth with microcephaly, impaired intellectual development, poor or absent speech, poor eye contact, and motor problems, such as inability to walk, hypotonia, and spasticity. Brain imaging typically shows cerebral and cerebellar atrophy, thin corpus callosum, and delayed myelination. The associated hematologic abnormalities are variable, but are mostly consistent with congenital dyserythropoietic anemia. Eight unrelated patients with de novo heterozygous missense mutations in the VPS4A gene.
Sources: Expert list
Fetal anomalies v0.4310 CHKA Zornitza Stark Marked gene: CHKA as ready
Fetal anomalies v0.4309 CENPE Zornitza Stark Marked gene: CENPE as ready
Fetal anomalies v0.4308 CDK6 Zornitza Stark Marked gene: CDK6 as ready
Fetal anomalies v0.4307 CCDC88A Zornitza Stark Marked gene: CCDC88A as ready
Fetal anomalies v0.4305 VPS50 Chirag Patel gene: VPS50 was added
gene: VPS50 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to PMID: 34037727
Phenotypes for gene: VPS50 were set to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis , MIM#619685
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants. Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging. Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)). VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor. As discussed by Schneeberger et al (refs provided in text): - VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development. - Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality. Studies performed by Schneeberger et al included: - Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del). - Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels. - Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts. - Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function. As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders". There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.
Sources: Expert list
Fetal anomalies v0.4303 VPS51 Chirag Patel gene: VPS51 was added
gene: VPS51 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: VPS51 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS51 were set to PMID: 30624672; 31207318
Phenotypes for gene: VPS51 were set to Pontocerebellar hypoplasia, type 13, MIM# 618606
Review for gene: VPS51 was set to AMBER
Added comment: Pontocerebellar hypoplasia type 13 (PCH13) is an autosomal recessive disorder characterized by global developmental delay, impaired intellectual development with absent speech, microcephaly, and progressive atrophy of the cerebellar vermis and brainstem. Additional features, including seizures and visual impairment. Two families reported with bi-allelic variants in this gene.
Sources: Expert list
Fetal anomalies v0.4301 WDR37 Chirag Patel gene: WDR37 was added
gene: WDR37 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR37 were set to PMID: 31327508, 31327510
Phenotypes for gene: WDR37 were set to Neurooculocardiogenitourinary syndrome MIM#618652
Review for gene: WDR37 was set to GREEN
Added comment: Neurooculocardiogenitourinary syndrome (NOCGUS) is a multisystem disorder characterized by poor growth and anomalies of the ocular, craniofacial, neurologic, cardiovascular, genitourinary, skeletal, and gastrointestinal systems. Lethality before 2 years of age has been observed. Nine unrelated patients reported with de novo missense mutations in the WDR37 gene.
Sources: Expert list
Fetal anomalies v0.4299 WDR4 Chirag Patel gene: WDR4 was added
gene: WDR4 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WDR4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR4 were set to PubMed: 26416026; 28617965
Phenotypes for gene: WDR4 were set to Microcephaly, growth deficiency, seizures, and brain malformations, OMIM # 618346
Review for gene: WDR4 was set to GREEN
Added comment: Microcephaly, growth deficiency, seizures, and brain malformations (MIGSB) is a severe autosomal recessive disorder characterized by intrauterine growth retardation, postnatal growth deficiency with severe microcephaly, and poor or absent psychomotor development. Additional features include optic atrophy, early-onset seizures, dysmorphic facial features, and brain malformations, such as partial agenesis of the corpus callosum and simplified gyration.

Biallelic variants in the WDR4 gene reported in 4 patients from 3 unrelated families. Studies of patient cells in one family and modeling of the corresponding mutation in yeast showed that the mutation caused a significant reduction in m(7)G46 methylation of specific tRNAs species, particularly at higher temperatures. This was associated with a growth defect in yeast, thus offering a potential mechanism for the growth defects observed in patients with the mutation. The findings suggested that abnormal tRNA modification is a major contributor to disease pathogenesis.
Sources: Literature
Fetal anomalies v0.4297 YIPF5 Chirag Patel gene: YIPF5 was added
gene: YIPF5 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to PMID: 33164986
Phenotypes for gene: YIPF5 were set to Microcephaly, epilepsy, and diabetes syndrome 2 , MIM#619278
Review for gene: YIPF5 was set to GREEN
Added comment: 6 patients from 5 consanguineous families who had microcephaly, epilepsy, and diabetes syndrome (MEDS). All had severe microcephaly (standard deviation of -6.2); epilepsy diagnosed at ages ranging from 1 to 7 months; and neonatal/early-onset diabetes. All patients had low birth weight consistent with reduced insulin secretion in utero.
Sources: Expert list
Fetal anomalies v0.4295 YIF1B Chirag Patel gene: YIF1B was added
gene: YIF1B was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to PMID: 32006098; 26077767
Phenotypes for gene: YIF1B were set to Kaya-Barakat-Masson syndrome, MIM# 619125
Review for gene: YIF1B was set to GREEN
Added comment: Kaya-Barakat-Masson syndrome (KABAMAS) is a severe autosomal recessive neurodevelopmental disorder characterized by profoundly impaired global development, peripheral spasticity, dystonia, impaired intellectual development with absent speech, poor eye contact, and feeding difficulties, resulting in poor overall growth, sometimes with microcephaly. Additional more variable features include early-onset seizures, ocular anomalies, foot deformities, and nonspecific brain imaging findings, such as thin corpus callosum and cerebral, cerebellar, or pontine atrophy. Some patients may die in infancy or early childhood.

6 individuals (from 5 families) with biallelic YIF1B truncating variants reported. Presenting features: hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3. Affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.
Sources: Expert list
Fetal anomalies v0.4294 NFIB Krithika Murali gene: NFIB was added
gene: NFIB was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NFIB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NFIB were set to 30388402; 33130023; 32902921
Phenotypes for gene: NFIB were set to Macrocephaly, acquired, with impaired intellectual development - MIM#618286
Review for gene: NFIB was set to GREEN
Added comment: NFIB haploinsufficiency associated with syndromic ID. Macrocephaly and corpus callosum anomalies are recurrent phenotypic features. OMIM notes macrocephaly postnatal in onset, but review of published cases shows some instances of relative macrocephaly at birth. Also corpus callosal anomalies - agenesis and dysgenesis, noted on MRI-B in childhood but possibility of detecting this antenatally in future cases. 2 unrelated individuals reported with minor cardiac anomalies also.

---

OMIM notes macrocephaly postnatal in onset. PMID: 30388402 - 18 individuals reported, of whom 11 had deletions of this gene and the rest had SNVs. Relative macrocephaly noted based on growth parameters in 4 individuals (e.g. x1 male with BW 22nd centile and HC 99th centile in an apparently uncomplicated pregnancy) - macrocephaly became more pronounced with age. In addition, 2 individuals had congenital cardiac anomalies (x1 small VSD and x1 narrow pulmonary artery) and 2 individuals had complete agenesis of the corpus callosum.

33130023 - Report one affected individual. Birth weight was 4.13 kg (Z-score 1.50, 93rd percentile), length was 52 cm (Z-score 1.12, 87th percentile) and his head circumference was 37 cm (Z-score 2.00, 98th percentile). MRI-B at 12 months confirmed agenesis of the corpus callosum

32902921 - report one patient with normal antenatal history, no birth HC provided, macrocephaly noted at 7 months. MRI-B showed mild dysgensis of the corpus callosum age 5. 2nd unrelated patient's birth weight 3.43 kg(57th centile,Zscore 0.17), length 52.8 cm (94th centile, Zscore1.54), and OFC 37.5 cm (99th centile,Zscore 2.39). MRI-B age 5 showed dysgenesis of the corpus callosum.
Sources: Literature
Fetal anomalies v0.4293 YRDC Chirag Patel gene: YRDC was added
gene: YRDC was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: YRDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YRDC were set to PMID: 31481669, 34545459
Phenotypes for gene: YRDC were set to Galloway-Mowat syndrome 10, OMIM # 619609
Review for gene: YRDC was set to GREEN
Added comment: Galloway-Mowat syndrome-10 (GAMOS10) is a severe autosomal recessive disorder characterized by onset of symptoms soon after birth. Affected individuals have progressive renal dysfunction with proteinuria associated with diffuse mesangial sclerosis (DMS) on renal biopsy. Other features include global developmental delay, microcephaly, hypothyroidism, arachnodactyly, and dysmorphic facial features. Some patients may have seizures or abnormalities on brain imaging. All reported patients have died in infancy.

4 individuals from 3 unrelated families with typical features of Galloway-Mowat syndrome including proteinuria, microcephaly, developmental delay and brain malformations. Supportive functional data.
Sources: Expert list
Fetal anomalies v0.4291 ZNF526 Chirag Patel gene: ZNF526 was added
gene: ZNF526 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: ZNF526 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF526 were set to PMID: 33397746, 21937992, 25558065,
Phenotypes for gene: ZNF526 were set to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Review for gene: ZNF526 was set to GREEN
Added comment: - PMID: 21937992 (2011) - Two unrelated families (with 4 affected individuals in each) with non-syndromic ID (mild or moderate, respectively) identified harbouring different biallelic missense variants in the ZNF526 gene.

- PMID: 25558065 (2015) - One family with ID, Noonan-like facies, pulmonary stenosis and a homozygous missense variant in this gene. No further details provided.

- PMID: 33397746 (2021) - Five individuals from four unrelated families with homozygous ZNF526 variants. Four harboured truncating variants, and were all affected by profound DD and severe ID, severe pre/postnatal microcephaly (ranging from -4 SD to -8 SD), bilateral progressive cataracts, hypertonic-dystonic movements, epilepsy and brain MRI anomalies. The fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe ID, and normal brain MRI. Zebrafish model demonstrated brain and eye malformations resembling findings seen in the human holoprosencephaly spectrum
Sources: Expert list
Fetal anomalies v0.4290 PIDD1 Daniel Flanagan gene: PIDD1 was added
gene: PIDD1 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010
Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum
Review for gene: PIDD1 was set to AMBER
Added comment: Doesn't appear to have an antenatal onset. Clinical findings in supplementary table for PMID: 34163010 doesn't mention any prenatal findings. For family M278, two affected siblings were "born at term after uneventful pregnancies, neonatal periods and normal development." Mean age of cohort was 13.2 years.

Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested.

The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families].

Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants.

Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder.

PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage.

There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation.

Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants.

Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26

Evidence so far provided includes:
- Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern.
- Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability.
- Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp]
- Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain.
- Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD.

Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects.
Sources: Expert list
Fetal anomalies v0.4289 ZNF668 Chirag Patel gene: ZNF668 was added
gene: ZNF668 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF668 were set to PMID: 34313816, 26633546
Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism
Review for gene: ZNF668 was set to AMBER
Added comment: 2 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts.
Sources: Expert list
Fetal anomalies v0.4287 ZNHIT3 Chirag Patel gene: ZNHIT3 was added
gene: ZNHIT3 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: ZNHIT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNHIT3 were set to PMID: 28335020; 28335020; 31048081
Phenotypes for gene: ZNHIT3 were set to PEHO syndrome, MIM# 260565
Review for gene: ZNHIT3 was set to GREEN
Added comment: PEHO is a severe autosomal recessive neurodevelopmental disorder characterized by extreme cerebellar atrophy due to almost total loss of granule neurons. Affected individuals present in early infancy with hypotonia, profoundly delayed psychomotor development, optic atrophy, progressive atrophy of the cerebellum and brainstem, and dysmyelination. Most patients also develop infantile seizures that are often associated with hypsarrhythmia on EEG, and many have peripheral oedema. More than 20 affected individuals reported of Finnish origin, p.Ser31Leu is a founder variant. One compound het reported and supportive animal model.
Sources: Expert list
Fetal anomalies v0.4286 APC2 Zornitza Stark Marked gene: APC2 as ready
Fetal anomalies v0.4285 C7orf43 Zornitza Stark Marked gene: C7orf43 as ready
Fetal anomalies v0.4284 ATRIP Zornitza Stark Marked gene: ATRIP as ready
Fetal anomalies v0.4283 ATP9A Zornitza Stark Marked gene: ATP9A as ready
Fetal anomalies v0.4282 ARPC4 Zornitza Stark Marked gene: ARPC4 as ready
Fetal anomalies v0.4282 ARPC4 Zornitza Stark Gene: arpc4 has been classified as Red List (Low Evidence).
Fetal anomalies v0.4282 ARPC4 Zornitza Stark Classified gene: ARPC4 as Red List (low evidence)
Fetal anomalies v0.4282 ARPC4 Zornitza Stark Gene: arpc4 has been classified as Red List (Low Evidence).
Fetal anomalies v0.4281 ANKLE2 Zornitza Stark Marked gene: ANKLE2 as ready
Fetal anomalies v0.4280 AGMO Zornitza Stark Marked gene: AGMO as ready
Fetal anomalies v0.4279 ADD3 Zornitza Stark Marked gene: ADD3 as ready
Fetal anomalies v0.4278 ADARB1 Zornitza Stark Marked gene: ADARB1 as ready
Fetal anomalies v0.4278 ADARB1 Zornitza Stark Gene: adarb1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v0.4278 ADARB1 Zornitza Stark Classified gene: ADARB1 as Amber List (moderate evidence)
Fetal anomalies v0.4278 ADARB1 Zornitza Stark Gene: adarb1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v0.4277 D2HGDH Zornitza Stark Marked gene: D2HGDH as ready
Fetal anomalies v0.4277 D2HGDH Zornitza Stark Phenotypes for gene: D2HGDH were changed from to D-2-hydroxyglutaric aciduria, MIM# 600721
Fetal anomalies v0.4275 D2HGDH Zornitza Stark reviewed gene: D2HGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: D-2-hydroxyglutaric aciduria, MIM# 600721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.4275 HEXB Krithika Murali gene: HEXB was added
gene: HEXB was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: HEXB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEXB were set to 23046579; 24613245; 33407268; 27697305; 11869411; 33363784
Phenotypes for gene: HEXB were set to Sandhoff disease, infantile, juvenile, and adult forms-MIM#268800
Review for gene: HEXB was set to RED
Added comment: Biallelic variants associated with Sandhoff disease which includes a severe, infantile onset form. Authors of reported cases note normal antenatal and immediate postnatal course with onset of phenotypic features generally from 2 months of age onwards. Note subset with cardiomyopathy and secondary valvular incompetence, not congenital heart defects.
Sources: Literature
Fetal anomalies v0.4273 GTPBP2 Ain Roesley gene: GTPBP2 was added
gene: GTPBP2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GTPBP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTPBP2 were set to 26675814; 29449720; 30790272
Phenotypes for gene: GTPBP2 were set to Jaberi-Elahi syndrome MIM#617988
Review for gene: GTPBP2 was set to GREEN
gene: GTPBP2 was marked as current diagnostic
Added comment: Nine individuals from six unrelated families

microcephaly noted but measurements at birth not provided.
1x weight 5th percentile and OFC 25-50 percentile

scoliosis consistently reported
Other features include clenched hands, talipes, abnormal brain imaging, pectus excavatum
Sources: Literature
Fetal anomalies v0.4273 MCF2 Daniel Flanagan gene: MCF2 was added
gene: MCF2 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: MCF2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MCF2 were set to 31846234
Phenotypes for gene: MCF2 were set to Perisylvian polymicrogyria
Review for gene: MCF2 was set to RED
Added comment: Single individual reported, inherited missense variant from unaffected mother, some support from mouse model.
Sources: Expert list
Fetal anomalies v0.4273 MAN2C1 Daniel Flanagan gene: MAN2C1 was added
gene: MAN2C1 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: MAN2C1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2C1 were set to 35045343
Phenotypes for gene: MAN2C1 were set to MAN2C1-related neurodevelopmental disorder MONDO:0700092
Review for gene: MAN2C1 was set to GREEN
Added comment: Six individuals from four different families, including two fetuses, exhibiting dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Variants include PTC and missense.
*3 unrelated individuals presented polymicrogyria
Sources: Expert list
Fetal anomalies v0.4273 INTS8 Daniel Flanagan gene: INTS8 was added
gene: INTS8 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: INTS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS8 were set to 28542170
Phenotypes for gene: INTS8 were set to Neurodevelopmental disorder with cerebellar hypoplasia and spasticity (MIM#618572)
Review for gene: INTS8 was set to RED
Added comment: Single family with three affected sibs with compound het INTS8 variants, Microcephaly, Cerebellar hypoplasia, Nodular heterotopia. Some functional evidence.
Sources: Expert list
Fetal anomalies v0.4273 GRM7 Ain Roesley gene: GRM7 was added
gene: GRM7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GRM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRM7 were set to 32286009; 32248644
Phenotypes for gene: GRM7 were set to Neurodevelopmental disorder with seizures, hypotonia, and brain abnormalities MIM#618922
Review for gene: GRM7 was set to GREEN
gene: GRM7 was marked as current diagnostic
Added comment: progressive/post-natal microcephaly consistently reported

6 families with 11 affecteds
5 of the pregnancies were complicated by polyhydramnios/decreased fetal movements
Sources: Literature
Fetal anomalies v0.4273 ERMARD Daniel Flanagan gene: ERMARD was added
gene: ERMARD was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: ERMARD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ERMARD were set to 27087860; 24056535
Phenotypes for gene: ERMARD were set to Periventricular nodular heterotopia 6 (MIM#615544)
Review for gene: ERMARD was set to RED
Added comment: Single individual described with heterozygous ERMARD missense and periventricular nodular heterotopia, developmental delay and epilepsy.

PMID: 27087860. Fetus was diagnosed by prenatal ultrasound with symmetric bilateral ventriculomegaly. The fetus carried a 0.78-Mb deletion of chromosomal region 6q27 (ERMARD included).
Sources: Expert list
Fetal anomalies v0.4273 GPT2 Ain Roesley gene: GPT2 was added
gene: GPT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GPT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPT2 were set to 25758935; 27601654; 28130718; 29226631; 29882329; 31471722
Phenotypes for gene: GPT2 were set to Neurodevelopmental disorder with microcephaly and spastic paraplegia MIM#616281
Review for gene: GPT2 was set to RED
gene: GPT2 was marked as current diagnostic
Added comment: post-natal microcephaly

of note;
1x family where fisting was observed in a 4 yr old
1x adducted thumbs and scoliosis
a handful had reduced white matter volume and/or thin corpus callosum
Sources: Literature
Fetal anomalies v0.4273 GON7 Ain Roesley gene: GON7 was added
gene: GON7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GON7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GON7 were set to 31481669
Phenotypes for gene: GON7 were set to Galloway-Mowat syndrome 9, MIM# 619603
Review for gene: GON7 was set to GREEN
gene: GON7 was marked as current diagnostic
Added comment: 11 individuals from 5 families. Four of the families had the same homozygous variant, shared haplotype suggestive of founder effect.

post-natal microcephaly and brain malformations such as cerebellar atrophy, atrophic/thin corpus callosum. Cranial imaging done as young as 6 months.

Maybe detectable antenatally
Sources: Literature
Fetal anomalies v0.4273 GOLGA2 Ain Roesley edited their review of gene: GOLGA2: Changed phenotypes: neuromuscular disease, GOLGA2-related MONDO#0019056
Fetal anomalies v0.4273 GOLGA2 Ain Roesley gene: GOLGA2 was added
gene: GOLGA2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GOLGA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOLGA2 were set to 34424553; 26742501; 30237576
Review for gene: GOLGA2 was set to GREEN
gene: GOLGA2 was marked as current diagnostic
Added comment: 3x unrelated families

1x noted with a smaller head at birth head circumference 32.5 cm (7th percentile). weight 3.22 kg (37th percentile), length 49.5 cm (53rd percentile)

Nonspecific cerebral volume loss / cortical atrophy with delayed myelination and thin corpus callosum reported in all post-natally. Maybe detectable antenatally
Sources: Literature
Fetal anomalies v0.4273 CEP85L Daniel Flanagan gene: CEP85L was added
gene: CEP85L was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: CEP85L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CEP85L were set to 32097630
Phenotypes for gene: CEP85L were set to Lissencephaly 10, posterior predominant (MIM618873)
Review for gene: CEP85L was set to RED
Added comment: Thirteen individuals reported with mono allelic variants in this gene, inherited in two of the families. Mouse model had neuronal migration defects. Earliest symptom onset 5 months, most develop seizures after several years.
Sources: Expert list
Fetal anomalies v0.4273 FOXR1 Ain Roesley gene: FOXR1 was added
gene: FOXR1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FOXR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXR1 were set to 34723967
Phenotypes for gene: FOXR1 were set to Postnatal microcephaly, progressive brain atrophy and global developmental delay
Review for gene: FOXR1 was set to AMBER
gene: FOXR1 was marked as current diagnostic
Added comment: 1 individual with functional studies done for the specific variant

post-natal microcephaly with progressive brain atrophy from 1 yr onwards
Sources: Literature
Fetal anomalies v0.4273 HERC1 Krithika Murali gene: HERC1 was added
gene: HERC1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: HERC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HERC1 were set to 28323226; 27108999; 26153217; 26138117
Phenotypes for gene: HERC1 were set to Macrocephaly, dysmorphic facies, and psychomotor retardation - MIM#617011
Review for gene: HERC1 was set to GREEN
Added comment: Multiple individuals reported with macrosomia and macrocephaly detected at birth.
Sources: Literature
Fetal anomalies v0.4273 FDXR Ain Roesley gene: FDXR was added
gene: FDXR was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FDXR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDXR were set to 30250212; 28965846
Phenotypes for gene: FDXR were set to Auditory neuropathy and optic atrophy, MIM# 617717
Review for gene: FDXR was set to RED
gene: FDXR was marked as current diagnostic
Added comment: Bi-allelic variants in FDXR cause an autosomal recessive neurologic disorder characterised by onset of visual and hearing impairment in the first or second decades. Two individuals described with a more severe phenotype, including one with microcephaly.
Sources: Literature
Fetal anomalies v0.4273 CDK5 Daniel Flanagan gene: CDK5 was added
gene: CDK5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CDK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK5 were set to 25560765
Phenotypes for gene: CDK5 were set to Lissencephaly 7 with cerebellar hypoplasia (MIM#616342)
Review for gene: CDK5 was set to RED
Added comment: Single consanguineous family with multiple affected individuals reported, lissencephaly prominent. Head circumference at the low-normal range (5th–25th percentile).
Sources: Literature
Fetal anomalies v0.4273 EXOC7 Ain Roesley gene: EXOC7 was added
gene: EXOC7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: EXOC7 were set to Neurodevelopmental disorder with seizures and brain atrophy MIM#619072
Review for gene: EXOC7 was set to GREEN
gene: EXOC7 was marked as current diagnostic
Added comment: 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families.
Sources: Literature
Fetal anomalies v0.4273 DYNC1I2 Ain Roesley gene: DYNC1I2 was added
gene: DYNC1I2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DYNC1I2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DYNC1I2 were set to 31079899
Phenotypes for gene: DYNC1I2 were set to Neurodevelopmental disorder with microcephaly and structural brain anomalies , MIM#618492
Review for gene: DYNC1I2 was set to GREEN
gene: DYNC1I2 was marked as current diagnostic
Added comment: 5 affecteds from 3 families

1x microcephaly at birth and head ultrasound at 2 months detected absent corpus callosum. Furthermore, abrain MRI revealed the absence of the rostrum and genu ofthe corpus callosum and partial absence of the splenium,as well as absence of the septum pellucidum and megacisterna magna.

1x microcephaly at birth (-2 SD). Brain MRI at 3 months of age re-vealed a hypoplastic corpus callosum, prominent ventri-cles, reduced white matter volume, and simplified gyralpattern
Sources: Literature
Fetal anomalies v0.4273 FIBP Krithika Murali gene: FIBP was added
gene: FIBP was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FIBP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FIBP were set to 27183861; 26660953
Phenotypes for gene: FIBP were set to Thauvin-Robinet-Faivre syndrome - MIM#617107
Review for gene: FIBP was set to AMBER
Added comment: Thauvin-Robinet-Faivre syndrome is an autosomal recessive disorder characterized by generalized overgrowth, mainly of height, and mildly delayed psychomotor development with mild or severe learning difficulties. More variable features may include congenital heart defects, kidney abnormalities, and skeletal defects. Patients may have an increased risk for Wilms tumor.

2 unrelated families reported.

27183861 - report one family with 3 affected children. Prenatally relevant phenotypic features include:
- congenital heart disease in one child
- preterm delivery and bilateral talipes equinovarus 2nd child
- cystic kidney disease, nephromegaly and polyhydramnios 3rd child

26660953 - report one child with ventricular septal defect, mitral valve prolapse, renal malrotation with left bifid ureter, macrocephaly and macrosomia noted at birth.
Sources: Literature
Fetal anomalies v0.4273 B3GNT2 Daniel Flanagan gene: B3GNT2 was added
gene: B3GNT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: B3GNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B3GNT2 were set to 23359570; 23877401
Phenotypes for gene: B3GNT2 were set to Walker-Warburg syndrome
Review for gene: B3GNT2 was set to AMBER
Added comment: Only 2 families reported

PMID: 23877401. Homozygous frameshift in B3GNT1 identified in a proband born with occipital encephalocele, anencephaly, cloudy cornea, proptotic eyes, spastic posture and micropenis.

PMID: 23359570. Family with two homozygous B3GNT1 missense in affected. 4 pregnancies with abnormalities identified by ultrasound, including: hydrocephalus with the lateral ventricles, severe cerebral ventriculomegaly, cystic dysplastic kidney
Sources: Literature
Fetal anomalies v0.4273 CTNNA2 Ain Roesley gene: CTNNA2 was added
gene: CTNNA2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CTNNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTNNA2 were set to 30013181
Phenotypes for gene: CTNNA2 were set to Cortical dysplasia, complex, with other brain malformations 9, MIM#618174
Review for gene: CTNNA2 was set to GREEN
gene: CTNNA2 was marked as current diagnostic
Added comment: acquired microcephaly. Pachygyria is also a feature, which can be detectable in a prenatal MRI, though none of the reports thus far were diagnosed antenatally

3 families with 7 affecteds
Sources: Literature
Fetal anomalies v0.4273 DICER1 Krithika Murali gene: DICER1 was added
gene: DICER1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DICER1 were set to 27960159; 29343557; 26227654; 33208384; 35114704; 31232238; 24676357
Phenotypes for gene: DICER1 were set to GLOW syndrome, somatic mosaic - MIM#618272; Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors - MIM#138800; Pleuropulmonary blastoma - MIM#601200
Review for gene: DICER1 was set to GREEN
Added comment: Heterozygous pathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic somatic missense DICER1 variants in the RNase IIIb domain are linked to GLOW syndrome (global developmental delay, lung cysts, overgrowth, and Wilms’ tumor) syndrome. While the DICER1 syndrome is classically caused by frameshift, nonsense or other mutations that ablate DICER1 function in a true heterozygous state, GLOW-syndrome mutations occur at specific residues within the RNase IIIb domain that only affect the function of this domain.

Both syndromes have been reported to have features that can be detected prenatally.

PMID 33208384 - report a patient with heterozygous germline DICER1 variant. The patient was born at gestational week 39 after a difficult delivery due to macrocephaly. Clinical findings at birth included two blood vessels in the umbilical cord, undescended testis, inguinal hernia, postaxial polydactyly, ear pits and rocker bottom feet.

PMID: 34331184 - report 4 unrelated families with germline DICER1 variants. In family 1 - one child was born with Pierre Robin sequence, shortening of the left arm and leg and bilateral
hip dysplasia. In Family 2 a child had macrosomia and macrocephaly at birth. Family 4 - born at 33 weeks, dysmorphic facies including hypertelorism and macroglossia.

PMID 24676357 - report 2 unrelated children with GLOW syndrome. Patient 1 was noted to have enlarged kidneys on 24 week ultrasound. At birth was found to have renal and pulmonary cysts. Patient 2 - macrocephaly was noted at birth.

DICER1 implicated in ~60% of PPB - reports of PPB detecteed antenatally, although no reports in the context of confirmed DICER1 syndrome.
Sources: Literature
Fetal anomalies v0.4273 COLGALT1 Zornitza Stark Marked gene: COLGALT1 as ready
Fetal anomalies v0.4271 COLGALT1 Zornitza Stark commented on gene: COLGALT1: 3 unrelated cases with biallelic variants, and supporting functional assays. The main features of the cases were porencephalic cysts, leukoencephalopathy, lacunar infarcts, cerebral microbleeds/haemorrhages and calcifications. A null mouse model was embryonic lethal, but had defects in the vascular networks of the embryos.
Fetal anomalies v0.4270 C2orf69 Zornitza Stark Marked gene: C2orf69 as ready
Fetal anomalies v0.4268 ABHD16A Zornitza Stark Marked gene: ABHD16A as ready
Fetal anomalies v0.4268 ABHD16A Zornitza Stark Phenotypes for gene: ABHD16A were changed from to Spastic paraplegia 86, autosomal recessive, MIM# 619735
Fetal anomalies v0.4266 ABHD16A Zornitza Stark reviewed gene: ABHD16A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 86, autosomal recessive, MIM# 619735; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.4266 COPB2 Ain Roesley gene: COPB2 was added
gene: COPB2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: COPB2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: COPB2 were set to 29036432; 34450031
Phenotypes for gene: COPB2 were set to Microcephaly 19, primary, autosomal recessive, MIM# 617800
Review for gene: COPB2 was set to RED
gene: COPB2 was marked as current diagnostic
Added comment: IUGR or small at birth (including microcephaly) not noted for any of the probands. Fractures and osteopenia were not detected antenatally.
Sources: Literature
Fetal anomalies v0.4266 ARF1 Daniel Flanagan gene: ARF1 was added
gene: ARF1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ARF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF1 were set to 28868155; 34353862
Phenotypes for gene: ARF1 were set to Periventricular nodular heterotopia 8 (MIM#618185)
Review for gene: ARF1 was set to RED
Added comment: Three unrelated individuals reported with de novo missense in this gene. PMID: 34353862: Additional report of affected parent and child.

1 patient had microcephaly in teens but normal head circumference at first examination.
Sources: Literature
Fetal anomalies v0.4266 ATXN2L Krithika Murali gene: ATXN2L was added
gene: ATXN2L was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ATXN2L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATXN2L were set to 33283965; 33057194
Phenotypes for gene: ATXN2L were set to macrocephaly; intellectual disability
Review for gene: ATXN2L was set to AMBER
Added comment: Combined data from three large exome groups identified several de novo variants, including frameshift and missense, in ATXN2L in patients with developmental delay (Kaplanis et al., 2020). pLI=1.0

33283965 - Single case report of a novel de novo missense variant in a child with macrocephaly and developmental delay. No functional work. Macrocephaly was detected prenatally. This together with breech presentation resulted in elective C-section at 36 weeks.
Sources: Literature
Fetal anomalies v0.4266 COPB1 Ain Roesley gene: COPB1 was added
gene: COPB1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: COPB1 were set to Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts
Review for gene: COPB1 was set to RED
gene: COPB1 was marked as current diagnostic
Added comment: Two unrelated families, some supportive functional data. Microcephaly is not a consistent feature in the families reported to date.

Cataracts were also post-natal
Sources: Literature
Fetal anomalies v0.4266 CHKA Ain Roesley gene: CHKA was added
gene: CHKA was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHKA were set to 35202461
Phenotypes for gene: CHKA were set to neurodevelopmental disorder, CHKA-related MONDO#0700092
Review for gene: CHKA was set to RED
gene: CHKA was marked as current diagnostic
Added comment: post-natal microcephaly and short stature.
Symptoms which were present within the first few months post birth include developmental delay and seizures
Sources: Literature
Fetal anomalies v0.4266 CENPE Ain Roesley gene: CENPE was added
gene: CENPE was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CENPE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CENPE were set to 24748105; 30086807
Phenotypes for gene: CENPE were set to Microcephaly 13, primary, autosomal recessive (MIM#616051)
Review for gene: CENPE was set to RED
gene: CENPE was marked as current diagnostic
Added comment: PMID: 24748105;
- 2 siblings from non-consanguineous family of European descent
- patient A: at birth, OFC of -5SD which progressed to -9SD at 5 years of age
- patient B: no measurement at birth but OFC was -7SD at 3 years of age
- cHet for 2 missense

*no new reports since. A review of AR primary microcephaly in 2018 still states just 1 family (PMID: 30086807)
Sources: Literature
Fetal anomalies v0.4266 CDK6 Ain Roesley changed review comment from: 1x 8-generational family with 10 affecteds

unclear of microcephaly was present at birth or acquired
Sources: Literature; to: 1x 8-generational family with 10 affecteds

unclear if microcephaly was present at birth or acquired
Sources: Literature
Fetal anomalies v0.4266 CDK6 Ain Roesley gene: CDK6 was added
gene: CDK6 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CDK6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK6 were set to 23918663
Phenotypes for gene: CDK6 were set to Microcephaly 12, primary, autosomal recessive, MIM#616080
Review for gene: CDK6 was set to AMBER
gene: CDK6 was marked as current diagnostic
Added comment: 1x 8-generational family with 10 affecteds

unclear of microcephaly was present at birth or acquired
Sources: Literature
Fetal anomalies v0.4266 CCDC88A Ain Roesley gene: CCDC88A was added
gene: CCDC88A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CCDC88A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC88A were set to 30392057; 26917597
Phenotypes for gene: CCDC88A were set to PEHO syndrome-like (MIM#617507)
Review for gene: CCDC88A was set to AMBER
gene: CCDC88A was marked as current diagnostic
Added comment: PMID: 26917597;
1x family with 3 affecteds microcephaly (birth OFC -3 - -4 SD)

total of 2 consanguineous families with 5 affecteds and functional studies of KO mice
Sources: Literature
Fetal anomalies v0.4266 PPP2R3C Zornitza Stark Marked gene: PPP2R3C as ready
Fetal anomalies v0.4266 APC2 Belinda Chong gene: APC2 was added
gene: APC2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APC2 were set to 31585108
Phenotypes for gene: APC2 were set to Cortical dysplasia, complex, with other brain malformations 10, MIM#618677
Review for gene: APC2 was set to RED
gene: APC2 was marked as current diagnostic
Added comment: Onset in infancy

12 individuals from 8 unrelated families; intellectual disability, seizures, cortical dysplasia including posterior to anterior predominant pattern of lissencephaly, heterotopias, paucity of white matter, thin corpus callosum.
Sources: Literature
Fetal anomalies v0.4264 C7orf43 Ain Roesley gene: C7orf43 was added
gene: C7orf43 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: C7orf43 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C7orf43 were set to 30715179
Phenotypes for gene: C7orf43 were set to Microcephaly 25, primary, autosomal recessive, MIM# 618351
Penetrance for gene: C7orf43 were set to Complete
Review for gene: C7orf43 was set to AMBER
gene: C7orf43 was marked as current diagnostic
Added comment: HGNC approved name TRAPPC14

Single family reported: three affected siblings with homozygous truncating variant. Supportive zebrafish model.

Occipital-frontal circumferences were below2 SD at birth, with microcephaly progressing later in life
Sources: Literature
Fetal anomalies v0.4264 ATRIP Ain Roesley gene: ATRIP was added
gene: ATRIP was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ATRIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATRIP were set to 23144622
Phenotypes for gene: ATRIP were set to Seckel Syndrome
Review for gene: ATRIP was set to RED
gene: ATRIP was marked as current diagnostic
Added comment: Red in Mendeliome - only 1 report of post-natal progressive microcephaly
Sources: Literature
Fetal anomalies v0.4264 ATP9A Ain Roesley gene: ATP9A was added
gene: ATP9A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP9A were set to 34764295; 34379057
Phenotypes for gene: ATP9A were set to neurodevelopmental disorder, ATP9A-related MONDO#0700092
Penetrance for gene: ATP9A were set to Complete
Review for gene: ATP9A was set to AMBER
gene: ATP9A was marked as current diagnostic
Added comment: post-natal microcephaly, 4 unrelated families

1x polyhydramnios noted and born small, weight of 3570g (−0.41 SD), a length of 50cm (−1.37 SD) and an OFC of 34cm (−1.47 SD).
Sources: Literature
Fetal anomalies v0.4264 ARPC4 Ain Roesley gene: ARPC4 was added
gene: ARPC4 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ARPC4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARPC4 were set to 35047857
Phenotypes for gene: ARPC4 were set to neurodevelopmental disorder, ARPC4-related MONDO#0700092
Penetrance for gene: ARPC4 were set to Complete
Review for gene: ARPC4 was set to RED
gene: ARPC4 was marked as current diagnostic
Added comment: post natal microcephaly except for 1 noted as 4% at birth

7 affected individuals from 6 families (gonadal mosaicism was confirmed in the mother of the 2 affected siblings) with a recurrent missense variant (NM_005718.4:c.472C>T; p.R158C).

Core features in affected individuals include microcephaly, mild motor delays, and significant speech impairment
Sources: Literature
Fetal anomalies v0.4264 ANKLE2 Ain Roesley gene: ANKLE2 was added
gene: ANKLE2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ANKLE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANKLE2 were set to 25259927; 30214071; 31735666
Phenotypes for gene: ANKLE2 were set to Microcephaly 16, primary, autosomal recessive, MIM# 616681
Review for gene: ANKLE2 was set to GREEN
gene: ANKLE2 was marked as current diagnostic
Added comment: total of 4 unrelated born with microcephaly
Sources: Literature
Fetal anomalies v0.4264 AGMO Ain Roesley gene: AGMO was added
gene: AGMO was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: AGMO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGMO were set to 31555905; 27000257
Phenotypes for gene: AGMO were set to neurodevelopmental disorder, AGMO-related MONDO#0700092
Penetrance for gene: AGMO were set to Complete
Review for gene: AGMO was set to RED
gene: AGMO was marked as current diagnostic
Added comment: syndromic neurodevelopmental disorder with ID, microcephaly and epilesy reported

1x oligo-hydramnios, maternal hypothyroidism, and decreased fetal movement
birth weight was 2892 g (23%) and length was 49.5 cm (50%). Head circumference was not known but noted to be 5–10%

1x uneventful pregnancy
birth weight was 2977 g (55%) and length was 53.3 cm (98%)

1x siblings with post natal microcephaly
Sources: Literature
Fetal anomalies v0.4264 ADD3 Ain Roesley gene: ADD3 was added
gene: ADD3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ADD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADD3 were set to 23836506; 29768408
Phenotypes for gene: ADD3 were set to Cerebral palsy, spastic quadriplegic, 3 MIM#617008
Penetrance for gene: ADD3 were set to Complete
Review for gene: ADD3 was set to RED
gene: ADD3 was marked as current diagnostic
Added comment: post natal borderline microcephaly and cataract
Sources: Literature
Fetal anomalies v0.4264 ADARB1 Ain Roesley gene: ADARB1 was added
gene: ADARB1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ADARB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADARB1 were set to 32220291; 32719099
Phenotypes for gene: ADARB1 were set to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, MIM#618862
Penetrance for gene: ADARB1 were set to Complete
Review for gene: ADARB1 was set to AMBER
gene: ADARB1 was marked as current diagnostic
Added comment: 6 unrelated families

1 microcephalic at birth (-2.2 SD) + 1 birth length at -4.3 SD
Sources: Literature
Fetal anomalies v0.4264 UNC13A Zornitza Stark Marked gene: UNC13A as ready
Fetal anomalies v0.4263 SYT2 Zornitza Stark Marked gene: SYT2 as ready
Fetal anomalies v0.4262 SLC25A1 Zornitza Stark Marked gene: SLC25A1 as ready
Fetal anomalies v0.4262 SLC25A1 Zornitza Stark Phenotypes for gene: SLC25A1 were changed from ?Myasthenic syndrome, congenital, 23, presynaptic MIM#618197; Combined D-2- and L-2-hydroxyglutaric aciduria MIM#615182 to Myasthenic syndrome, congenital, 23, presynaptic MIM#618197; Combined D-2- and L-2-hydroxyglutaric aciduria MIM#615182
Fetal anomalies v0.4259 RPH3A Zornitza Stark Marked gene: RPH3A as ready
Fetal anomalies v0.4258 NHEJ1 Zornitza Stark changed review comment from: Clinical presentation is with SCID, short stature and microcephaly. ID was part of the phenotype in only one individual in the original paper describing this condition.; to: Clinical presentation is with SCID, short stature and microcephaly.
Fetal anomalies v0.4258 PLEC Zornitza Stark Marked gene: PLEC as ready
Fetal anomalies v0.4257 LAMA5 Zornitza Stark Marked gene: LAMA5 as ready
Fetal anomalies v0.4256 D2HGDH Chloe Stutterd gene: D2HGDH was added
gene: D2HGDH was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: D2HGDH was set to BIALLELIC, autosomal or pseudoautosomal
Review for gene: D2HGDH was set to GREEN
Added comment: Antenatal features: macrocephaly, enlarged cerebral ventricles, micrognathia
Sources: Literature
Fetal anomalies v0.4255 PPP2R3C Chirag Patel gene: PPP2R3C was added
gene: PPP2R3C was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PPP2R3C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP2R3C were set to PMID: 30893644, 34714774, 34750818
Phenotypes for gene: PPP2R3C were set to Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy, OMIM # 618419
Review for gene: PPP2R3C was set to GREEN
Added comment: Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy (GDRM) is characterized by 46,XY complete gonadal dysgenesis in association with extragonadal anomalies, low birth weight, typical facial gestalt, rod and cone dystrophy, sensorineural hearing loss, omphalocele, anal atresia, renal agenesis, skeletal abnormalities, dry and scaly skin, severe myopathy, and neuromotor delay. 11 unrelated families with syndromic complete gonadal dysgenesis. 9 families had 46,XY females with complete gonadal dysgenesis, but 2 families had 46,XX patients with hypergonadotropic hypogonadism, nonvisualized gonads, primary amenorrhea, and absence of secondary sexual characteristics. Variants segregated with disease in each family and were not found in ethnically matched controls or in public variant databases. The heterozygous fathers exhibited morphologic abnormalities of spermatozoa and reduced fertility.
Sources: Literature
Fetal anomalies v0.4253 UNC13A Belinda Chong gene: UNC13A was added
gene: UNC13A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: UNC13A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: UNC13A were set to 27648472; 28192369
Phenotypes for gene: UNC13A were set to Congenital myasthenia; dyskinesia; autism; developmental delay
Review for gene: UNC13A was set to RED
Added comment: One individual described with biallelic variants in this gene and a myasthenic syndrome; another individual reported with de novo variant in this gene and a different neurological phenotype (abnormal movements, developmental delay and autism).
Sources: Literature
Fetal anomalies v0.4253 SYT2 Belinda Chong gene: SYT2 was added
gene: SYT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SYT2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SYT2 were set to 25192047; 32776697; 32250532; 30533528
Phenotypes for gene: SYT2 were set to Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040; Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461
Review for gene: SYT2 was set to GREEN
gene: SYT2 was marked as current diagnostic
Added comment: Myasthenic syndrome bi-allelic #619461- Decreased fetal movements

Mono-allelic disease, PMID 25192047 and 30533528: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in three families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated.

Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function.
Sources: Literature
Fetal anomalies v0.4253 SLC25A1 Belinda Chong gene: SLC25A1 was added
gene: SLC25A1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SLC25A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A1 were set to 26870663; 31527857; 29226520
Phenotypes for gene: SLC25A1 were set to ?Myasthenic syndrome, congenital, 23, presynaptic MIM#618197; Combined D-2- and L-2-hydroxyglutaric aciduria MIM#615182
Review for gene: SLC25A1 was set to RED
gene: SLC25A1 was marked as current diagnostic
Added comment: Neonatal onset.

Green for MIM#618197
Four unrelated families. mild congenital myasthenic syndrome.

Red for MIM#615182
Five infants of two consanguineous Bedouin families of the same tribe homozygous for the same variant with EEG compatible with white matter disorder. Death usually occurs in childhood.
Sources: Literature
Fetal anomalies v0.4253 NHS Alison Yeung Marked gene: NHS as ready
Fetal anomalies v0.4253 NHS Alison Yeung Phenotypes for gene: NHS were changed from CATARACT CONGENITAL X-LINKED; NANCE-HORAN SYNDROME to Nance-Horan syndrome, MIM# 302350
Fetal anomalies v0.4251 RPH3A Belinda Chong gene: RPH3A was added
gene: RPH3A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RPH3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPH3A were set to 29441694
Phenotypes for gene: RPH3A were set to Congenital myasthenic syndrome
Review for gene: RPH3A was set to RED
gene: RPH3A was marked as current diagnostic
Added comment: Only one patient with a complex phenotype that included myasthenia, with compound het missense variants, of which only one variant had plausible functional expression data.
Sources: Literature
Fetal anomalies v0.4251 NHEJ1 Alison Yeung Marked gene: NHEJ1 as ready
Fetal anomalies v0.4251 NHEJ1 Alison Yeung Phenotypes for gene: NHEJ1 were changed from Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation 611291 to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291; Cernunnos-XLF deficiency MONDO:0012650
Fetal anomalies v0.4249 NHEJ1 Alison Yeung reviewed gene: NHEJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30898087, 30666249, 28741180, 25288157, 24511403, 21721379, 21535335; Phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291, Cernunnos-XLF deficiency MONDO:0012650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.4249 NF1 Alison Yeung Marked gene: NF1 as ready
Fetal anomalies v0.4247 PLEC Belinda Chong gene: PLEC was added
gene: PLEC was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLEC was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PLEC were set to 22144912; 31509265; 21263134; 20624679; 20624679; 21109228; 28824526
Phenotypes for gene: PLEC were set to Epidermolysis bullosa simplex 5C, with pyloric atresia MIM#612138; Epidermolysis bullosa simplex with muscular dystrophy, MIM# 226670; Epidermolysis bullosa simplex 5A, Ogna type MIM#131950; Muscular dystrophy, limb-girdle, autosomal recessive 17 (MIM#613723)
Review for gene: PLEC was set to GREEN
gene: PLEC was marked as current diagnostic
Added comment: Multiple variations of EB and also associated with limb-girdle muscular dystrophy. Neonatal to Early childhood onset. However, Epidermolysis bullosa simplex 5C, with pyloric atresia MIM#612138 has prenatal manifestation of Polyhydramnios.
Sources: Literature
Fetal anomalies v0.4247 NEK1 Alison Yeung Marked gene: NEK1 as ready
Fetal anomalies v0.4245 NEB Alison Yeung Marked gene: NEB as ready
Fetal anomalies v0.4245 NEB Alison Yeung Phenotypes for gene: NEB were changed from AUTOSOMAL RECESSIVE TYPICAL NEMALINE MYOPATHY to Arthrogryposis multiplex congenita 6, MIM# 619334
Fetal anomalies v0.4243 NDUFAF5 Alison Yeung Marked gene: NDUFAF5 as ready
Fetal anomalies v0.4243 NDUFAF5 Alison Yeung Phenotypes for gene: NDUFAF5 were changed from Mitochondrial complex I deficiency, nuclear type 16, 618238 to Mitochondrial complex I deficiency, nuclear type 16, MIM# 618238
Fetal anomalies v0.4241 NDUFAF5 Alison Yeung reviewed gene: NDUFAF5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex I deficiency, nuclear type 16, MIM# 618238; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.4241 NDP Alison Yeung Marked gene: NDP as ready
Fetal anomalies v0.4240 NDE1 Alison Yeung Marked gene: NDE1 as ready
Fetal anomalies v0.4237 LAMA5 Belinda Chong gene: LAMA5 was added
gene: LAMA5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: LAMA5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: LAMA5 were set to 33242826; 29534211; 16790509; 30589377; 28735299; 30631761
Phenotypes for gene: LAMA5 were set to bent bone dysplasia; nephrotic syndrome; Presynaptic congenital myasthenic syndrome; multisystem syndrome; developmental delay
Review for gene: LAMA5 was set to RED
Added comment: Currently amber gene and appears postnatal onset (not enough information)

PMID: 29534211 - Three consanguineous families with homozygous missense variants (VUS) identified in two affected siblings with paediatric nephrotic syndrome within each family. No functional studies conducted on the missense variants.
PMID: 16790509 - A hypomorphic Lama5 homozygous mouse model demonstrated proteinuria, cystic kidney disease and death from progressive renal failure at 3–4 weeks of age.
PMID: 24130771 - a single case focal segmental glomerulosclerosis (proteinuria) with biallelic missense variants (VUS - S1469A & V2440I). Also reports p.Gly3685Arg in 2 other cases, which has 11 homozygotes in gnomAD v2.1
PMID: 29764427, 30808327 - Four families with haematuria and proteinuria reported with digenic inheritance of a LAMA5 missense variant with a COL4A4/5 variant. One of those variants (p.His1717Tyr) has 892 homozygotes in gnomAD v2.1
PMID: 28735299, 30589377 - A single large multigenerational family with a multisystem syndrome (including ophthalmic fetures), segregating a heterozygous missense p.V3140M, and supporting knock-in mouse model that recapitulates the phenotype.
PMID: 33242826 - A single family with a bent bone dysplasia in 3 affected siblings with biallelic variants, and some supporting in vitro functional assays.
PMID: 28544784, 29377152 - Single family with congenital myasthenic syndrome with a homozygous missense reported twice.
PMID: 30631761 - a single case with a de novo splice site variant with developmental delay, epilepsy, and hypotonia
Sources: Literature
Fetal anomalies v0.4237 NBN Alison Yeung Marked gene: NBN as ready
Fetal anomalies v0.4235 NACC1 Alison Yeung Marked gene: NACC1 as ready
Fetal anomalies v0.4235 NACC1 Alison Yeung Added comment: Comment on phenotypes: Fetal anomalies reported include cataracts (5/7 patients) and microcephaly (5/7) patients
Fetal anomalies v0.4235 NACC1 Alison Yeung Phenotypes for gene: NACC1 were changed from Infantile Epilepsy, Cataracts, and Profound Developmental Delay to Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination delayed brain myelination, MIM# 617393)
Fetal anomalies v0.4232 MYT1 Alison Yeung Marked gene: MYT1 as ready
Fetal anomalies v0.4232 MYT1 Alison Yeung Phenotypes for gene: MYT1 were changed from Oculo-auriculo-vertebral spectrum (OAVS); OAVS/Goldenhar syndrome to Hemifacial microsomia, MONDO:0015398
Fetal anomalies v0.4229 MYRF Alison Yeung Marked gene: MYRF as ready
Fetal anomalies v0.4229 MYRF Alison Yeung Phenotypes for gene: MYRF were changed from Congenital diaphragmatic hernia (CDH); Cardiac-urogenital syndrome, 618280; Disorders of sex development (DSD) to Cardiac-urogenital syndrome, MIM# 618280
Fetal anomalies v0.4227 SNRPB Zornitza Stark Marked gene: SNRPB as ready
Fetal anomalies v0.4227 SNRPB Zornitza Stark Phenotypes for gene: SNRPB were changed from CEREBRO-COSTO-MANDIBULAR SYNDROME to Cerebrocostomandibular syndrome, MIM# 117650
Fetal anomalies v0.4224 SON Zornitza Stark Marked gene: SON as ready
Fetal anomalies v0.4221 SOS1 Zornitza Stark Marked gene: SOS1 as ready
Fetal anomalies v0.4219 SOS1 Zornitza Stark Mode of pathogenicity for gene: SOS1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.4217 SOS2 Zornitza Stark Marked gene: SOS2 as ready
Fetal anomalies v0.4216 ATN1 Zornitza Stark Marked gene: ATN1 as ready
Fetal anomalies v0.4215 NFIA Zornitza Stark Marked gene: NFIA as ready
Fetal anomalies v0.4214 PACS2 Zornitza Stark Marked gene: PACS2 as ready
Fetal anomalies v0.4213 PPP2CA Zornitza Stark Marked gene: PPP2CA as ready
Fetal anomalies v0.4212 ZMIZ1 Zornitza Stark Marked gene: ZMIZ1 as ready
Fetal anomalies v0.4211 SEMA3E Zornitza Stark Marked gene: SEMA3E as ready
Fetal anomalies v0.4211 SEMA3E Zornitza Stark Phenotypes for gene: SEMA3E were changed from ?CHARGE syndrome - MIM#214800 to CHARGE syndrome - MIM#214800
Fetal anomalies v0.4209 TMEM53 Zornitza Stark Marked gene: TMEM53 as ready
Fetal anomalies v0.4208 SGMS2 Zornitza Stark Marked gene: SGMS2 as ready
Fetal anomalies v0.4207 UBA2 Zornitza Stark Marked gene: UBA2 as ready
Fetal anomalies v0.4207 SCNN1B Zornitza Stark Marked gene: SCNN1B as ready
Fetal anomalies v0.4207 SCNN1A Zornitza Stark Marked gene: SCNN1A as ready
Fetal anomalies v0.4207 PAM16 Zornitza Stark Marked gene: PAM16 as ready
Fetal anomalies v0.4207 NME8 Zornitza Stark Marked gene: NME8 as ready
Fetal anomalies v0.4206 MIA3 Zornitza Stark Marked gene: MIA3 as ready
Fetal anomalies v0.4205 MBTPS1 Zornitza Stark Marked gene: MBTPS1 as ready
Fetal anomalies v0.4205 PPP2CA Krithika Murali gene: PPP2CA was added
gene: PPP2CA was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: PPP2CA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP2CA were set to 30595372
Phenotypes for gene: PPP2CA were set to Neurodevelopmental disorder and language delay with or without structural brain abnormalities - MIM#618354
Review for gene: PPP2CA was set to GREEN
Added comment: Syndromic ID associated with congenital brain and heart anomalies.
Sources: Literature, Expert list
Fetal anomalies v0.4205 HOXA11 Zornitza Stark Marked gene: HOXA11 as ready
Fetal anomalies v0.4205 PACS2 Krithika Murali gene: PACS2 was added
gene: PACS2 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: PACS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PACS2 were set to 34894068; 34859793
Phenotypes for gene: PACS2 were set to Developmental and epileptic encephalopathy 66 - MIM#618067
Review for gene: PACS2 was set to GREEN
Added comment: Associated with syndromic ID/infantile onset epileptic encephalopathy. Phenotypic features include brain and cardiac malformations.
Sources: Literature, Expert list
Fetal anomalies v0.4205 GDF3 Zornitza Stark changed review comment from: The variants originally reported are present at a high frequency in gnomad which is not consistent with a rare Mendelian disorder.; to: The variants originally reported are present at a high frequency in gnomad which is not consistent with a rare Mendelian disorder. Some individuals had skeletal features.

More recent publication PMID 29260090: variant inherited from phenotypically normal parent, leading authors to speculate about reduced penetrance.
Fetal anomalies v0.4205 NFIA Krithika Murali gene: NFIA was added
gene: NFIA was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: NFIA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NFIA were set to 35018717; 33973697; 32926563
Phenotypes for gene: NFIA were set to Brain malformations with or without urinary tract defects - MIM#613735
Review for gene: NFIA was set to GREEN
Added comment: Haploinsufficiency of the NFIA gene causes NFIA-related disorder, which includes brain abnormalities and intellectual disability, with or without urinary tract defects.
Sources: Literature, Expert list
Fetal anomalies v0.4204 GDF3 Zornitza Stark Marked gene: GDF3 as ready
Fetal anomalies v0.4204 COL27A1 Zornitza Stark Marked gene: COL27A1 as ready
Fetal anomalies v0.4204 CHST11 Zornitza Stark Marked gene: CHST11 as ready
Fetal anomalies v0.4204 PRDM15 Zornitza Stark Marked gene: PRDM15 as ready
Fetal anomalies v0.4204 NODAL Zornitza Stark Marked gene: NODAL as ready
Fetal anomalies v0.4201 RNF113A Zornitza Stark Marked gene: RNF113A as ready
Fetal anomalies v0.4201 RAP1B Zornitza Stark Marked gene: RAP1B as ready
Fetal anomalies v0.4201 RAD50 Zornitza Stark Marked gene: RAD50 as ready
Fetal anomalies v0.4201 FRA10AC1 Zornitza Stark Marked gene: FRA10AC1 as ready
Fetal anomalies v0.4200 ATN1 Krithika Murali gene: ATN1 was added
gene: ATN1 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: ATN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATN1 were set to 34212383; 30827498
Phenotypes for gene: ATN1 were set to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies - MIM#618494
Review for gene: ATN1 was set to GREEN
Added comment: Monoallelic variants associated with syndromic ID. Phenotypic features include arthrogryposis, epilepsy and congenital malformations of the brain, heart, and genitourinary systems.
Sources: Literature, Expert list
Fetal anomalies v0.4200 DNA2 Zornitza Stark Marked gene: DNA2 as ready
Fetal anomalies v0.4200 BRD4 Zornitza Stark Marked gene: BRD4 as ready
Fetal anomalies v0.4198 PPP1R12A Zornitza Stark Marked gene: PPP1R12A as ready
Fetal anomalies v0.4198 MNS1 Zornitza Stark Marked gene: MNS1 as ready
Fetal anomalies v0.4198 CFAP52 Zornitza Stark Marked gene: CFAP52 as ready
Fetal anomalies v0.4198 CFAP45 Zornitza Stark Marked gene: CFAP45 as ready
Fetal anomalies v0.4198 EDN3 Zornitza Stark Marked gene: EDN3 as ready
Fetal anomalies v0.4198 RASGRP2 Zornitza Stark Marked gene: RASGRP2 as ready
Fetal anomalies v0.4196 ALG14 Zornitza Stark Marked gene: ALG14 as ready
Fetal anomalies v0.4196 ALG14 Zornitza Stark Phenotypes for gene: ALG14 were changed from Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036; Disorder of N-glycosylation to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036
Fetal anomalies v0.4194 ALG14 Zornitza Stark reviewed gene: ALG14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myasthenic syndrome, congenital, 15, without tubular aggregates 616227, Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.4194 PLEKHM1 Zornitza Stark Marked gene: PLEKHM1 as ready
Fetal anomalies v0.4192 SEMA3E Krithika Murali gene: SEMA3E was added
gene: SEMA3E was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SEMA3E was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA3E were set to 31691538; 31464029; 15235037
Phenotypes for gene: SEMA3E were set to ?CHARGE syndrome - MIM#214800
Review for gene: SEMA3E was set to AMBER
Added comment: Heterozygous variant identified in a fetus given a clinical diagnosis of CHARGE syndrome.
One individual with a translocation and one individual with a missense variant reported in 2004; some functional data.
Sources: Literature
Fetal anomalies v0.4192 TMEM53 Krithika Murali gene: TMEM53 was added
gene: TMEM53 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TMEM53 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM53 were set to 33824347
Phenotypes for gene: TMEM53 were set to Craniotubular dysplasia, Ikegawa type - MIM#619727
Review for gene: TMEM53 was set to RED
Added comment: 33824347 Guo et al 2021 report 5 individuals from 4 unrelated Indian families with a sclerosing bone disorder. Authors report normal prenatal and early postnatal development.
Sources: Literature
Fetal anomalies v0.4192 SGMS2 Krithika Murali gene: SGMS2 was added
gene: SGMS2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SGMS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SGMS2 were set to 34236445; 32028018; 30779713; 34761145; 34504906
Phenotypes for gene: SGMS2 were set to Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia - MIM#126550
Review for gene: SGMS2 was set to RED
Added comment: Heterozygous variants in SGMS2 associated with childhood-onset osteoporosis and skeletal
dysplasia. Evidence suggests that some heterozygous missense variants have a dominant negative effect and lead to severe bone fragility and spondylometaphyseal dysplasia, while one recurrent nonsense variant (c.148C > T, p.Arg50*) has been associated with milder bone fragility with or without cranial sclerosis (cranial doughnut lesions). No antenatal features reported in published cases including growth parameters.

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PMID 32028018 Robinson et al 2020 - provide phenotypic information for 2 unrelated individuals with c.148C > T, p.Arg50* variant. No antenatal history reported.

PMID: 30779713 Pekkinen et al 2019 - identified heterozygous SGMS2 variants in 13 individuals from 6 unrelated families with early-onset osteoporosis and skeletal dysplasia. Identified recurrent nonsense variant in 4 families ( p.Arg50*) presented with childhood-onset osteoporosis with or without cranial sclerosis. 2 families had p.Ile62Ser or p.Met64Arg and. more severe phenotype including with neonatal fracture (clavicular fracture at birth), severe short stature, and spondylometaphyseal dysplasia. No antenatal phenotype/birth growth parameters provided.

PMID: 34761145 Makitie et al 2021 - further examination of bone changes in two individuals already reported in Pekkinen et al 2019 paper with recurrent nonsense variant.

PMID: 34504906 Basalom et al 2021 - no antenatal features reported
Sources: Literature
Fetal anomalies v0.4191 UBA2 Chirag Patel gene: UBA2 was added
gene: UBA2 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: UBA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBA2 were set to PMID: 31332306; 31587267
Phenotypes for gene: UBA2 were set to Split-Hand/Foot Malformation; Aplasia Cutis Congenita; Ectrodactyly
Review for gene: UBA2 was set to GREEN
Added comment: 2x unrelated probands with isolated split hand malformation. fs variants - 1x de novo and 1x inherited from apparent unaffected mother (no radiographs of her hand available.

1x proband with unilateral split-hand malformation (missense). Her daughter and grandson reported to have ectrofactyly but were unavailable for testing

PMID: 31332306 - a single individual with a de novo PTC and split hand/foot malformation (SHFM). Additional two multigenic CNVs including this gene in individuals with SHFM and ectrodactyly. Authors mention an additional de novo missense but the patient didnt have SHFM, argue low penetrance PMID: 31587267 - a mother and son with aplasia cutis congenita (ACC), with a heterozygous PTC. Son also has ectrodactyly. Authors note an additional de novo missense in a patient with ACC.
Sources: Expert list
Fetal anomalies v0.4189 SCNN1B Chirag Patel gene: SCNN1B was added
gene: SCNN1B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SCNN1B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SCNN1B were set to PubMed: 8589714
Phenotypes for gene: SCNN1B were set to Pseudohypoaldosteronism, type I - MIM#264350
Review for gene: SCNN1B was set to GREEN
Added comment: Autosomal recessive pseudohypoaldosteronism type I caused by homozygous or compound heterozygous mutation in SCNN1B is characterized by renal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder involves multiple organ systems and is especially threatening in the neonatal period. Multiple patients reported.
Sources: Literature
Fetal anomalies v0.4187 SCNN1A Chirag Patel gene: SCNN1A was added
gene: SCNN1A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SCNN1A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SCNN1A were set to PubMed: 8589714, 31301676
Phenotypes for gene: SCNN1A were set to Pseudohypoaldosteronism, type I - MIM#264350
Review for gene: SCNN1A was set to GREEN
Added comment: Autosomal recessive pseudohypoaldosteronism type I caused by homozygous or compound heterozygous mutation in SCNN1A is characterized by renal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder involves multiple organ systems and is especially threatening in the neonatal period. Multiple patients reported.
Sources: Literature
Fetal anomalies v0.4184 PAM16 Chirag Patel gene: PAM16 was added
gene: PAM16 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: PAM16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAM16 were set to PubMed: 24786642, 27354339
Phenotypes for gene: PAM16 were set to Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type, OMIM # 613320
Review for gene: PAM16 was set to GREEN
Added comment: Megarbane-Dagher-Melki type of spondylometaphyseal dysplasia (SMDMDM) has chondrodysplasia, developmental delay, severe pre- and postnatal short stature, dysmorphic facial appearance, narrow chest, prominent abdomen, and short limbs. 5 patients from 3 unrelated families with homozygous missense mutations which segregate with disease.
Sources: Expert list
Fetal anomalies v0.4182 NME8 Chirag Patel gene: NME8 was added
gene: NME8 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NME8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NME8 were set to PubMed: 12032915, 12483741, 12928894
Phenotypes for gene: NME8 were set to CINCA syndrome, OMIM # 607115
Review for gene: NME8 was set to GREEN
Added comment: Chronic infantile neurologic cutaneous and articular (CINCA) syndrome also known as 'neonatal onset multisystem inflammatory disease,' or NOMID, is a rare congenital inflammatory disorder characterized by a triad of neonatal onset of cutaneous symptoms, chronic meningitis, and joint manifestations with recurrent fever and inflammation. 14 families with heterozygous missense mutations in exon 3. Presenting perinatally so suitable for fetal anomalies panel.
Sources: Literature
Fetal anomalies v0.4180 MIA3 Chirag Patel gene: MIA3 was added
gene: MIA3 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MIA3 were set to PMID: 32101163, 33778321
Phenotypes for gene: MIA3 were set to Ondontochondrodysplasia 2 with hearing loss and diabetes , MIM#619269
Review for gene: MIA3 was set to AMBER
Added comment: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability. Four affected siblings reported, homozygous variant affecting splicing. Mouse model has absence of bone mineralization. Can present with IUGR antenatally. Suitable for fetal anomalies panel.
Sources: Expert list
Fetal anomalies v0.4178 MBTPS1 Chirag Patel gene: MBTPS1 was added
gene: MBTPS1 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: MBTPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MBTPS1 were set to PMID: 32857899; 32420688; 30046013
Phenotypes for gene: MBTPS1 were set to Skeletal dysplasia, no OMIM #
Review for gene: MBTPS1 was set to GREEN
Added comment: Three unrelated individuals reported with bi-allelic variants in this gene and a skeletal dysplasia, one described with SRS-like features. Elevated blood lysosomal enzymes are also a feature.
Sources: Expert list
Fetal anomalies v0.4176 HOXA11 Chirag Patel gene: HOXA11 was added
gene: HOXA11 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: HOXA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HOXA11 were set to PubMed: 11101832
Phenotypes for gene: HOXA11 were set to Radioulnar synostosis with amegakaryocytic thrombocytopenia 1 , OMIM #605432
Review for gene: HOXA11 was set to AMBER
Added comment: Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is characterized by thrombocytopenia that progresses to pancytopenia, in association with congenital proximal fusion of the radius and ulna that results in extremely limited pronation and supination of the forearm. A heterozygous mutation in the HOXA11 gene was found in affected members of 2 families segregating radioulnar synostosis and amegakaryocytic thrombocytopenia.
Sources: Literature
Fetal anomalies v0.4172 COL27A1 Chirag Patel gene: COL27A1 was added
gene: COL27A1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: COL27A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COL27A1 were set to PubMed: 24986830, 28276056, 28322503
Phenotypes for gene: COL27A1 were set to Steel syndrome, OMIM #615155
Review for gene: COL27A1 was set to GREEN
Added comment: Steel syndrome is characterized by characteristic facies, congenital dislocated hips and radial heads, carpal coalition (fusion of carpal bones), short stature, scoliosis, and cervical spine anomalies. The dislocated hips are resistant to surgical intervention. 3 families with biallelic variants reported.
Sources: Literature
Fetal anomalies v0.4170 CHST11 Chirag Patel gene: CHST11 was added
gene: CHST11 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: CHST11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHST11 were set to PMID: 26436107; 29514872
Phenotypes for gene: CHST11 were set to Osteochondrodysplasia, brachydactyly, and overlapping malformed digits, MIM# 618167
Review for gene: CHST11 was set to GREEN
Added comment: Osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD) is characterized by bilateral symmetric skeletal defects that primarily affect the limbs. Affected individuals have mild short stature due to shortening of the lower leg bones, as well as hand and foot malformations, predominantly brachydactyly and overlapping digits. Other skeletal defects include scoliosis, dislocated patellae and fibulae, and pectus excavatum. Two unrelated families reported, note one had a homozygous deletion.
Sources: Expert list
Fetal anomalies v0.4168 PRDM15 Chirag Patel gene: PRDM15 was added
gene: PRDM15 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: PRDM15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM15 were set to PMID: 31950080
Phenotypes for gene: PRDM15 were set to Holoprosenephaly; Steroid resistant nephrotic syndrome; Multiple congenital anomalies
Review for gene: PRDM15 was set to AMBER
Added comment: Four consanguineous families reported with same homozygous variant, C844Y, shown to be LoF. Syndromic HPE including SRNS, brain malformations, polydactyly, congenital heart disease. Mouse model, extensive functional data. Two additional homozygous missense identified with isolated SRNS.
Sources: Expert list
Fetal anomalies v0.4166 FERMT3 Zornitza Stark Marked gene: FERMT3 as ready
Fetal anomalies v0.4165 RNF113A Chirag Patel gene: RNF113A was added
gene: RNF113A was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: RNF113A was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: RNF113A were set to PMID: 25612912; 31793730; 31880405
Phenotypes for gene: RNF113A were set to Trichothiodystrophy 5, nonphotosensitive; OMIM #300953
Review for gene: RNF113A was set to GREEN
Added comment: Four families reported, two with same variant. Clinical features include ID, microcephaly, IUGR/growth failure, hypogonadism, and sparse/brittle hair. One of the families had antenatal presentation.
Sources: Expert list
Fetal anomalies v0.4163 RAP1B Chirag Patel gene: RAP1B was added
gene: RAP1B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAP1B were set to PMID: 32627184; 26280580
Phenotypes for gene: RAP1B were set to Syndromic intellectual disability; short stature
Review for gene: RAP1B was set to GREEN
Added comment: Three unrelated individuals reported, Kabuki-like disorder (multiple malformations, microcephaly, learning difficulties, dysmorphism and other features).
Sources: Literature
Fetal anomalies v0.4161 RAD50 Chirag Patel gene: RAD50 was added
gene: RAD50 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: RAD50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAD50 were set to PMID: 19409520; 32212377; 33378670
Phenotypes for gene: RAD50 were set to Nijmegen breakage syndrome-like disorder, MIM# 613078; MONDO:0013118
Review for gene: RAD50 was set to GREEN
Added comment: Nijmegen breakage syndrome-like disorder (NBSLD) is an autosomal recessive disorder characterized by severe prenatal growth retardation and persistent postnatal growth restriction, congenital microcephaly, borderline to mildly impaired intellectual development, normal sexual development, and radioresistant DNA synthesis with no immunodeficiency, myelodysplasia, or early neurodegeneration. Three unrelated families reported.
Sources: Expert list
Fetal anomalies v0.4157 FRA10AC1 Chirag Patel gene: FRA10AC1 was added
gene: FRA10AC1 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: FRA10AC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FRA10AC1 were set to PMID: 34694367
Phenotypes for gene: FRA10AC1 were set to Neurodevelopmental disorder, MONDO:0700092, FRA10AC1-related
Review for gene: FRA10AC1 was set to GREEN
Added comment: 5 individuals from 3 unrelated families reported. Variable ID, possibly related to variant type with LoF variants associated with more severe ID. All individuals had microcephaly, hypoplasia or agenesis of the corpus callosum, growth retardation, and craniofacial dysmorphism.
Sources: Expert list
Fetal anomalies v0.4155 DNA2 Chirag Patel gene: DNA2 was added
gene: DNA2 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: DNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNA2 were set to PMID: 24389050; 31045292
Phenotypes for gene: DNA2 were set to Seckel syndrome 8, MIM#615807
Review for gene: DNA2 was set to GREEN
Added comment: Three families described with bi-allelic variants in this gene and a primordial dwarfism/Seckel syndrome phenotype (intrauterine growth retardation, dwarfism, microcephaly with mental retardation, and a characteristic 'bird-headed' facial appearance). Note this gene is associated with multiple phenotypes.
Sources: Expert list
Fetal anomalies v0.4153 BRD4 Chirag Patel gene: BRD4 was added
gene: BRD4 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: BRD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRD4 were set to PMID: 29379197, 30302754, 11997514, 34035299
Phenotypes for gene: BRD4 were set to Cornelia de Lange syndrome (no OMIM# yet)
Review for gene: BRD4 was set to GREEN
Added comment: Cornelia de Lange syndrome is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Affected individuals have dysmorphic facial features, cleft palate, distal limb defects, prenatal onset growth retardation, and developmental delay. About 1% of patients have mutations in the BRD4 gene. % patients reported with functional evidence.
Sources: Expert list
Fetal anomalies v0.4149 MNS1 Chirag Patel gene: MNS1 was added
gene: MNS1 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: MNS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MNS1 were set to PMID: 31534215; 30148830
Phenotypes for gene: MNS1 were set to Heterotaxy; male infertility; Heterotaxy, visceral, 9, autosomal, with male infertility 618948
Review for gene: MNS1 was set to GREEN
Added comment: Eight families reported altogether. However, four are Amish and share same homozygous founder variant, and some of the other reported families are consanguineous and share another founder. A reported female with a third variant, also had a homozygous variant in DNAH5 with a blended phenotype postulated.
Sources: Expert list
Fetal anomalies v0.4145 CFAP45 Chirag Patel gene: CFAP45 was added
gene: CFAP45 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: CFAP45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP45 were set to PMID: 33139725
Phenotypes for gene: CFAP45 were set to Heterotaxy, visceral, 11, autosomal, with male infertility, MIM#619608
Review for gene: CFAP45 was set to GREEN
Added comment: Three unrelated individuals reported with bi-alleic LOF variants, mouse model recapitulated phenotype.
Sources: Expert list
Fetal anomalies v0.4143 EDN3 Chirag Patel gene: EDN3 was added
gene: EDN3 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: EDN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EDN3 were set to PMID: 8630502; 11303518; 9359047; 10231870; 30171849; 27370713
Phenotypes for gene: EDN3 were set to Central hypoventilation syndrome, congenital, MIM# 209880; Waardenburg syndrome, type 4B, MIM# 613265; {Hirschsprung disease, susceptibility to, 4}, MIM# 613712
Review for gene: EDN3 was set to GREEN
Added comment: Variants in this gene have been reported in both isolated HD and syndromic HD, variable penetrance. However, the variants reported in PMID 9359047 with isolated HD are present at high frequencies in gnomad: p.Ala17Thr >800 hets in gnomad, p.Ala224Thr >100 hets. Association with syndromic neural crest disorders is more definitive, and HD is reported in a proportion of individuals.
Sources: Expert list
Fetal anomalies v0.4142 SOST Seb Lunke Marked gene: SOST as ready
Fetal anomalies v0.4142 SOST Seb Lunke changed review comment from: Well established association with recessive Sclerosteosis 1 (OMIM#122860) characterised by overgrowth and multiple facial and skeletal abnormalities

Dominant association with Craniodiaphyseal dysplasia (OMIM#122860) has been described in two indipendent patients only, with different missense variants at the same residue (V21M, V21L)

NOTE: Common 52-kb deletion downstream of SOST (van Buchem disease, MIM#239100); to: Well established association with recessive Sclerosteosis 1 (OMIM#269500) characterised by overgrowth and multiple facial and skeletal abnormalities

Dominant association with Craniodiaphyseal dysplasia (OMIM#122860) has been described in two indipendent patients only, with different missense variants at the same residue (V21M, V21L)

NOTE: Common 52-kb deletion downstream of SOST (van Buchem disease, MIM#239100)
Fetal anomalies v0.4141 SOX2 Seb Lunke Marked gene: SOX2 as ready
Fetal anomalies v0.4138 SOX3 Seb Lunke Marked gene: SOX3 as ready
Fetal anomalies v0.4137 SOX3 Seb Lunke Mode of pathogenicity for gene: SOX3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.4136 SOX3 Seb Lunke Added comment: Comment on list classification: Ala Repeat expansion linked to growth hormone deficiency, but not much evidence so far, onset appears post-natal, and described brain MRI findings appear subtle.
Fetal anomalies v0.4134 SPAG1 Seb Lunke Marked gene: SPAG1 as ready
Fetal anomalies v0.4134 SPAG1 Seb Lunke Added comment: Comment when marking as ready: Situs inversus in 50% of patients
Fetal anomalies v0.4134 SPAG1 Seb Lunke Phenotypes for gene: SPAG1 were changed from PRIMARY CILIARY DYSKINESIA ASSOCIATED WITH DEFECTIVE OUTER AND INNER DYNEIN ARMS. to Ciliary dyskinesia, primary, 28 (MIM#615505)
Fetal anomalies v0.4132 ALG14 Belinda Chong gene: ALG14 was added
gene: ALG14 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ALG14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG14 were set to 23404334; 28733338; 30221345; 23404334; 28733338
Phenotypes for gene: ALG14 were set to Myasthenic syndrome, congenital, 15, without tubular aggregates 616227; Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036; Disorder of N-glycosylation
Review for gene: ALG14 was set to GREEN
gene: ALG14 was marked as current diagnostic
Added comment: Three OMIM disorders however, only Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036 with prenatal manifestations.

5 individuals from unrelated families described in the literature: one with myasthenic syndrome, no report of ID; second with predominantly ID phenotype; and three more with a neurodegenerative phenotype. ALG14 is part of the UDP-GlcNAc transferase, which catalyzes a key step in endoplasmic reticulum N-linked glycosylation. The three OMIM disorders may represent a spectrum of severity for CDG.
Sources: Literature
Fetal anomalies v0.4132 PLEKHM1 Krithika Murali gene: PLEKHM1 was added
gene: PLEKHM1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLEKHM1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PLEKHM1 were set to 17404618; 17997709; 27291868; 27777970; 28290981
Phenotypes for gene: PLEKHM1 were set to ?Osteopetrosis, autosomal recessive 6 - MIM#611497; Osteopetrosis, autosomal dominant 3 - MIM#618107
Review for gene: PLEKHM1 was set to RED
Added comment: No antenatal features reported.

--
PMID: 17997709 Del Fattore et al 2008 - female proband with monoallelic variant, no antenatal features reported.

PMID: 27291868 Bo et al 2016 - male proband with osteopetrosis and heterozygous de novo variant. No antenatal features reported.

PMID: 28290981 Moore et al 2017 - compound het variants, osteopetrosis diagnosis in a 19 year old. No antenatal features reported.

PMID: 21054159 Almarzooqi et al 2010 - heterozygous variant, infantile osteopetrosis and xanthogranuloma, uncomplicated pregnancy.
Sources: Literature
Fetal anomalies v0.4132 FERMT3 Krithika Murali gene: FERMT3 was added
gene: FERMT3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FERMT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FERMT3 were set to 31068971; 34485203; 33391282; 31724816; 30412664; 25854317; 28095295; 26359933; 25072369; 22134107; 20216991; 19234463; 19234460; 18779414
Phenotypes for gene: FERMT3 were set to Leukocyte adhesion deficiency, type III - MIM#612840
Review for gene: FERMT3 was set to RED
Added comment: Biallelic variants associated with LAD3 syndrome (primary immunodeficiency and platelet function defects). Symptom onset reported from birth, no antenatal features reported.

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PMID: 34485203 Yahya et al 2021 - no antenatal issues reported

PMID: 33391282 Kambli et al 2020 - no antenatal features reported for 5 individuals with LAD3

PMID 31068971 Shahid et al 2019 - no antenatal features

PMID: 31724816 Manukjan et al 2019 - no antenatal issues reported in 1 affected individual

PMID: 28095295 Palagano et al 2017 - report female proband with infantile-onset osteopetrosis and symptomatic haematological anomalies at birth requiring bone marrow transplant. Authors postulate in utero onset but no antenatal features reported.

PMID: 26359933 Suratannon et al 2016 - report a female Thai proband with a milder/atypical phenotype, no antenatal features reported

PMID: 25854317 Crazzolara et al 2015 - presented D7 of life with infection, bleeeding issues and noted radiologically to have dense bones. No antenatal features.

PMID: 25072369 Stepensky et al 2015 - report 3 individuals with bleeding tendency from birth and onset of recurrent infections as an infant, normal antenatal history.

PMID: 20357244 McDowall et al 2010 - symptom onset from birth, no antenatal features

PMID: 20216991 Jurk et al 2010 - 2 affected siblings, no antenatal features reported.

PMID: 19234463 Svensson et al 2009 - no antenatal features reported

PMID: 19234460 Malinin et al 2009 - no antenatal features reported

PMID: 19064721 Kuijpers et al 2009 - 9 individuals from 7 unrelated families, no antenatal features reported.
Sources: Literature
Fetal anomalies v0.4132 SPATA5 Zornitza Stark Marked gene: SPATA5 as ready
Fetal anomalies v0.4132 SPATA5 Zornitza Stark Phenotypes for gene: SPATA5 were changed from EPILEPSY, HEARING LOSS, AND MENTAL RETARDATION SYNDROME to Epilepsy, hearing loss, and mental retardation syndrome MIM#616577
Fetal anomalies v0.4130 SPEG Zornitza Stark Marked gene: SPEG as ready
Fetal anomalies v0.4130 SPEG Zornitza Stark Phenotypes for gene: SPEG were changed from CENTRONUCLEAR MYOPATHY WITH DILATED CARDIOMYOPATHY to Centronuclear myopathy 5, MIM# 615959
Fetal anomalies v0.4129 SPEG Zornitza Stark reviewed gene: SPEG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Centronuclear myopathy 5, MIM# 615959; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.4129 SPG11 Zornitza Stark Marked gene: SPG11 as ready
Fetal anomalies v0.4129 SPG11 Zornitza Stark Phenotypes for gene: SPG11 were changed from SPASTIC PARAPLEGIA-11 to Spastic paraplegia 11, autosomal recessive, MIM# 604360
Fetal anomalies v0.4126 SPG11 Zornitza Stark changed review comment from: Bi-alllelic variants in this gene also cause spastic paraplegia-11 (OMIM# 604360) but also juvenile amyotrophic lateral sclerosis-5 (OMIM# 602099), and CMT2X. Same variants have been reported in association with different phenotypes, poor genotype-phenotype correlation.

Recent review of >300 individuals with SPG11-related disease. Mean age at onset was 13.10 ± 3.65 years, with initial symptoms like gait disturbance (107/195, 54.87%) and intellectual disability (47/195, 24.10%). Cognitive decline (228/270, 84.44%) was the most common complex manifestation stepped by dysarthria (134/195, 68.72%), neuropathy (112/177, 63.28%), amyatrophy, sphincter disturbance (60/130, 46.15%) and ataxia (90/194, 46.39%).; to: Bi-alllelic variants in this gene also cause spastic paraplegia-11 (OMIM# 604360) but also juvenile amyotrophic lateral sclerosis-5 (OMIM# 602099), and CMT2X. Same variants have been reported in association with different phenotypes, poor genotype-phenotype correlation.

Recent review of >300 individuals with SPG11-related disease. Mean age at onset was 13.10 ± 3.65 years, with initial symptoms like gait disturbance (107/195, 54.87%) and intellectual disability (47/195, 24.10%). Cognitive decline (228/270, 84.44%) was the most common complex manifestation stepped by dysarthria (134/195, 68.72%), neuropathy (112/177, 63.28%), amyatrophy, sphincter disturbance (60/130, 46.15%) and ataxia (90/194, 46.39%).

Although onset of clinical features is typically in childhood or later, absent CC/CC abnormalities reported.
Fetal anomalies v0.4126 SPRED1 Zornitza Stark Marked gene: SPRED1 as ready
Fetal anomalies v0.4122 SPRED1 Zornitza Stark changed review comment from: Multiple affected individuals reported, deletions account for ~10% of causative variants. Legius syndrome is characterised by multiple cafe-au-lait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism or macrocephaly, lipomas, and mild learning disabilities or attention problems. It is not associated with neurofibromas, optic gliomas, Lisch nodules, or tumor predisposition. The SPRED1 gene encodes a negative regulator of the RAS-MAPK pathway, similar to neurofibromin.; to: Multiple affected individuals reported, deletions account for ~10% of causative variants. Legius syndrome is characterised by multiple cafe-au-lait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism or macrocephaly, lipomas, and mild learning disabilities or attention problems. It is not associated with neurofibromas, optic gliomas, Lisch nodules, or tumor predisposition. The SPRED1 gene encodes a negative regulator of the RAS-MAPK pathway, similar to neurofibromin.

Clinical presentation is typically post-natal.
Fetal anomalies v0.4122 SRCAP Zornitza Stark Marked gene: SRCAP as ready
Fetal anomalies v0.4122 SRCAP Zornitza Stark Phenotypes for gene: SRCAP were changed from FLOATING-HARBOR SYNDROME to Floating-Harbor syndrome, MIM# 136140
Fetal anomalies v0.4119 SRCAP Zornitza Stark edited their review of gene: SRCAP: Added comment: IUGR and multiple congenital anomalies.; Changed phenotypes: Floating-Harbor syndrome, MIM# 136140
Fetal anomalies v0.4119 SRD5A3 Zornitza Stark Marked gene: SRD5A3 as ready
Fetal anomalies v0.4117 STAG2 Zornitza Stark Marked gene: STAG2 as ready
Fetal anomalies v0.4117 STAG2 Zornitza Stark Phenotypes for gene: STAG2 were changed from STAG2-related developmental delay with microcephaly and congenital anomalies to Mullegama-Klein-Martinez syndrome, MIM# 301022; Holoprosencephaly 13, X-linked, MIM# 301043
Fetal anomalies v0.4115 STAMBP Zornitza Stark Marked gene: STAMBP as ready
Fetal anomalies v0.4115 STAMBP Zornitza Stark Phenotypes for gene: STAMBP were changed from MICROCEPHALY CAPILLARY MALFORMATION (MIC-CAP) SYNDROME to Microcephaly-capillary malformation syndrome, MIM# 614261; MONDO:0013659
Fetal anomalies v0.4113 STRA6 Zornitza Stark Marked gene: STRA6 as ready
Fetal anomalies v0.4111 SUMF1 Zornitza Stark Marked gene: SUMF1 as ready
Fetal anomalies v0.4109 SUZ12 Zornitza Stark Marked gene: SUZ12 as ready
Fetal anomalies v0.4106 TAF1 Zornitza Stark Marked gene: TAF1 as ready
Fetal anomalies v0.4106 TAF1 Zornitza Stark Phenotypes for gene: TAF1 were changed from Dysmorphic Features, Intellectual Disability, and Neurological Manifestations to Mental retardation, X-linked, syndromic 33, MIM# 300966
Fetal anomalies v0.4104 TAZ Zornitza Stark Marked gene: TAZ as ready
Fetal anomalies v0.4104 TAZ Zornitza Stark Phenotypes for gene: TAZ were changed from BARTH SYNDROME to Barth syndrome, MIM#302060
Fetal anomalies v0.4102 TBC1D20 Zornitza Stark Marked gene: TBC1D20 as ready
Fetal anomalies v0.4102 TBC1D20 Zornitza Stark Phenotypes for gene: TBC1D20 were changed from Warburg micro syndrome 4; Warburg micro syndrome 4 615663 to Warburg micro syndrome 4, MIM# 615663
Fetal anomalies v0.4101 TBCD Zornitza Stark Marked gene: TBCD as ready
Fetal anomalies v0.4100 TBCD Zornitza Stark changed review comment from: CC abnormalities.; to: CC abnormalities, arthrogryposis are relevant to fetal panel.
Fetal anomalies v0.4100 TBX1 Zornitza Stark Marked gene: TBX1 as ready
Fetal anomalies v0.4096 TBX3 Zornitza Stark Marked gene: TBX3 as ready
Fetal anomalies v0.4096 TBX3 Zornitza Stark Phenotypes for gene: TBX3 were changed from ULNAR-MAMMARY SYNDROME to Ulnar-mammary syndrome, MIM# 181450; MONDO:0008411
Fetal anomalies v0.4093 TBX5 Zornitza Stark Marked gene: TBX5 as ready
Fetal anomalies v0.4090 TCF4 Zornitza Stark Marked gene: TCF4 as ready
Fetal anomalies v0.4087 TCIRG1 Zornitza Stark Marked gene: TCIRG1 as ready
Fetal anomalies v0.4087 TCTN1 Zornitza Stark Marked gene: TCTN1 as ready
Fetal anomalies v0.4085 TCTN2 Zornitza Stark Marked gene: TCTN2 as ready
Fetal anomalies v0.4083 TCTN3 Zornitza Stark Marked gene: TCTN3 as ready
Fetal anomalies v0.4081 TFAP2A Zornitza Stark Marked gene: TFAP2A as ready
Fetal anomalies v0.4078 TFAP2B Zornitza Stark Marked gene: TFAP2B as ready
Fetal anomalies v0.4078 TFAP2B Zornitza Stark Phenotypes for gene: TFAP2B were changed from CHAR SYNDROME to Char syndrome, MIM# 169100; Syndromic craniosynostosis
Fetal anomalies v0.4074 TFAP2B Zornitza Stark changed review comment from: PDA, facial dysmorphism and clinodactyly unlikely to be detectable antenatally.; to: Char syndrome: PDA, facial dysmorphism and clinodactyly unlikely to be detectable antenatally.

Craniosynostosis: Four individuals reported in PMID: 31292255 (Correction in PMID: 31405973) as part of a craniosynostosis cohort: 2 de novo and 2 inherited. There is evidence for reduced penetrance as in one case the variant was inherited from an unaffected parent (affected parent for the other inherited variant).
Fetal anomalies v0.4074 TFAP2B Zornitza Stark edited their review of gene: TFAP2B: Changed rating: GREEN; Changed publications: 31292255; Changed phenotypes: Char syndrome, MIM# 169100, Syndromic craniosynostosis
Fetal anomalies v0.4073 TFAP2B Zornitza Stark reviewed gene: TFAP2B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Char syndrome, MIM# 169100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.4073 TGFBR1 Zornitza Stark Marked gene: TGFBR1 as ready
Fetal anomalies v0.4071 TGFBR2 Zornitza Stark Marked gene: TGFBR2 as ready
Fetal anomalies v0.4069 TGIF1 Zornitza Stark Marked gene: TGIF1 as ready
Fetal anomalies v0.4066 TINF2 Zornitza Stark Marked gene: TINF2 as ready
Fetal anomalies v0.4066 TINF2 Zornitza Stark Phenotypes for gene: TINF2 were changed from EXUDATIVE RETINOPATHY WITH BONE MARROW FAILURE to Revesz syndrome, MIM# 268130
Fetal anomalies v0.4063 TINF2 Zornitza Stark changed review comment from: Bone marrow failure is the main presenting feature. DD is part of the phenotype, neurological involvement progressive.; to: IUGR.
Fetal anomalies v0.4063 TMEM138 Zornitza Stark Marked gene: TMEM138 as ready
Fetal anomalies v0.4061 TMEM165 Zornitza Stark Marked gene: TMEM165 as ready
Fetal anomalies v0.4059 TMEM231 Zornitza Stark Marked gene: TMEM231 as ready
Fetal anomalies v0.4057 TMEM237 Zornitza Stark Marked gene: TMEM237 as ready
Fetal anomalies v0.4055 TMEM5 Zornitza Stark Marked gene: TMEM5 as ready
Fetal anomalies v0.4055 TMEM5 Zornitza Stark Phenotypes for gene: TMEM5 were changed from SEVERE COBBLESTONE LISSENCEPHALY to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 10, MIM# 615041, MONDO:0014022
Fetal anomalies v0.4053 TMEM67 Zornitza Stark Marked gene: TMEM67 as ready
Fetal anomalies v0.4051 TMEM94 Zornitza Stark Marked gene: TMEM94 as ready
Fetal anomalies v0.4051 TOP3A Zornitza Stark Marked gene: TOP3A as ready
Fetal anomalies v0.4049 TP63 Zornitza Stark Marked gene: TP63 as ready
Fetal anomalies v0.4049 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE; ACRO-DERMATO-UNGUAL-LACRIMAL-TOOTH SYNDROME; ECTRODACTYLY-ECTODERMAL DYSPLASIA-CLEFT LIP/PALATE SYNDROME TYPE 3; SPLIT-HAND/FOOT MALFORMATION TYPE 4; ECTODERMAL DYSPLASIA RAPP-HODGKIN TYPE; NON-SYNDROMIC OROFACIAL CLEFT TYPE 8; LIMB-MAMMARY SYNDROME to ADULT syndrome, OMIM #103285; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM #604292; Hay-Wells syndrome, OMIM #106260; Limb-mammary syndrome, OMIM #603543; Orofacial cleft 8, OMIM #618149; Rapp-Hodgkin syndrome, OMIM #129400; Split-hand/foot malformation 4, OMIM #605289
Fetal anomalies v0.4047 TP63 Zornitza Stark reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ADULT syndrome, OMIM #103285, Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM #604292, Hay-Wells syndrome, OMIM #106260, Limb-mammary syndrome, OMIM #603543, Orofacial cleft 8, OMIM #618149, Rapp-Hodgkin syndrome, OMIM #129400, Split-hand/foot malformation 4, OMIM #605289; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.4047 TPM2 Zornitza Stark Marked gene: TPM2 as ready
Fetal anomalies v0.4047 TPM2 Zornitza Stark Phenotypes for gene: TPM2 were changed from Arthrogryposis multiplex congenita, distal, type 1, 108120; Arthrogryposis, distal, type 2B, 601680; ARTHROGRYPOSIS, DISTAL, TYPE 1 to Arthrogryposis multiplex congenita, distal, type 1, 108120; Arthrogryposis, distal, type 2B, 601680; Multiple pterygium syndrome
Fetal anomalies v0.4044 TRAF7 Zornitza Stark Marked gene: TRAF7 as ready
Fetal anomalies v0.4044 TRAF7 Zornitza Stark Phenotypes for gene: TRAF7 were changed from Developmental Delay, Congenital Anomalies, and Dysmorphic Features; Cardiac, facial, and digital anomalies with developmental delay, 618164 to Cardiac, facial, and digital anomalies with developmental delay, MIM# 618164
Fetal anomalies v0.4041 TRAPPC9 Zornitza Stark Marked gene: TRAPPC9 as ready
Fetal anomalies v0.4041 TRAPPC9 Zornitza Stark Phenotypes for gene: TRAPPC9 were changed from MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 13 to Intellectual disability, autosomal recessive 13 (MIM# 613192)
Fetal anomalies v0.4039 TRIM37 Zornitza Stark Marked gene: TRIM37 as ready
Fetal anomalies v0.4038 TRIP11 Zornitza Stark Marked gene: TRIP11 as ready
Fetal anomalies v0.4036 TRIP12 Zornitza Stark Marked gene: TRIP12 as ready
Fetal anomalies v0.4036 TRIP12 Zornitza Stark Phenotypes for gene: TRIP12 were changed from TRIP12-related intellectual disability with/without autism spectrum disorder to Mental retardation autosomal dominant 49, Clark-Baraitser Syndrome, MIM#617752
Fetal anomalies v0.4032 TRIP12 Zornitza Stark reviewed gene: TRIP12: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation autosomal dominant 49, Clark-Baraitser Syndrome, MIM#617752; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.4032 TRIP4 Zornitza Stark Marked gene: TRIP4 as ready
Fetal anomalies v0.4032 TRIP4 Zornitza Stark Phenotypes for gene: TRIP4 were changed from Prenatal-onset spinal muscular atrophy with congenital bone fractures, MONDO:0000209; Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome, MONDO:0014896; ?Muscular dystrophy, congenital, Davignon-Chauveau type, OMIM:617066; Spinal muscular atrophy with congenital bone fractures 1, OMIM:616866; Spinal muscular atrophy with congenital bone fractures 1, MONDO:0014806 to Spinal muscular atrophy with congenital bone fractures 1, OMIM:616866; Spinal muscular atrophy with congenital bone fractures 1, MONDO:0014806
Fetal anomalies v0.4031 TSEN54 Zornitza Stark Marked gene: TSEN54 as ready
Fetal anomalies v0.4031 TSEN54 Zornitza Stark Phenotypes for gene: TSEN54 were changed from ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 4, OMIM:225753; Pontocerebellar hypoplasia type 2A, OMIM:277470 to Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 4, OMIM:225753; Pontocerebellar hypoplasia type 2A, OMIM:277470
Fetal anomalies v0.4029 TTC21B Zornitza Stark Marked gene: TTC21B as ready
Fetal anomalies v0.4027 TTC8 Zornitza Stark Marked gene: TTC8 as ready
Fetal anomalies v0.4027 TTC8 Zornitza Stark Phenotypes for gene: TTC8 were changed from RETINITIS PIGMENTOSA TYPE 51; BARDET-BIEDL SYNDROME TYPE 8 to Bardet-Biedl syndrome 8, MIM# 615985
Fetal anomalies v0.4025 TTN Zornitza Stark Marked gene: TTN as ready
Fetal anomalies v0.4025 TTN Zornitza Stark Phenotypes for gene: TTN were changed from congenital titinopathy with arthrogryposis to Salih myopathy; Muscular dystrophy, limb-girdle, autosomal recessive 10
Fetal anomalies v0.4023 TUBB Zornitza Stark Marked gene: TUBB as ready
Fetal anomalies v0.4020 TUBB2A Zornitza Stark Marked gene: TUBB2A as ready
Fetal anomalies v0.4018 TUBB2B Zornitza Stark Marked gene: TUBB2B as ready
Fetal anomalies v0.4016 TUBGCP6 Zornitza Stark Marked gene: TUBGCP6 as ready
Fetal anomalies v0.4016 TUBGCP6 Zornitza Stark Phenotypes for gene: TUBGCP6 were changed from MICROCEPHALY AND CHORIORETINOPATHY WITH OR WITHOUT MENTAL RETARDATION to Microcephaly and chorioretinopathy, autosomal recessive, 1, MIM#251270
Fetal anomalies v0.4014 UBA1 Zornitza Stark Marked gene: UBA1 as ready
Fetal anomalies v0.4014 UBA1 Zornitza Stark Phenotypes for gene: UBA1 were changed from Spinal muscular atrophy, X-linked 2, infantile 301830 to Spinal muscular atrophy, X-linked 2, infantile, MIM# 301830
Fetal anomalies v0.4012 UBE3B Zornitza Stark Marked gene: UBE3B as ready
Fetal anomalies v0.4012 UBE3B Zornitza Stark Phenotypes for gene: UBE3B were changed from BLEPHAROPHIMOSIS-MENTAL RETARDATION to Kaufman oculocerebrofacial syndrome, MIM# 244450; MONDO:0009485
Fetal anomalies v0.4010 UBE3B Zornitza Stark changed review comment from: Intellectual disability, microcephaly, dysmorphic features, including blepharophimosis and ptosis. Over 20 families reported.; to: Intellectual disability, microcephaly, dysmorphic features, including blepharophimosis and ptosis. Congenital heart disease. Over 20 families reported.
Fetal anomalies v0.4010 UBR1 Zornitza Stark Marked gene: UBR1 as ready
Fetal anomalies v0.4010 UBR1 Zornitza Stark Phenotypes for gene: UBR1 were changed from JOHANSON-BLIZZARD SYNDROME to Johanson-Blizzard syndrome (MIM#243800)
Fetal anomalies v0.4008 UMPS Zornitza Stark Marked gene: UMPS as ready
Fetal anomalies v0.4006 VIPAS39 Zornitza Stark Marked gene: VIPAS39 as ready
Fetal anomalies v0.4006 VIPAS39 Zornitza Stark Phenotypes for gene: VIPAS39 were changed from ARTHROGRYPOSIS, RENAL DYSFUNCTION, AND CHOLESTASIS 2 to Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM #613404
Fetal anomalies v0.4004 VIPAS39 Zornitza Stark reviewed gene: VIPAS39: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 2, OMIM #613404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.4004 VPS13B Zornitza Stark Marked gene: VPS13B as ready
Fetal anomalies v0.4002 VPS33B Zornitza Stark Marked gene: VPS33B as ready
Fetal anomalies v0.4002 VPS33B Zornitza Stark Phenotypes for gene: VPS33B were changed from ARTHROGRYPOSIS, RENAL DYSFUNCTION, AND CHOLESTASIS 1 to Arthrogryposis, renal dysfunction, and cholestasis 1 (MIM#208085)
Fetal anomalies v0.4000 VSX2 Zornitza Stark Marked gene: VSX2 as ready
Fetal anomalies v0.4000 VSX2 Zornitza Stark Phenotypes for gene: VSX2 were changed from MICROPHTHALMIA ISOLATED TYPE 2; MICROPHTHALMIA WITH CATARACTS AND IRIS ABNORMALITIES; MICROPHTHALMIA ISOLATED WITH COLOBOMA TYPE 3 to Microphthalmia with coloboma 3, MIM# 610092; Microphthalmia, isolated 2, MIM# 610093
Fetal anomalies v0.3998 WDPCP Zornitza Stark Marked gene: WDPCP as ready
Fetal anomalies v0.3998 WDPCP Zornitza Stark Phenotypes for gene: WDPCP were changed from BARDET-BIEDL SYNDROME TYPE 15 to Bardet-Biedl syndrome 15, MIM# 615992; OFD; Congenital heart defects, hamartomas of tongue, and polysyndactyly, 217085
Fetal anomalies v0.3996 WDR19 Zornitza Stark Marked gene: WDR19 as ready
Fetal anomalies v0.3994 WDR19 Zornitza Stark changed review comment from: Variants in this gene are associated with a range of ciliopathies. Two families reported with a predominantly skeletal phenotype.; to: Variants in this gene are associated with a range of ciliopathies.
Fetal anomalies v0.3994 TBC1D1 Zornitza Stark Marked gene: TBC1D1 as ready
Fetal anomalies v0.3993 SRGAP1 Zornitza Stark Marked gene: SRGAP1 as ready
Fetal anomalies v0.3992 SLIT2 Zornitza Stark Marked gene: SLIT2 as ready
Fetal anomalies v0.3991 ANKRD17 Zornitza Stark Marked gene: ANKRD17 as ready
Fetal anomalies v0.3990 ALB Zornitza Stark Marked gene: ALB as ready
Fetal anomalies v0.3989 ACBD5 Zornitza Stark Marked gene: ACBD5 as ready
Fetal anomalies v0.3988 ZNF711 Zornitza Stark Marked gene: ZNF711 as ready
Fetal anomalies v0.3988 ZNF711 Zornitza Stark Phenotypes for gene: ZNF711 were changed from MENTAL RETARDATION X-LINKED ZNF711-RELATED to Mental retardation, X-linked 97, OMIM #300803
Fetal anomalies v0.3986 ZNF711 Zornitza Stark reviewed gene: ZNF711: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, X-linked 97, OMIM #300803; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v0.3986 ZNF3 Zornitza Stark Marked gene: ZNF3 as ready
Fetal anomalies v0.3986 XPA Zornitza Stark Marked gene: XPA as ready
Fetal anomalies v0.3984 XPA Zornitza Stark changed review comment from: Multiple families reported where ID is part of the phenotype, though some share haplotype and are likely distantly related.; to: Clinical presentation is typically post-natal.
Fetal anomalies v0.3984 WDR91 Zornitza Stark Marked gene: WDR91 as ready
Fetal anomalies v0.3983 WDR11 Zornitza Stark Marked gene: WDR11 as ready
Fetal anomalies v0.3979 WASHC5 Zornitza Stark Marked gene: WASHC5 as ready
Fetal anomalies v0.3979 WASHC5 Zornitza Stark Phenotypes for gene: WASHC5 were changed from Ritscher-Schinzel syndrome 1 220210; Spastic paraplegia 8, autosomal dominant 603563 to Ritscher-Schinzel syndrome 1, MIM# 220210
Fetal anomalies v0.3977 WAC Zornitza Stark Marked gene: WAC as ready
Fetal anomalies v0.3974 UROC1 Zornitza Stark Marked gene: UROC1 as ready
Fetal anomalies v0.3972 UPF3B Zornitza Stark Marked gene: UPF3B as ready
Fetal anomalies v0.3972 UPF3B Zornitza Stark Phenotypes for gene: UPF3B were changed from MENTAL RETARDATION SYNDROMIC X-LINKED TYPE 14 to Mental retardation, X-linked, syndromic 14, MIM# 300676
Fetal anomalies v0.3970 UNC80 Zornitza Stark Marked gene: UNC80 as ready
Fetal anomalies v0.3969 UFM1 Zornitza Stark Marked gene: UFM1 as ready
Fetal anomalies v0.3969 UFM1 Zornitza Stark Phenotypes for gene: UFM1 were changed from Severe early-onset encephalopathy with progressive microcephaly, to Leukodystrophy, hypomyelinating, 14 MIM#617899
Fetal anomalies v0.3967 UFC1 Zornitza Stark Marked gene: UFC1 as ready
Fetal anomalies v0.3967 UFC1 Zornitza Stark Phenotypes for gene: UFC1 were changed from Severe early-onset encephalopathy with progressive microcephaly to Neurodevelopmental disorder with spasticity and poor growth (MIM#618076)
Fetal anomalies v0.3965 UBE3A Zornitza Stark Marked gene: UBE3A as ready
Fetal anomalies v0.3964 UBE2A Zornitza Stark Marked gene: UBE2A as ready
Fetal anomalies v0.3964 UBE2A Zornitza Stark Phenotypes for gene: UBE2A were changed from UBE2A-RELATED X-LINKED SYNDROMIC MENTAL RETARDATION to Mental retardation, X-linked syndromic, Nascimento-type (MIM#300860)
Fetal anomalies v0.3962 UBE2A Zornitza Stark reviewed gene: UBE2A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, X-linked syndromic, Nascimento-type (MIM#300860); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v0.3962 UBA5 Zornitza Stark Marked gene: UBA5 as ready
Fetal anomalies v0.3962 UBA5 Zornitza Stark Phenotypes for gene: UBA5 were changed from Severe Infantile-Onset Encephalopathy to Epileptic encephalopathy, early infantile, 44 (MIM#617132)
Fetal anomalies v0.3960 UBA5 Zornitza Stark reviewed gene: UBA5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Epileptic encephalopathy, early infantile, 44 (MIM#617132); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3960 TUSC3 Zornitza Stark Marked gene: TUSC3 as ready
Fetal anomalies v0.3960 TUSC3 Zornitza Stark Phenotypes for gene: TUSC3 were changed from MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 7 to Mental retardation, autosomal recessive 7, MIM# 611093, MONDO:0012615; TUSC3-CDG (Disorders of protein N-glycosylation)
Fetal anomalies v0.3958 TMEM70 Zornitza Stark Marked gene: TMEM70 as ready
Fetal anomalies v0.3958 TMEM70 Zornitza Stark Phenotypes for gene: TMEM70 were changed from MITOCHONDRIAL COMPLEX V (ATP SYNTHASE) DEFICIENCY, NUCLEAR TYPE 2 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 MIM#614052
Fetal anomalies v0.3955 TIMM8A Zornitza Stark Marked gene: TIMM8A as ready
Fetal anomalies v0.3954 TGFB1 Zornitza Stark Marked gene: TGFB1 as ready
Fetal anomalies v0.3951 TERT Zornitza Stark Marked gene: TERT as ready
Fetal anomalies v0.3951 TERT Zornitza Stark Phenotypes for gene: TERT were changed from Dyskeratosis congenita, autosomal recessive 4 to Dyskeratosis congenita, autosomal recessive 4, OMIM #613989; Hoyeraal-Hreidarsson syndrome
Fetal anomalies v0.3948 TCN2 Zornitza Stark Marked gene: TCN2 as ready
Fetal anomalies v0.3946 SYNGAP1 Zornitza Stark Marked gene: SYNGAP1 as ready
Fetal anomalies v0.3946 SYNGAP1 Zornitza Stark Phenotypes for gene: SYNGAP1 were changed from MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 5; EPILEPTIC ENCEPHALOPATHY to Intellectual disability, autosomal dominant 5 (MIM # 612621)
Fetal anomalies v0.3943 STAG1 Zornitza Stark Marked gene: STAG1 as ready
Fetal anomalies v0.3943 STAG1 Zornitza Stark Phenotypes for gene: STAG1 were changed from STAG1 syndromic intellectual disability to Mental retardation, autosomal dominant 47, MIM# 617635
Fetal anomalies v0.3940 SLC9A6 Zornitza Stark Marked gene: SLC9A6 as ready
Fetal anomalies v0.3940 SLC9A6 Zornitza Stark Phenotypes for gene: SLC9A6 were changed from MENTAL RETARDATION SYNDROMIC X-LINKED CHRISTIANSON TYPE to Mental retardation, X-linked syndromic, Christianson type, MIM# 300243; MONDO:0010278
Fetal anomalies v0.3938 SLC46A1 Zornitza Stark Marked gene: SLC46A1 as ready
Fetal anomalies v0.3938 SLC46A1 Zornitza Stark Phenotypes for gene: SLC46A1 were changed from HEREDITARY FOLATE MALABSORPTION to Folate malabsorption, hereditary, MIM# 229050
Fetal anomalies v0.3936 SLC37A4 Zornitza Stark Marked gene: SLC37A4 as ready
Fetal anomalies v0.3934 SLC37A4 Zornitza Stark changed review comment from: Bi-allelic LOF variants in this gene cause glycogen storage disorder.

Single individual reported with heterozygous de novo variant in this gene. Clinical features included dysmorphic features (low set ears, a broad nose, mandibular micrognathia and facial asymmetry) and hepatopathy. The variant abolishes the ER retention signal of the transporter and generates a weak Golgi retention signal. Intracellular mislocalization of the transporter is postulated to lead to a congenital disorder of glycosylation instead of glycogen storage disease.
Sources: Literature; to: Bi-allelic LOF variants in this gene cause glycogen storage disorder. Clinical presentation is typically post-natal.

Single individual reported with heterozygous de novo variant in this gene. Clinical features included dysmorphic features (low set ears, a broad nose, mandibular micrognathia and facial asymmetry) and hepatopathy. The variant abolishes the ER retention signal of the transporter and generates a weak Golgi retention signal. Intracellular mislocalization of the transporter is postulated to lead to a congenital disorder of glycosylation instead of glycogen storage disease.
Sources: Literature
Fetal anomalies v0.3934 SLC2A2 Zornitza Stark Marked gene: SLC2A2 as ready
Fetal anomalies v0.3933 SLC22A5 Zornitza Stark Marked gene: SLC22A5 as ready
Fetal anomalies v0.3933 SLC22A5 Zornitza Stark Phenotypes for gene: SLC22A5 were changed from SYSTEMIC PRIMARY CARNITINE DEFICIENCY to Carnitine deficiency, systemic primary, MIM#212140
Fetal anomalies v0.3932 SLC22A5 Zornitza Stark changed review comment from: Encephalopathy due to episodes of hypoglycaemia, ID is not part of the phenotype.; to: Clinical presentation is typically post-natal.
Fetal anomalies v0.3932 SLC2A1 Zornitza Stark Marked gene: SLC2A1 as ready
Fetal anomalies v0.3930 SKIV2L Zornitza Stark Marked gene: SKIV2L as ready
Fetal anomalies v0.3928 SHROOM4 Zornitza Stark Marked gene: SHROOM4 as ready
Fetal anomalies v0.3927 SHROOM4 Zornitza Stark changed review comment from: Two families only, clinical presentation is typically post-natal.; to: Two families only, clinical presentation is typically post-natal; there are only two P/LP variants in this gene in ClinVar. Fetus identified as part of an ACC cohort with LoF variant in SHROOM4, PMID 32565546.
Fetal anomalies v0.3926 SGCA Zornitza Stark Marked gene: SGCA as ready
Fetal anomalies v0.3926 SGCA Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: Clinical presentation is typically post-natal.
Fetal anomalies v0.3926 SELENON Zornitza Stark Marked gene: SELENON as ready
Fetal anomalies v0.3925 SELENON Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: Clinical presentation is typically post-natal.
Fetal anomalies v0.3925 SDHAF1 Zornitza Stark Marked gene: SDHAF1 as ready
Fetal anomalies v0.3925 SDHAF1 Zornitza Stark Phenotypes for gene: SDHAF1 were changed from MITOCHONDRIAL COMPLEX II DEFICIENCY to Mitochondrial complex II deficiency, nuclear type 2, MIM# 619166
Fetal anomalies v0.3923 SCO1 Zornitza Stark Marked gene: SCO1 as ready
Fetal anomalies v0.3922 SCN7A Zornitza Stark Marked gene: SCN7A as ready
Fetal anomalies v0.3922 SCN1B Zornitza Stark Marked gene: SCN1B as ready
Fetal anomalies v0.3922 SCN1B Zornitza Stark Phenotypes for gene: SCN1B were changed from EPILEPSY, GENERALIZED, WITH FEBRILE SEIZURES PLUS, TYPE 1; BRUGADA SYNDROME 5 to Epileptic encephalopathy, early infantile, 52, MIM#617350; Atrial fibrillation, familial, 13, MIM# 615377
Fetal anomalies v0.3920 SCN1B Zornitza Stark changed review comment from: Note heterozygous variants linked to cardiac phenotypes and to GEFS+. Bi-allelic variants cause EE/ID.; to: Note heterozygous variants linked to cardiac phenotypes and to GEFS+. Bi-allelic variants cause EE/ID.

Clinical presentation is typically post-natal.
Fetal anomalies v0.3920 SCN1B Zornitza Stark edited their review of gene: SCN1B: Changed phenotypes: Epileptic encephalopathy, early infantile, 52, MIM#617350, Atrial fibrillation, familial, 13, MIM# 615377
Fetal anomalies v0.3920 PURA Zornitza Stark Marked gene: PURA as ready
Fetal anomalies v0.3920 PURA Zornitza Stark Phenotypes for gene: PURA were changed from INTELLECTUAL DISABILITY to Mental retardation, autosomal dominant 31, MIM# 616158
Fetal anomalies v0.3916 PURA Zornitza Stark changed review comment from: Multiple individuals reported with de novo variants in this gene and severe ID, hypotonia, apnoea, seizures.; to: Multiple individuals reported with de novo variants in this gene and severe ID, hypotonia, apnoea, seizures.

Typically presents post-natally, but congenital heart disease reported in some.
Fetal anomalies v0.3916 RASA2 Zornitza Stark Marked gene: RASA2 as ready
Fetal anomalies v0.3915 ALB Krithika Murali gene: ALB was added
gene: ALB was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ALB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALB were set to 23730173; 15300429; 31057599
Phenotypes for gene: ALB were set to Analbuminemia- MIM#616000
Review for gene: ALB was set to GREEN
Added comment: Biallelic variants associated with congenital analbuminaemia. Prenatal features include IUGR and oligohydramnios.

Allelic condition OMIM# 615999
Mono-allelic disease and dysalbuminemic hyperthyroxinemia: gain-of-function mechanism, missense variants of ALB with increased affinity for thyroid hormones. Immunoassay methods may show variably elevated free thyroid hormone levels. Individuals are euthyroid and identification is important to avoid unnecessary medical or surgical treatment.
Sources: Literature
Fetal anomalies v0.3915 MAPK1 Zornitza Stark Marked gene: MAPK1 as ready
Fetal anomalies v0.3914 PLOD3 Zornitza Stark Marked gene: PLOD3 as ready
Fetal anomalies v0.3912 LOXL3 Zornitza Stark Marked gene: LOXL3 as ready
Fetal anomalies v0.3911 PDIA6 Zornitza Stark Marked gene: PDIA6 as ready
Fetal anomalies v0.3910 GRK2 Zornitza Stark Marked gene: GRK2 as ready
Fetal anomalies v0.3908 RASA2 Krithika Murali gene: RASA2 was added
gene: RASA2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RASA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RASA2 were set to 25049390
Phenotypes for gene: RASA2 were set to Noonan syndrome
Review for gene: RASA2 was set to AMBER
Added comment: No OMIM gene disease association. Borderline red-amber gene. No new publications since last PanelApp review in 2020

--

One previous paper from 2014 described 3 patients with Noonan Syndrome and novel variants in RASA2. No segregation or functional data on the specific variants was provided. One of the three patients had an alternative variant in a different candidate gene.

A more recent review using ClinGen criteria (2018) only found the disease association to have limited evidence, with no further patients identified since the 2014 paper, and none since.
Sources: Literature
Fetal anomalies v0.3908 MAPK1 Krithika Murali gene: MAPK1 was added
gene: MAPK1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK1 were set to 32721402
Phenotypes for gene: MAPK1 were set to Noonan syndrome 13 - MIM#619087
Review for gene: MAPK1 was set to GREEN
Added comment: Associated with Noonan syndrome including congenital heart defects. No new publications since last PanelApp review Aug 2020

--
Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants.

The phenotype corresponded to a neurodevelopmental disorder and - as the authors comment - consistently included DD, ID , behavioral problems. Postnatal growth delay was observed in approximately half. Hypertelorism, ptosis, downslant of palpebral fissures, wide nasal bridge as low-set/posteriorly rotated ears were among the facial features observed (each in 3 or more subjects within this cohort). Together with short/webbed neck and abnormalities of skin (lentigines / CAL spots) and growth delay these led to clinical suspicion of Noonan s. or disorder of the same pathway in some. Congenital heart defects (ASD, mitral valve insufficiency, though not cardiomyopathy) occurred in 4/7. Bleeding diathesis and lymphedema were reported only once.

MAPK1 encodes the mitogen-activated protein kinase 1 (also known as ERK2) a serine/threonine kinase of the RAS-RAF-MEK-(MAPK/)ERK pathway.

MAPK1 de novo variants were identified in all individuals following trio exome sequencing (and extensive previous genetic investigations which were non-diagnostic).

The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome).
Sources: Literature
Fetal anomalies v0.3908 PLOD3 Krithika Murali gene: PLOD3 was added
gene: PLOD3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLOD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLOD3 were set to 30237576; 18834968
Phenotypes for gene: PLOD3 were set to Lysyl hydroxylase 3 deficiency - MIM#612394
Review for gene: PLOD3 was set to GREEN
Added comment: 4 unrelated families reported with biallelic PLOD3 variants and Stickler-syndrome like phenotype including antenatal phenotype of IUGR in one family.
--
PMID 30237576 Maddirevula et al 2019 - report homozygous nonsense variant in a proband with dysmorphic facies, microcephaly, ptosis and contractures. No antenatal information provided.

PMID 31129566 Ewans et al 2019 - report 3 affected siblings with a Stickler-syndrome like disorder.
- Patient 1 had congenital nystagmus and presented with hearing loss and myopia. On examination aged 2, noted to have dysmorphic features - prominent eyes, hypertelorism, malar hypoplasia, an upturned nose, low-set ears and microretrognathia.
- Patient 2 noted to have camptodactyly and clinodactyly postnatally. On examination age 5 noted to have DIP joint contractures and mild skin syndactyly.
- Patient 3 - breech delivery. bilateral hand foot camptodactyly, facial dysmorphism.
- No antenatal features reported.

PMID 30463024 Vahidnehzad et al 2019 - report a male proband from a consanguineous Iranian Baloch family referred for assessment age 4.5. Noted to have developmental delay, musculoskeletal manifestations including scoliosis, flexion contractions, cutaneous syndactyly, right diaphragmatic eventration, ocular anomalies, growth failure and skin blisters. No concerns antenatally. Postnatally noted to have cataract and facial dysmorphism (midface hypoplasia). Homozygous PLOD3 missense variant identified, parents unaffected carriers. PLOD3 mRNA levels in the patient’s fibroblasts measured by whole-transcriptome sequencing and confirmed by RT-PCR, were the same as in control cells, however, the expression of type VII collagen was reduced significantly. No antenatal features reported.

PMID: 18834968 Salo et al 2008 - a female proband with significant IUGR, characteristic craniofacial profile, diaphragm eventration, skeletal anomalies (bilateral talipes equinovarus, flexion contractures, scoliosis from age 7), skin anomalies incl blistering and ocular anomalies. One 28 week male stillborn sibling noted to have significant IUGR and skeletal anomalies on post-mortem. Supportive functional evidence. Compound het PLOD3 variants.
Sources: Literature
Fetal anomalies v0.3908 LOXL3 Krithika Murali gene: LOXL3 was added
gene: LOXL3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LOXL3 were set to 25663169; 26307084; 26957899; 29802726; 30362103; 34787502
Phenotypes for gene: LOXL3 were set to Stickler syndrome; cleft lip/palate
Review for gene: LOXL3 was set to AMBER
Added comment: Biallelic variants reported in association with Stickler syndrome in 2 unrelated families. Also identified in one individual with non-syndromic Pierre Robin sequence who had a CNV also.

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PMID 34787502 Sood et al 2021 - proband with non-syndromic Pierre Robin sequence - homozygous missense LOXL3 variant identified. Sibling also had non-syndromic PRS, but genetic testing declined by family. In addition 551 kb chr10q26.2 duplication identified, no parental testing information provided, not previously reported to be associated with CL/P.

PMID 30362103 Chan et al 2019 - report father and son with Stickler syndrome and homozygous LOXL3 missense variants. Predominantly ocular phenotype with no antenatal features reported.

PMID: 29802726 Khan et al 2018 - genotyping of 258 probands with non-syndromic cleft palate (nsCP) and their parents, focusing in particular on common missense variant p.Ile615Phe. Identified four Phe/Phe homozygotes, report significant association between infant’s homozygote Phe/Phe genotype and the risk of nsCP, compared to common Ile/Ile homozygotes

PMID 26957899 Li et al 2016 - A homozygous frameshift mutation (c.39dup; p.L14Afs*21) and a compound heterozygous frameshift mutation (c.39dup; p.L14Afs*21 and c.594delG; p.Q199Kfs*35) in LOXL3 were separately identified in two of 298 probands with early-onset high myopia.

PMID: 26307084 Zhang et al 2015 - Mice lacking LOXL3 exhibited perinatal lethality and were noted to have cleft palate and spinal deformity.

PMID: 25663169 Alzahrani et al 2015 - homozygous variant identified in 2 children with Stickler syndrome from the same family, both children had cleft lip/palate.
Sources: Literature
Fetal anomalies v0.3908 PDIA6 Krithika Murali gene: PDIA6 was added
gene: PDIA6 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PDIA6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDIA6 were set to 33495992
Phenotypes for gene: PDIA6 were set to Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes
Review for gene: PDIA6 was set to AMBER
Added comment: No new publications since last PanelApp review. Single case upgraded to Amber on the basis of functional data

---

1 case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage‐dependent manner, supporting a loss‐of‐function effect of this variant. Phenotypic correlation with the previously reported mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. The phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans.
Sources: Literature
Fetal anomalies v0.3908 SCN1A Zornitza Stark Marked gene: SCN1A as ready
Fetal anomalies v0.3906 SCN1A Zornitza Stark changed review comment from: Arthrogryposis reported.; to: Arthrogryposis and malformations of cortical development reported.
Fetal anomalies v0.3905 SCN1A Zornitza Stark edited their review of gene: SCN1A: Added comment: Arthrogryposis reported.; Changed publications: 33820833
Fetal anomalies v0.3905 RSPH3 Zornitza Stark Marked gene: RSPH3 as ready
Fetal anomalies v0.3905 RSPH3 Zornitza Stark Phenotypes for gene: RSPH3 were changed from PRIMARY CILIARY DYSKINESIA WITH CENTRAL-COMPLEX DEFECTS to Ciliary dyskinesia, primary, 32 (MIM#616481)
Fetal anomalies v0.3903 RSPH1 Zornitza Stark Marked gene: RSPH1 as ready
Fetal anomalies v0.3903 RSPH1 Zornitza Stark Phenotypes for gene: RSPH1 were changed from PRIMARY CILIARY DYSKINESIA WITH CENTRAL-COMPLEX AND RADIAL-SPOKE DEFECTS to Ciliary dyskinesia, primary, 24 (MIM#615481)
Fetal anomalies v0.3901 PTEN Zornitza Stark Marked gene: PTEN as ready
Fetal anomalies v0.3897 PYCR1 Zornitza Stark Marked gene: PYCR1 as ready
Fetal anomalies v0.3896 PTS Zornitza Stark Marked gene: PTS as ready
Fetal anomalies v0.3895 PTH1R Zornitza Stark Marked gene: PTH1R as ready
Fetal anomalies v0.3895 PTH1R Zornitza Stark Phenotypes for gene: PTH1R were changed from PRIMARY FAILURE OF TOOTH ERUPTION; EIKEN SKELETAL DYSPLASIA; CHONDRODYSPLASIA BLOMSTRAND TYPE; JANSEN METAPHYSEAL CHONDRODYSPLASIA to Chondrodysplasia, Blomstrand type, MIM# 215045
Fetal anomalies v0.3893 PTHLH Zornitza Stark Marked gene: PTHLH as ready
Fetal anomalies v0.3891 PTF1A Zornitza Stark Marked gene: PTF1A as ready
Fetal anomalies v0.3891 PTF1A Zornitza Stark Phenotypes for gene: PTF1A were changed from PANCREATIC AGENESIS; DIABETES MELLITUS, PERMANENT NEONATAL, WITH CEREBELLAR AGENESIS to Pancreatic and cerebellar agenesis, MIM# 609069
Fetal anomalies v0.3889 PTF1A Zornitza Stark reviewed gene: PTF1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 21749365, 10507728, 15543146, 19650412; Phenotypes: Pancreatic and cerebellar agenesis, MIM# 609069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3889 PTDSS1 Zornitza Stark Marked gene: PTDSS1 as ready
Fetal anomalies v0.3889 PTDSS1 Zornitza Stark Phenotypes for gene: PTDSS1 were changed from LENZ-MAJEWSKI HYPEROSTOTIC DWARFISM to Lenz-Majewski hyperostotic dwarfism MIM#151050
Fetal anomalies v0.3886 PTDSS1 Zornitza Stark reviewed gene: PTDSS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24241535, 29341480, 31403251; Phenotypes: Lenz-Majewski hyperostotic dwarfism MIM#151050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3886 PSPH Zornitza Stark Marked gene: PSPH as ready
Fetal anomalies v0.3884 POLR1D Zornitza Stark Marked gene: POLR1D as ready
Fetal anomalies v0.3881 PDGFRB Zornitza Stark Marked gene: PDGFRB as ready
Fetal anomalies v0.3879 STAR Zornitza Stark Marked gene: STAR as ready
Fetal anomalies v0.3879 STAR Zornitza Stark Gene: star has been classified as Green List (High Evidence).
Fetal anomalies v0.3879 STAR Zornitza Stark Phenotypes for gene: STAR were changed from CHOLESTEROL DESMOLASE-DEFICIENT CONGENITAL ADRENAL HYPERPLASIA to Lipoid adrenal hyperplasia (MIM#201710)
Fetal anomalies v0.3878 STAR Zornitza Stark Publications for gene: STAR were set to
Fetal anomalies v0.3877 STAR Zornitza Stark reviewed gene: STAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lipoid adrenal hyperplasia (MIM#201710); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3877 STAR Daniel Flanagan reviewed gene: STAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 8948562, 16968793; Phenotypes: Lipoid adrenal hyperplasia (MIM#201710); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3877 SRD5A2 Zornitza Stark Marked gene: SRD5A2 as ready
Fetal anomalies v0.3876 SOX9 Zornitza Stark Marked gene: SOX9 as ready
Fetal anomalies v0.3873 SOX17 Zornitza Stark Marked gene: SOX17 as ready
Fetal anomalies v0.3873 SOX17 Zornitza Stark Phenotypes for gene: SOX17 were changed from VESICOURETERAL REFLUX TYPE 3 to Vesicoureteral reflux 3 MIM#613674; Pulmonary arterial hypertension
Fetal anomalies v0.3869 STAR Belinda Chong reviewed gene: STAR: Rating: RED; Mode of pathogenicity: None; Publications: 7892608, 8948562, 9097960, 11061515, 11297612, 14764819, 16968793, 9326645; Phenotypes: Lipoid adrenal hyperplasia MIM#201710; Mode of inheritance: None
Fetal anomalies v0.3869 PRRT2 Zornitza Stark Marked gene: PRRT2 as ready
Fetal anomalies v0.3869 PRRT2 Zornitza Stark Phenotypes for gene: PRRT2 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; BENIGN FAMILIAL INFANTILE EPILEPSY AND INFANTILE CONVULSIONS WITH CHOREOATHETOSIS SYNDROME to Convulsions, familial infantile, with paroxysmal choreoathetosis, MIM# 602066; Episodic kinesigenic dyskinesia 1, MIM# 128200; Seizures, benign familial infantile, 2, MIM# 605751; intellectual disability, autosomal recessive
Fetal anomalies v0.3867 PRRT2 Zornitza Stark changed review comment from: ID is not part of the phenotype for the mono allelic conditions; two families described with bi-allelic variants and more severe neurological phenotype, including ID.; to: Clinical presentation is typically post-natal.
Fetal anomalies v0.3867 PPM1D Zornitza Stark Marked gene: PPM1D as ready
Fetal anomalies v0.3864 POLG Zornitza Stark Marked gene: POLG as ready
Fetal anomalies v0.3860 POLG Zornitza Stark changed review comment from: Cataracts are described in individuals with bi-allelic and mono-allelic POLG variants.

Fetal presentation with cerebellar abnormalities reported PMID 29574624.; to: Cataracts are described in individuals with bi-allelic and mono-allelic POLG variants, though onset may be later.

Fetal presentation with cerebellar abnormalities reported PMID 29574624.
Fetal anomalies v0.3860 POLG Zornitza Stark changed review comment from: Cataracts are described in individuals with bi-allelic and mono-allelic POLG variants.; to: Cataracts are described in individuals with bi-allelic and mono-allelic POLG variants.

Fetal presentation with cerebellar abnormalities reported PMID 29574624.
Fetal anomalies v0.3860 POLD1 Zornitza Stark Marked gene: POLD1 as ready
Fetal anomalies v0.3860 POLD1 Zornitza Stark Phenotypes for gene: POLD1 were changed from SUBCUTANEOUS LIPODYSTROPHY, DEAFNESS, MANDIBULAR HYPOPLASIA AND MALE HYPOGONADISM to Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome 615381
Fetal anomalies v0.3856 POLD1 Zornitza Stark edited their review of gene: POLD1: Added comment: Four unrelated individuals with deletion of ser605 residue reported. Mandibular hypoplasia would be identifiable antenatally.; Changed rating: GREEN; Changed publications: 23770608; Changed phenotypes: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome 615381; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3856 PDHB Zornitza Stark Marked gene: PDHB as ready
Fetal anomalies v0.3853 PDHB Zornitza Stark edited their review of gene: PDHB: Added comment: Fetal presentation at 22 weeks reported with intrauterine growth retardation, short corpus callosum, ventricular dilation, and cerebellar hypoplasia, PMID 26865159.; Changed publications: 15138885, 26014431, 26865159
Fetal anomalies v0.3853 NT5C2 Zornitza Stark Marked gene: NT5C2 as ready
Fetal anomalies v0.3853 NT5C2 Zornitza Stark Phenotypes for gene: NT5C2 were changed from Spastic paraplegia 45, autosomal recessive 613162 to Spastic paraplegia 45, autosomal recessive, MIM# 613162; MONDO:0013165
Fetal anomalies v0.3850 NT5C2 Zornitza Stark changed review comment from: ID and CC abnormalities are associated variable features. Nine unrelated families reported, ID reported in >3.; to: ID and CC abnormalities are associated variable features. Nine unrelated families reported.
Fetal anomalies v0.3850 NR2F1 Zornitza Stark Marked gene: NR2F1 as ready
Fetal anomalies v0.3847 NR2F1 Zornitza Stark changed review comment from: Recent review of 54 affected individuals with Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS): 22 individuals with point mutations or in-frame deletions in the DNA-binding domain (DBD), and 32 individuals with other types of variants including whole-gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. A more severe phenotype appears to be associated with DBD variants.

Clinical characteristics include developmental delay, intellectual disability, autism spectrum disorder diagnoses/features thereof, cognitive/behavioral anomalies, hypotonia, feeding difficulties, abnormal brain MRI findings, and seizures. Vision phenotype includes optic nerve hypoplasia, optic atrophy, and cortical visual impairment; rarely, alacrima and latent nystagmus (fusional maldevelopment). The behavioural phenotypic spectrum includes a love of music, an unusually good long-term memory, sleep difficulties, a high pain tolerance, and touch sensitivity.; to: Recent review of 54 affected individuals with Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS): 22 individuals with point mutations or in-frame deletions in the DNA-binding domain (DBD), and 32 individuals with other types of variants including whole-gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. A more severe phenotype appears to be associated with DBD variants.

Clinical characteristics include developmental delay, intellectual disability, autism spectrum disorder diagnoses/features thereof, cognitive/behavioral anomalies, hypotonia, feeding difficulties, abnormal brain MRI findings, and seizures. Vision phenotype includes optic nerve hypoplasia, optic atrophy, and cortical visual impairment; rarely, alacrima and latent nystagmus (fusional maldevelopment). The behavioural phenotypic spectrum includes a love of music, an unusually good long-term memory, sleep difficulties, a high pain tolerance, and touch sensitivity.

Clinical presentation is typically post-natal.
Fetal anomalies v0.3847 NGLY1 Zornitza Stark Marked gene: NGLY1 as ready
Fetal anomalies v0.3845 NGLY1 Zornitza Stark changed review comment from: Over 20 affected individuals reported with bi-allelic variants in this gene. Rat model.; to: Over 20 affected individuals reported with bi-allelic variants in this gene. Rat model.

Clinical presentation is typically post-natal with predominantly neurological features.
Fetal anomalies v0.3845 NFU1 Zornitza Stark Marked gene: NFU1 as ready
Fetal anomalies v0.3843 NFU1 Zornitza Stark changed review comment from: Bi-allelic variants in this gene cause multiple mitochondrial dysfunctions syndrome, a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death. Cavitating leukodystrophy and other white matter changes described in multiple affected individuals.; to: Bi-allelic variants in this gene cause multiple mitochondrial dysfunctions syndrome, a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death. Cavitating leukodystrophy and other white matter changes described in multiple affected individuals.

Clinical presentation is typically post-natal.
Fetal anomalies v0.3843 SOX17 Daniel Flanagan reviewed gene: SOX17: Rating: RED; Mode of pathogenicity: None; Publications: 29650961, 31406341; Phenotypes: Vesicoureteral reflux 3 MIM#613674, Pulmonary arterial hypertension; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3843 NDUFS7 Zornitza Stark Marked gene: NDUFS7 as ready
Fetal anomalies v0.3843 NDUFS7 Zornitza Stark Phenotypes for gene: NDUFS7 were changed from MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX I DEFICIENCY to Mitochondrial complex I deficiency, nuclear type 3, MIM#618224
Fetal anomalies v0.3841 NDUFS4 Zornitza Stark Marked gene: NDUFS4 as ready
Fetal anomalies v0.3841 NDUFS4 Zornitza Stark Phenotypes for gene: NDUFS4 were changed from MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX I DEFICIENCY; LEIGH SYNDROME; LEIGH SYNDROME DUP to Mitochondrial complex I deficiency, nuclear type 1, 252010; Leigh syndrome, MIM#252010
Fetal anomalies v0.3839 NDUFS1 Zornitza Stark Marked gene: NDUFS1 as ready
Fetal anomalies v0.3839 NDUFS1 Zornitza Stark Phenotypes for gene: NDUFS1 were changed from MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX I DEFICIENCY; LEIGH SYNDROME to Mitochondrial complex I deficiency, nuclear type 5, MIM# 618226
Fetal anomalies v0.3837 MYT1L Zornitza Stark Marked gene: MYT1L as ready
Fetal anomalies v0.3837 MYT1L Zornitza Stark Phenotypes for gene: MYT1L were changed from MYT1L syndrome to Mental retardation, autosomal dominant 39, MIM# 616521
Fetal anomalies v0.3834 MYT1L Zornitza Stark changed review comment from: Over 50 individuals reported with deletions and SNVs affecting MYT1L, and variable phenotype comprising intellectual disability, obesity, and behavioral problems.; to: Over 50 individuals reported with deletions and SNVs affecting MYT1L, and variable phenotype comprising intellectual disability, obesity, and behavioral problems. Clinical presentation is typically post-natal.
Fetal anomalies v0.3834 MYBPC2 Zornitza Stark Marked gene: MYBPC2 as ready
Fetal anomalies v0.3834 MPZ Zornitza Stark Marked gene: MPZ as ready
Fetal anomalies v0.3834 MPZ Zornitza Stark Phenotypes for gene: MPZ were changed from Roussy-Levy syndrome 180800; Charcot-Marie-Tooth disease, type 2I 607677; Charcot-Marie-Tooth disease, type 1B 118200; Dejerine-Sottas disease 145900; Charcot-Marie-Tooth disease, type 2J 607736; Charcot-Marie-Tooth disease, dominant intermediate D 607791; Neuropathy, congenital hypomyelinating 605253 to Hypomyelinating neuropathy, congenital, 2, MIM# 618184
Fetal anomalies v0.3831 MPZ Zornitza Stark edited their review of gene: MPZ: Added comment: Variants in this gene are associated with various types of neuropathy, most with post-natal onset.

However, at the severe end of the spectrum can present antenatally with decreased fetal movements and arthrogryposis.; Changed rating: GREEN; Changed phenotypes: Hypomyelinating neuropathy, congenital, 2, MIM# 618184; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3831 SOX10 Zornitza Stark Marked gene: SOX10 as ready
Fetal anomalies v0.3831 SOX10 Zornitza Stark Phenotypes for gene: SOX10 were changed from KALLMANN SYNDROME WITH DEAFNESS; PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATING LEUKODYSTROPHY, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE; WAARDENBURG SYNDROME TYPE 4C; WAARDENBURG SYNDROME TYPE 2E; YEMENITE DEAF-BLIND HYPOPIGMENTATION SYNDROME to PCWH syndrome (MIM#609136); Waardenburg syndrome, type 2E, with or without neurologic involvement (MIM#611584); Waardenburg syndrome, type 4C (MIM#613266)
Fetal anomalies v0.3829 SOX10 Zornitza Stark reviewed gene: SOX10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: PCWH syndrome (MIM#609136), Waardenburg syndrome, type 2E, with or without neurologic involvement (MIM#611584), Waardenburg syndrome, type 4C (MIM#613266); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3829 SNX14 Zornitza Stark Marked gene: SNX14 as ready
Fetal anomalies v0.3829 SNX14 Zornitza Stark Phenotypes for gene: SNX14 were changed from ID, MACROCEPHALY AND CEREBELLAR HYPOPLASIA to Spinocerebellar ataxia, autosomal recessive 20 (MIM#616354)
Fetal anomalies v0.3826 TSHR Zornitza Stark Marked gene: TSHR as ready
Fetal anomalies v0.3825 SOX10 Daniel Flanagan reviewed gene: SOX10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: PCWH syndrome (MIM#609136), Waardenburg syndrome, type 2E, with or without neurologic involvement (MIM#611584), Waardenburg syndrome, type 4C (MIM#613266); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3825 SNX14 Daniel Flanagan reviewed gene: SNX14: Rating: AMBER; Mode of pathogenicity: None; Publications: 25848753, 25439728; Phenotypes: Spinocerebellar ataxia, autosomal recessive 20 (MIM#616354); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3825 TSHR Krithika Murali changed review comment from: Heterozygous variants associated with hyperthyroidism. De novo GoF variants in particular associated with more severe, non-autoimmune congenital hyperthyroidism. Biallelic LoF variants associated with congenital hypothyroidism.

Premature delivery, IUGR and fetal tachycardia are reported antenatal phenotypes. Goitre also noted at birth in some cases. Craniosynostosis also a feature, but diagnosed postnatally in the context of rapidly advancing bone age.

---
PMID: 9360555 Holzapfel 1997 - report IUGR and antenatal fetal tachycardia

PMID: 7800007 Kopp et al 1995 - proband born prematurely at 32 weeks gestation with BW of 1660g. Fetal tachycardia and diffuse goitre noted postnatally.

PMID: 18655531 Chester et al 2008 - proband born at 34 weeks. Antenatal ultrasound had shown thickened nuchal fold.

PMID: 15163335 Vaidya et al 2004 - report two siblings born premature with IUGR, heterozygous variant inherited from affected father.
Sources: Literature; to: Heterozygous variants associated with hyperthyroidism. De novo GoF variants in particular associated with more severe, non-autoimmune congenital hyperthyroidism. Biallelic LoF variants associated with congenital hypothyroidism.

Premature delivery, IUGR and fetal tachycardia are reported antenatal phenotypes. Goitre also noted at birth in some cases. Craniosynostosis also a feature, but diagnosed postnatally in the context of rapidly advancing bone age.

---
PMID: 9360555 Holzapfel 1997 - report IUGR and antenatal fetal tachycardia

PMID: 7800007 Kopp et al 1995 - proband born prematurely at 32 weeks gestation with BW of 1660g. Fetal tachycardia and diffuse goitre noted postnatally.

PMID: 18655531 Chester et al 2008 - proband born at 34 weeks. Antenatal ultrasound had shown thickened nuchal fold.

PMID: 15163335 Vaidya et al 2004 - report two siblings born premature with IUGR, heterozygous variant inherited from affected father.

PMID: 11081252 M Tonacchera et al 2000 - report SGA

PMID: 16960398 Nishihara et al 2006 - proband born 32 weeks with 1860g birthweight, postnatal goitre and craniosynostosis





Sources: Literature
Fetal anomalies v0.3825 TSHR Krithika Murali gene: TSHR was added
gene: TSHR was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TSHR was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TSHR were set to 23295291; 9360555; 7800007; 18655531; 15163335
Phenotypes for gene: TSHR were set to Hyperthyroidism, nonautoimmune - MIM#609152; Hypothyroidism, congenital, nongoitrous, 1 - MIM#275200
Review for gene: TSHR was set to GREEN
Added comment: Heterozygous variants associated with hyperthyroidism. De novo GoF variants in particular associated with more severe, non-autoimmune congenital hyperthyroidism. Biallelic LoF variants associated with congenital hypothyroidism.

Premature delivery, IUGR and fetal tachycardia are reported antenatal phenotypes. Goitre also noted at birth in some cases. Craniosynostosis also a feature, but diagnosed postnatally in the context of rapidly advancing bone age.

---
PMID: 9360555 Holzapfel 1997 - report IUGR and antenatal fetal tachycardia

PMID: 7800007 Kopp et al 1995 - proband born prematurely at 32 weeks gestation with BW of 1660g. Fetal tachycardia and diffuse goitre noted postnatally.

PMID: 18655531 Chester et al 2008 - proband born at 34 weeks. Antenatal ultrasound had shown thickened nuchal fold.

PMID: 15163335 Vaidya et al 2004 - report two siblings born premature with IUGR, heterozygous variant inherited from affected father.
Sources: Literature
Fetal anomalies v0.3825 MPV17 Zornitza Stark Marked gene: MPV17 as ready
Fetal anomalies v0.3823 MPI Zornitza Stark Marked gene: MPI as ready
Fetal anomalies v0.3822 MGAT2 Zornitza Stark Marked gene: MGAT2 as ready
Fetal anomalies v0.3819 MECP2 Zornitza Stark Marked gene: MECP2 as ready
Fetal anomalies v0.3819 MECP2 Zornitza Stark Phenotypes for gene: MECP2 were changed from MENTAL RETARDATION SYNDROMIC X-LINKED TYPE 13; MENTAL RETARDATION SYNDROMIC X-LINKED LUBS TYPE; CHROMOSOME XQ28 DUPLICATION SYNDROME; ENCEPHALOPATHY NEONATAL SEVERE DUE TO MECP2 MUTATIONS; RETT SYNDROME (RTT)[ to Rett syndrome, MIM# 312750; Encephalopathy, neonatal severe 300673
Fetal anomalies v0.3818 MAOA Zornitza Stark Marked gene: MAOA as ready
Fetal anomalies v0.3816 MAN2B1 Zornitza Stark Marked gene: MAN2B1 as ready
Fetal anomalies v0.3815 TPO Zornitza Stark Marked gene: TPO as ready
Fetal anomalies v0.3814 PRMT7 Zornitza Stark Marked gene: PRMT7 as ready
Fetal anomalies v0.3814 PRMT7 Zornitza Stark Phenotypes for gene: PRMT7 were changed from Pseudohypoparathyroidism-like disorder to Short stature, brachydactyly, intellectual developmental disability, and seizures, OMIM #617157
Fetal anomalies v0.3812 TBC1D24 Zornitza Stark Marked gene: TBC1D24 as ready
Fetal anomalies v0.3812 TBC1D24 Zornitza Stark Phenotypes for gene: TBC1D24 were changed from NON SYNDROMAL HEARING LOSS; DOORS SYNDROME; MYOCLONIC EPILEPSY, INFANTILE, FAMILIAL to DOORS syndrome MIM#220500
Fetal anomalies v0.3810 PHOX2B Zornitza Stark Marked gene: PHOX2B as ready
Fetal anomalies v0.3807 PRG4 Zornitza Stark Marked gene: PRG4 as ready
Fetal anomalies v0.3806 PIEZO1 Zornitza Stark Marked gene: PIEZO1 as ready
Fetal anomalies v0.3806 PIEZO1 Zornitza Stark Phenotypes for gene: PIEZO1 were changed from Congenital lymphatic dysplasia with hydrops and/or lymphoedema; hydrops fetalis gene 616843 to Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, OMIM #194380; Lymphatic malformation 6, OMIM #616843
Fetal anomalies v0.3804 PLOD2 Zornitza Stark Marked gene: PLOD2 as ready
Fetal anomalies v0.3802 PLOD1 Zornitza Stark Marked gene: PLOD1 as ready
Fetal anomalies v0.3800 THRB Zornitza Stark Marked gene: THRB as ready
Fetal anomalies v0.3799 PHF6 Zornitza Stark Marked gene: PHF6 as ready
Fetal anomalies v0.3798 PEPD Zornitza Stark Marked gene: PEPD as ready
Fetal anomalies v0.3797 TBC1D23 Zornitza Stark Marked gene: TBC1D23 as ready
Fetal anomalies v0.3797 TBC1D23 Zornitza Stark Phenotypes for gene: TBC1D23 were changed from Non-degenerative Pontocerebellar Hypoplasia to Pontocerebellar hypoplasia, type 11, MIM# 617695
Fetal anomalies v0.3794 PITX2 Zornitza Stark Marked gene: PITX2 as ready
Fetal anomalies v0.3791 TAPT1 Zornitza Stark Marked gene: TAPT1 as ready
Fetal anomalies v0.3791 TAPT1 Zornitza Stark Phenotypes for gene: TAPT1 were changed from COMPLEX LETHAL OSTEOCHONDRODYSPLASIA to Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897)
Fetal anomalies v0.3789 TAPT1 Zornitza Stark reviewed gene: TAPT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26365339; Phenotypes: Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3789 PKD2 Zornitza Stark Marked gene: PKD2 as ready
Fetal anomalies v0.3786 PKD1 Zornitza Stark Marked gene: PKD1 as ready
Fetal anomalies v0.3784 TBL1X Zornitza Stark Marked gene: TBL1X as ready
Fetal anomalies v0.3783 SMARCB1 Zornitza Stark Marked gene: SMARCB1 as ready
Fetal anomalies v0.3783 SMARCB1 Zornitza Stark Gene: smarcb1 has been classified as Green List (High Evidence).
Fetal anomalies v0.3783 SMARCB1 Zornitza Stark Phenotypes for gene: SMARCB1 were changed from RHABDOID PREDISPOSITION SYNDROME 1; ?COFFIN-SIRIS SYNDROME to Coffin-Siris syndrome 3, OMIM #614608
Fetal anomalies v0.3782 SMARCB1 Zornitza Stark Publications for gene: SMARCB1 were set to
Fetal anomalies v0.3781 SMARCB1 Zornitza Stark Mode of inheritance for gene: SMARCB1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3780 TALDO1 Zornitza Stark Marked gene: TALDO1 as ready
Fetal anomalies v0.3779 PLK4 Zornitza Stark Marked gene: PLK4 as ready
Fetal anomalies v0.3777 SUCLG1 Zornitza Stark Marked gene: SUCLG1 as ready
Fetal anomalies v0.3775 SRY Zornitza Stark Marked gene: SRY as ready
Fetal anomalies v0.3773 TG Zornitza Stark Marked gene: TG as ready
Fetal anomalies v0.3772 SLC5A5 Zornitza Stark Marked gene: SLC5A5 as ready
Fetal anomalies v0.3771 TRPS1 Zornitza Stark Marked gene: TRPS1 as ready
Fetal anomalies v0.3768 TBCE Zornitza Stark Marked gene: TBCE as ready
Fetal anomalies v0.3768 TBCE Zornitza Stark Phenotypes for gene: TBCE were changed from HYPOPARATHYROIDISM-RETARDATION-DYSMORPHISM SYNDROME; Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy; KENNY-CAFFEY SYNDROME TYPE 1 to Hypoparathyroidism-retardation-dysmorphism syndrome, OMIM #241410; Kenny-Caffey syndrome, type 1, OMIM #244460; Encephalopathy, progressive, with amyotrophy and optic atrophy OMIM #617207
Fetal anomalies v0.3766 SLC26A7 Zornitza Stark Marked gene: SLC26A7 as ready
Fetal anomalies v0.3765 PEX7 Zornitza Stark Marked gene: PEX7 as ready
Fetal anomalies v0.3763 RUNX2 Zornitza Stark Marked gene: RUNX2 as ready
Fetal anomalies v0.3760 SLC26A4 Zornitza Stark Marked gene: SLC26A4 as ready
Fetal anomalies v0.3759 RTEL1 Zornitza Stark Marked gene: RTEL1 as ready
Fetal anomalies v0.3759 RTEL1 Zornitza Stark Phenotypes for gene: RTEL1 were changed from DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 5; DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 4 to Dyskeratosis congenita, autosomal recessive 5 MIM#615190; Hoyeraal-Hreidarsson syndrome
Fetal anomalies v0.3757 PROP1 Zornitza Stark Marked gene: PROP1 as ready
Fetal anomalies v0.3756 TPO Krithika Murali gene: TPO was added
gene: TPO was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TPO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPO were set to 34220711; 30662777
Phenotypes for gene: TPO were set to Thyroid dyshormonogenesis 2A - MIM#274500
Review for gene: TPO was set to GREEN
Added comment: Well-established association with thyroid dyshormonogenesis. 3 affected individuals from 2 unrelated families reported with fetal goitre.

34220711 Rodrigues et al 2021 - report 2 siblings who were diagnosed with fetal goitre on antenatal ultrasound at 26 and 32 weeks gestation. Pathogenic compound het TPO variants identified inherited from unaffected carrier parents.

30662777 - report a proband diagnosed with fetal goitre at 29 weeks gestation. Compound heterozygous TPO variants identified.
Sources: Literature
Fetal anomalies v0.3756 RRM2B Zornitza Stark Marked gene: RRM2B as ready
Fetal anomalies v0.3753 RPS6KA3 Zornitza Stark Marked gene: RPS6KA3 as ready
Fetal anomalies v0.3751 ROR2 Zornitza Stark Marked gene: ROR2 as ready
Fetal anomalies v0.3751 ROR2 Zornitza Stark Phenotypes for gene: ROR2 were changed from BRACHYDACTYLY, TYPE B1; ROBINOW SYNDROME, AUTOSOMAL DOMINANT; ROR2-RELATED DISORDERS AR to Brachydactyly, type B1 MIM#113000; Robinow syndrome, autosomal recessive MIM#268310
Fetal anomalies v0.3748 RNASET2 Zornitza Stark Marked gene: RNASET2 as ready
Fetal anomalies v0.3745 RNASEH2C Zornitza Stark Marked gene: RNASEH2C as ready
Fetal anomalies v0.3745 RNASEH2C Zornitza Stark Phenotypes for gene: RNASEH2C were changed from AICARDI-GOUTIERES SYNDROME 3 to Aicardi-Goutieres syndrome 3 (MIM# 610329), AR
Fetal anomalies v0.3743 NKX2-1 Zornitza Stark Marked gene: NKX2-1 as ready
Fetal anomalies v0.3742 IYD Zornitza Stark Marked gene: IYD as ready
Fetal anomalies v0.3741 IRS4 Zornitza Stark Marked gene: IRS4 as ready
Fetal anomalies v0.3740 DUOXA2 Zornitza Stark Marked gene: DUOXA2 as ready
Fetal anomalies v0.3739 DUOXA1 Zornitza Stark Marked gene: DUOXA1 as ready
Fetal anomalies v0.3738 DUOX2 Zornitza Stark Marked gene: DUOX2 as ready
Fetal anomalies v0.3737 DUOX1 Zornitza Stark Marked gene: DUOX1 as ready
Fetal anomalies v0.3736 RNASEH2B Zornitza Stark Marked gene: RNASEH2B as ready
Fetal anomalies v0.3736 RNASEH2B Zornitza Stark Phenotypes for gene: RNASEH2B were changed from AICARDI-GOUTIERES SYNDROME 2 to Aicardi-Goutieres syndrome 2, MIM# 610181
Fetal anomalies v0.3734 RNASEH2A Zornitza Stark Marked gene: RNASEH2A as ready
Fetal anomalies v0.3734 RNASEH2A Zornitza Stark Phenotypes for gene: RNASEH2A were changed from AICARDI-GOUTIERES SYNDROME 4 to Aicardi-Goutieres syndrome 4 MIM#610333
Fetal anomalies v0.3732 CDCA8 Zornitza Stark Marked gene: CDCA8 as ready
Fetal anomalies v0.3731 NPRL3 Zornitza Stark Marked gene: NPRL3 as ready
Fetal anomalies v0.3730 NPRL2 Zornitza Stark Marked gene: NPRL2 as ready
Fetal anomalies v0.3728 PKD1 Chirag Patel changed review comment from: Rare cases of ADPKD diagnosed antenatally, usually with biallelic variants. Suitable for fetal anomalies panel.; to: Rare cases of ADPKD diagnosed antenatally, usually with biallelic variants. Suitable for fetal anomalies panel.
Fetal anomalies v0.3728 PKD1 Chirag Patel edited their review of gene: PKD1: Added comment: Rare cases of ADPKD diagnosed antenatally, usually with biallelic variants. Suitable for fetal anomalies panel.; Changed rating: GREEN; Changed publications: PMID: 30631912, 26139440; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.3727 PKD1 Chirag Patel Phenotypes for gene: PKD1 were changed from Autosomal recessive polycystic kidney disease (ARPKD); Autosomal dominant polycystic kidney disease (ADPKD); Polycystic kidney disease, 173900 to Autosomal dominant polycystic kidney disease (ADPKD); Polycystic kidney disease, 173900
Fetal anomalies v0.3726 PRG4 Chirag Patel reviewed gene: PRG4: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 10545950, 29397575; Phenotypes: Camptodactyly-arthropathy-coxa vara-pericarditis syndrome, OMIM #208250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3726 PIEZO1 Chirag Patel reviewed gene: PIEZO1: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 26333996, 23479567, 23695678; Phenotypes: Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, OMIM #194380, Lymphatic malformation 6, OMIM #616843; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.3726 THRB Krithika Murali gene: THRB was added
gene: THRB was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: THRB was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: THRB were set to 35130567; 30430796; 30074255; 28938413; 4163616
Phenotypes for gene: THRB were set to Thyroid hormone resistance, autosomal recessive - MIM#274300; Thyroid hormone resistance - MIM#188570; Thyroid hormone resistance, selective pituitary - MIM#145650
Review for gene: THRB was set to GREEN
Added comment: Biallelic variants associated with thyroid hormone resistance. PMID 4163616 first reported this condition in a consanguineous Mexican family with congenital deafness, goitre and stippled epiphyses. Diagnosis was made incidentally at a later age but possibility of goitre being detected antenatally. SGA also reported but this is generally in the context of having a mother also affected by thyroid hormone resistance secondary to biallelic or monoallelic variants.
Sources: Literature
Fetal anomalies v0.3724 TBC1D23 Ain Roesley reviewed gene: TBC1D23: Rating: AMBER; Mode of pathogenicity: None; Publications: 28823707, 28823706; Phenotypes: Pontocerebellar hypoplasia, type 11, MIM# 617695; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3724 TAPT1 Ain Roesley reviewed gene: TAPT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26365339; Phenotypes: Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3722 SMARCB1 Chirag Patel reviewed gene: SMARCB1: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 22426308, 22726846, 23929686; Phenotypes: Coffin-Siris syndrome 3, OMIM #614608; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3722 SLC5A5 Krithika Murali gene: SLC5A5 was added
gene: SLC5A5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SLC5A5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC5A5 were set to 34806438; 34726525; 33815280; 32805706; 31115276
Phenotypes for gene: SLC5A5 were set to Thyroid dyshormonogenesis 1 - MIM#274400
Review for gene: SLC5A5 was set to GREEN
Added comment: Biallelic variants associated with congenital hypothyroidism. PMID 32805706 Stoupa et al 2020 report an affected male with antenatal goitre diagnosed at 25 weeks gestation and treated with intraamniotic levothyroxine injections.
Sources: Literature
Fetal anomalies v0.3721 TBCE Chirag Patel reviewed gene: TBCE: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12389028, 27666369; Phenotypes: Hypoparathyroidism-retardation-dysmorphism syndrome, OMIM #241410, Kenny-Caffey syndrome, type 1, OMIM #244460, Encephalopathy, progressive, with amyotrophy and optic atrophy OMIM #617207; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3721 SLC26A7 Krithika Murali gene: SLC26A7 was added
gene: SLC26A7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SLC26A7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC26A7 were set to 34780050; 32486989; 31372509; 30333321; 29546359
Phenotypes for gene: SLC26A7 were set to Thyroid dyshormogenesis - no OMIM gene disease association
Review for gene: SLC26A7 was set to GREEN
Added comment: Biallelic variants associated with congenital hypothyroidism secondary to thyroid dyshormogenesis. PMID 32486989 report an affected female diagnosed with goitre D4 of life.
Sources: Literature
Fetal anomalies v0.3721 SLC26A4 Krithika Murali gene: SLC26A4 was added
gene: SLC26A4 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SLC26A4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC26A4 were set to Pendred syndrome - MIM#274600
Review for gene: SLC26A4 was set to AMBER
Added comment: Known association with congenital hypothyroidism and bilateral sensorineural hearing loss. If goitre present, manifests later in childhood. No antenatal phenotype reported.
Sources: Literature
Fetal anomalies v0.3721 PROP1 Krithika Murali gene: PROP1 was added
gene: PROP1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PROP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PROP1 were set to 15941866; 11549703; 20301521; 32415500
Phenotypes for gene: PROP1 were set to Pituitary hormone deficiency, combined, 2- #262600
Review for gene: PROP1 was set to AMBER
Added comment: Biallelic variants associated with panhypopituitarism. Features include central congenital hypothyroidism and hypogonadotrophic hypogonadism including micropenis. Diagnosed postnatally in infancy or early childhood due to growth failure and failure to thrive. Antenatal diagnosis not reported, although severe micropenis due to other disorders has been detected antenatally.
Sources: Literature
Fetal anomalies v0.3721 RNASEH2C Ain Roesley reviewed gene: RNASEH2C: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301648, 24183309, 23322642; Phenotypes: Aicardi-Goutieres syndrome 3 (MIM# 610329), AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3721 KMT2E Zornitza Stark Marked gene: KMT2E as ready
Fetal anomalies v0.3718 KMT2E Zornitza Stark changed review comment from: 38 individuals from 36 families reported. Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. Additional common features include autism, macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. The four individuals with missense variants presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E postulated to explain this divergence in phenotype.; to: Micro/macrocephaly reported, see below, age of onset uncertain. Non-specific brain abnormalities also.

38 individuals from 36 families reported. Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. Additional common features include autism, macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. The four individuals with missense variants presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E postulated to explain this divergence in phenotype.
Fetal anomalies v0.3718 KCNQ3 Zornitza Stark Marked gene: KCNQ3 as ready
Fetal anomalies v0.3715 KCNQ1 Zornitza Stark Marked gene: KCNQ1 as ready
Fetal anomalies v0.3711 KCNQ1 Zornitza Stark changed review comment from: Can present antenatally with bradycardia, but no specific mention of hydrops.
Sources: Expert Review; to: Can present antenatally with bradycardia.
Sources: Expert Review
Fetal anomalies v0.3711 KARS Zornitza Stark Marked gene: KARS as ready
Fetal anomalies v0.3711 KARS Zornitza Stark Gene: kars has been classified as Red List (Low Evidence).
Fetal anomalies v0.3711 KARS Zornitza Stark Phenotypes for gene: KARS were changed from DEAFNESS, AUTOSOMAL RECESSIVE 89; CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE, B to Leukoencephalopathy with or without deafness (LEPID), MIM#619147
Fetal anomalies v0.3710 KARS Zornitza Stark Publications for gene: KARS were set to
Fetal anomalies v0.3709 KARS Zornitza Stark edited their review of gene: KARS: Changed rating: RED; Changed phenotypes: Leukoencephalopathy with or without deafness (LEPID), MIM#619147
Fetal anomalies v0.3709 NKX2-1 Krithika Murali gene: NKX2-1 was added
gene: NKX2-1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NKX2-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NKX2-1 were set to 23911641; 11854319; 24714694
Phenotypes for gene: NKX2-1 were set to Choreoathetosis, hypothyroidism, and neonatal respiratory distress - MIM#610978
Review for gene: NKX2-1 was set to GREEN
Added comment: Heterozygous variants associated with congenital hypothyroidism, choreathetosis with or without pulmonary dysfunction. Allelic disorder to benign hereditary chorea (118700), which is less severe. Hypoplasia of the thyroid reported in some individuals. OMIM also reports septal heart defects noted in some patients.
Sources: Literature
Fetal anomalies v0.3709 IYD Krithika Murali gene: IYD was added
gene: IYD was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: IYD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IYD were set to 18434651; 18765512; 838849; 14169503
Phenotypes for gene: IYD were set to Thyroid dyshormonogenesis 4 - MIM#274800
Review for gene: IYD was set to GREEN
Added comment: Known association with congenital hypothyroidism secondary to thyroid dyshormonogenesis. Although antenatal diagnosis not reported, goitre known phenotypic feature.
Sources: Literature
Fetal anomalies v0.3709 IRS4 Krithika Murali edited their review of gene: IRS4: Added comment: Associated with isolated central congenital hypothyroidism (insufficient pituitary TSH production). Postnatal diagnosis with no prenatal features reported. Small thyroid gland is a late postnatal phenotypic feature.; Changed rating: AMBER
Fetal anomalies v0.3709 IRS4 Krithika Murali gene: IRS4 was added
gene: IRS4 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: IRS4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IRS4 were set to 34566885; 34225927; 34093435; 33107432; 30061370
Phenotypes for gene: IRS4 were set to Hypothyroidism, congenital, nongoitrous, 9- MIM#301035
Review for gene: IRS4 was set to RED
Added comment: Associated with isolated central congenital hypothyroidism (insufficient pituitary TSH production). Postnatal diagnosis with no prenatal features reported.
Sources: Literature
Fetal anomalies v0.3709 DUOXA1 Krithika Murali gene: DUOXA1 was added
gene: DUOXA1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DUOXA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DUOXA1 were set to 31428054; 29650690
Phenotypes for gene: DUOXA1 were set to congenital hypothyroidism, No OMIM #
Review for gene: DUOXA1 was set to AMBER
Added comment: No new publications since last PanelApp review Feb 2021

--

12 cases, but digenic model with variants in other genes
Sources: Literature
Fetal anomalies v0.3709 DUOX1 Krithika Murali gene: DUOX1 was added
gene: DUOX1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DUOX1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DUOX1 were set to 29650690; 34019632
Phenotypes for gene: DUOX1 were set to congenital hypothyroidism, No OMIM #
Review for gene: DUOX1 was set to AMBER
Added comment: Gene reviewed for PanelApp in Feb 2021 - "11 cases, but digenic model, with variants in other genes". No further case reports published since. PMID 34019632 provide evidence of recapitulation of congenital hypothyroidism phenotype in duox mutant zebrafish.
Sources: Literature
Fetal anomalies v0.3709 RNASEH2B Ain Roesley reviewed gene: RNASEH2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 16845400, 33307271, 29239743; Phenotypes: Aicardi-Goutieres syndrome 2, MIM# 610181; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3709 RNASEH2A Ain Roesley reviewed gene: RNASEH2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 15870678, 25604658, 23592335; Phenotypes: Aicardi-Goutieres syndrome 4 MIM#610333; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3709 CDCA8 Krithika Murali gene: CDCA8 was added
gene: CDCA8 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CDCA8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDCA8 were set to 28025328; 29546359
Phenotypes for gene: CDCA8 were set to Congenital hypothyroidism, thyroid dysgenesis, no OMIM #
Review for gene: CDCA8 was set to GREEN
Added comment: Gene associated with congenital hypothyroidism secondary to thyroid dysgenesis. No new publications since last PanelApp review Feb 2021

---

4 families (1 with bilallelic variants [parent affected as HTZ], 3 with monoallelic variants) with functional evidence of variants. GREEN for mono allelic, RED for biallelic.
Sources: Literature
Fetal anomalies v0.3709 NPRL3 Krithika Murali gene: NPRL3 was added
gene: NPRL3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NPRL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPRL3 were set to 27173016; 26285051; 33461085
Phenotypes for gene: NPRL3 were set to Epilepsy, familial focal, with variable foci 3- MIM#617118
Review for gene: NPRL3 was set to GREEN
Added comment: Known association with focal epilepsy (variable penetrance) with focal cortical dysplasia being a reported feature. FCD has the potential to be detected prenatally.
Sources: Literature
Fetal anomalies v0.3709 NPRL2 Krithika Murali gene: NPRL2 was added
gene: NPRL2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NPRL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPRL2 were set to 29281825; 27173016; 31625153; 33461085; 22268191
Phenotypes for gene: NPRL2 were set to Epilepsy, familial focal, with variable foci 2 - MIM#617116
Review for gene: NPRL2 was set to GREEN
Added comment: Heterozygous NPRL2 variants associated with focal epilepsy of variable severity. Incomplete penetrance also a known feature. Probands from 3 unrelated families noted to have focal cortical dysplasia which has the potential to be detected prenatally.
Sources: Literature
Fetal anomalies v0.3709 ITGA7 Zornitza Stark Marked gene: ITGA7 as ready
Fetal anomalies v0.3709 ITGA7 Zornitza Stark Phenotypes for gene: ITGA7 were changed from CONGENITAL MUSCULAR DYSTROPHY to Muscular dystrophy, congenital, due to ITGA7 deficiency, MIM# 613204
Fetal anomalies v0.3708 ITGA7 Zornitza Stark changed review comment from: Primarily a muscle phenotype, accompanied by gross motor delay as expected. One out of 3 reported individuals had intellectual disability.; to: Primarily a muscle phenotype, typically presents post-natally.
Fetal anomalies v0.3708 IQSEC2 Zornitza Stark Marked gene: IQSEC2 as ready
Fetal anomalies v0.3708 IQSEC2 Zornitza Stark Phenotypes for gene: IQSEC2 were changed from MENTAL RETARDATION X-LINKED TYPE 1 to Mental retardation, X-linked 1/78, MIM# 309530, MONDO:0010656; Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347
Fetal anomalies v0.3706 HYDIN Zornitza Stark Marked gene: HYDIN as ready
Fetal anomalies v0.3706 HYDIN Zornitza Stark Phenotypes for gene: HYDIN were changed from CILIARY DYSKINESIA, PRIMARY, 5 to Ciliary dyskinesia, primary, 5 (MIM#08647)
Fetal anomalies v0.3704 HNRNPU Zornitza Stark Marked gene: HNRNPU as ready
Fetal anomalies v0.3704 HNRNPU Zornitza Stark Phenotypes for gene: HNRNPU were changed from EPILEPTIC ENCEPHALOPATHY to Epileptic encephalopathy, early infantile, 54, MIM#617391
Fetal anomalies v0.3701 HECW2 Zornitza Stark Marked gene: HECW2 as ready
Fetal anomalies v0.3697 HECW2 Zornitza Stark changed review comment from: Typically denovo missense variants in the HECT domain.
PMID: 29807643 - R1191Q single case with severe D/ID, EE and regression
PMID: 29395664 - single case with regression, loss of swallowing, increased abnormal movements/hand stereotypies, Rett like, cortical visual impairment and EE
PMID: 27334371 - propose GOF or dominant negative; 1 case plus references 5 previous cases
PMID: 27389779 - four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. p. Arg1330Trp, p.Glu1445Gly reported >1 case.
Regression reported in the context of refractory EE; to: Clinical presentation is typically post-natal.

Typically denovo missense variants in the HECT domain.
PMID: 29807643 - R1191Q single case with severe D/ID, EE and regression
PMID: 29395664 - single case with regression, loss of swallowing, increased abnormal movements/hand stereotypies, Rett like, cortical visual impairment and EE
PMID: 27334371 - propose GOF or dominant negative; 1 case plus references 5 previous cases
PMID: 27389779 - four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. p. Arg1330Trp, p.Glu1445Gly reported >1 case.
Regression reported in the context of refractory EE
Fetal anomalies v0.3697 HDAC4 Zornitza Stark Marked gene: HDAC4 as ready
Fetal anomalies v0.3697 HDAC4 Zornitza Stark Phenotypes for gene: HDAC4 were changed from BRACHYDACTYLY-MENTAL RETARDATION SYNDROME to Brachydactyly mental retardation syndrome; Brachydactyly without intellectual disability
Fetal anomalies v0.3693 HDAC4 Zornitza Stark changed review comment from: Contradictory evidence: deletions linked to brachydactyly-MR but note some individuals reported without MR. Only two reports of intragenic variants (still structural rather than SNVs).; to: Contradictory evidence: deletions linked to brachydactyly-MR but note some individuals reported without MR. Only two reports of intragenic variants (still structural rather than SNVs).

Subtle brain abnormalities, hip dislocation reported in PMID 33537682.
Fetal anomalies v0.3693 HADH Zornitza Stark Marked gene: HADH as ready
Fetal anomalies v0.3692 HACE1 Zornitza Stark Marked gene: HACE1 as ready
Fetal anomalies v0.3692 HACE1 Zornitza Stark Phenotypes for gene: HACE1 were changed from HACE1 related disorder to Spastic paraplegia and psychomotor retardation with or without seizures, 616756; MONDO:0014764
Fetal anomalies v0.3689 H3F3A Zornitza Stark Marked gene: H3F3A as ready
Fetal anomalies v0.3685 H3F3A Zornitza Stark changed review comment from: 33 unrelated individuals reported with missense variants in H3F3A. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.; to: 33 unrelated individuals reported with missense variants in H3F3A. Phenotype primarily comprised intellectual disability and minor congenital anomalies, including micro/macrocephaly, craniosynostosis, contractures, congenital heart disease.
Fetal anomalies v0.3685 H19 Zornitza Stark Marked gene: H19 as ready
Fetal anomalies v0.3685 H19 Zornitza Stark changed review comment from: Part of the BWS/RSS locus but ID not a feature.; to: Methylation changes rather than sequence variation are associated with BWS/RSS.
Fetal anomalies v0.3685 GRIN2A Zornitza Stark Marked gene: GRIN2A as ready
Fetal anomalies v0.3685 GRIN2A Zornitza Stark Phenotypes for gene: GRIN2A were changed from EPILEPSY WITH NEURODEVELOPMENTAL DEFECTS; LANDAU-KLEFFNER SYNDROME to Epilepsy, focal, with speech disorder and with or without mental retardation, MIM# 245570
Fetal anomalies v0.3681 GRIN2A Zornitza Stark changed review comment from: Large cohort of 248 individuals reported in PMID: 30544257: The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. Pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes. Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function.; to: Large cohort of 248 individuals reported in PMID: 30544257: The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. Pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes. Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function.

Clinical presentation is typically postnatal.
Fetal anomalies v0.3681 GRIK2 Zornitza Stark Marked gene: GRIK2 as ready
Fetal anomalies v0.3681 GRIK2 Zornitza Stark Phenotypes for gene: GRIK2 were changed from MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 6 to Neurodevelopmental disorder with impaired language and ataxia and with or without seizures, MIM# 619580
Fetal anomalies v0.3677 GRIA3 Zornitza Stark Marked gene: GRIA3 as ready
Fetal anomalies v0.3677 GRIA3 Zornitza Stark Phenotypes for gene: GRIA3 were changed from MENTAL RETARDATION X-LINKED TYPE 94 to Intellectual developmental disorder, X-linked, syndromic, Wu type (MIM#300699)
Fetal anomalies v0.3674 GMPPA Zornitza Stark Marked gene: GMPPA as ready
Fetal anomalies v0.3674 GMPPA Zornitza Stark Phenotypes for gene: GMPPA were changed from GLYCOSYLATION DISORDER CHARACTERIZED BY INTELLECTUAL DISABILITY AND AUTONOMIC DYSFUNCTION to Alacrima, achalasia, and mental retardation syndrome (MIM# 615510)
Fetal anomalies v0.3672 GMPPA Zornitza Stark reviewed gene: GMPPA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Alacrima, achalasia, and mental retardation syndrome (MIM# 615510); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3672 GLUD1 Zornitza Stark Marked gene: GLUD1 as ready
Fetal anomalies v0.3670 GHR Zornitza Stark Marked gene: GHR as ready
Fetal anomalies v0.3670 GHR Zornitza Stark Phenotypes for gene: GHR were changed from PITUITARY DWARFISM II to Growth hormone insensitivity, partial, MIM#604271; Laron dwarfism, MIM#262500
Fetal anomalies v0.3666 GHR Zornitza Stark edited their review of gene: GHR: Added comment: Birth weight and length are significantly decreased in the more severe, bi-allelic disorder (Laron).; Changed rating: GREEN; Changed publications: 9360502
Fetal anomalies v0.3666 GDF2 Zornitza Stark Marked gene: GDF2 as ready
Fetal anomalies v0.3666 DDOST Zornitza Stark Marked gene: DDOST as ready
Fetal anomalies v0.3664 CSTB Zornitza Stark Marked gene: CSTB as ready
Fetal anomalies v0.3662 CSTB Zornitza Stark changed review comment from: Myoclonic epilepsy of Unverricht and Lundborg is an autosomal recessive disorder characterized by onset of neurodegeneration between 6 and 13 years of age. Not appropriate for the ID panel.; to: Myoclonic epilepsy of Unverricht and Lundborg is an autosomal recessive disorder characterized by onset of neurodegeneration between 6 and 13 years of age. Not appropriate for the Fetal Anomalies panel.
Fetal anomalies v0.3662 COX6B1 Zornitza Stark Marked gene: COX6B1 as ready
Fetal anomalies v0.3662 GATM Zornitza Stark Marked gene: GATM as ready
Fetal anomalies v0.3662 GATM Zornitza Stark Phenotypes for gene: GATM were changed from ARGININE:GLYCINE AMIDINOTRANSFERASE DEFICIENCY to Cerebral creatine deficiency syndrome 3, MIM# 612718
Fetal anomalies v0.3660 GATM Zornitza Stark changed review comment from: Bi-allelic variants cause a disorder characterized by developmental delay/regression, intellectual disability, severe disturbance of expressive and cognitive speech, and severe depletion of creatine/phosphocreatine in the brain. At least four unrelated families reported.; to: Bi-allelic variants cause a disorder characterized by developmental delay/regression, intellectual disability, severe disturbance of expressive and cognitive speech, and severe depletion of creatine/phosphocreatine in the brain. At least four unrelated families reported.

Clinical presentation is typically post-natal.
Fetal anomalies v0.3660 GATAD2B Zornitza Stark Marked gene: GATAD2B as ready
Fetal anomalies v0.3656 MYH6 Zornitza Stark Marked gene: MYH6 as ready
Fetal anomalies v0.3656 MYH6 Zornitza Stark Phenotypes for gene: MYH6 were changed from ATRIAL SEPTAL DEFECT TYPE 3; CARDIOMYOPATHY FAMILIAL HYPERTROPHIC TYPE 14; CARDIOMYOPATHY DILATED TYPE 1EE to Atrial septal defect 3 (MIM#614089)
Fetal anomalies v0.3654 GAS8 Zornitza Stark Marked gene: GAS8 as ready
Fetal anomalies v0.3654 GAS8 Zornitza Stark Phenotypes for gene: GAS8 were changed from PRIMARY CILIARY DYSKINESIA to Ciliary dyskinesia, primary, 33, MIM# 616726
Fetal anomalies v0.3652 GALT Zornitza Stark Marked gene: GALT as ready
Fetal anomalies v0.3651 GALT Zornitza Stark changed review comment from: Most cases should be detected by newborn screening where available, but ID is part of the phenotype.; to: Clinical presentation is typically postnatal.
Fetal anomalies v0.3651 GABRB3 Zornitza Stark Marked gene: GABRB3 as ready
Fetal anomalies v0.3651 GABRB3 Zornitza Stark Phenotypes for gene: GABRB3 were changed from CHILDHOOD ABSENCE EPILEPSY TYPE 5; EPILEPTIC ENCEPHALOPATHIES to Epileptic encephalopathy, early infantile, 43, MIM# 617113
Fetal anomalies v0.3648 FTSJ1 Zornitza Stark Marked gene: FTSJ1 as ready
Fetal anomalies v0.3648 FTSJ1 Zornitza Stark Phenotypes for gene: FTSJ1 were changed from MENTAL RETARDATION X-LINKED TYPE 44 to Intellectual developmental disorder, X-linked 9, MIM# 309549
Fetal anomalies v0.3646 FOXP1 Zornitza Stark Marked gene: FOXP1 as ready
Fetal anomalies v0.3646 FOXP1 Zornitza Stark Phenotypes for gene: FOXP1 were changed from MENTAL RETARDATION WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES to Mental retardation with language impairment and with or without autistic features, MIM# 613670
Fetal anomalies v0.3643 FOXP1 Zornitza Stark changed review comment from: Single individual reported as part of a CDH cohort.
Sources: Literature; to: Single individual reported as part of a CDH cohort. Otherwise clinical presentation is typically post-natal.
Sources: Literature
Fetal anomalies v0.3643 FLVCR1 Zornitza Stark Marked gene: FLVCR1 as ready
Fetal anomalies v0.3642 FLVCR1 Zornitza Stark changed review comment from: progressive neurological condition, ID is not really part of the phenotype.; to: progressive neurological condition, postnatal onset.
Fetal anomalies v0.3642 FGF12 Zornitza Stark Marked gene: FGF12 as ready
Fetal anomalies v0.3639 FBXO11 Zornitza Stark Marked gene: FBXO11 as ready
Fetal anomalies v0.3639 FBXO11 Zornitza Stark Phenotypes for gene: FBXO11 were changed from Variable Neurodevelopmental Disorder to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities, MIM# 618089
Fetal anomalies v0.3636 FARS2 Zornitza Stark Marked gene: FARS2 as ready
Fetal anomalies v0.3636 FARS2 Zornitza Stark Gene: fars2 has been classified as Red List (Low Evidence).
Fetal anomalies v0.3636 FARS2 Zornitza Stark Phenotypes for gene: FARS2 were changed from Neurometabolic disorder due to FARS2 deficiency to Combined oxidative phosphorylation deficiency 14, MIM#614946
Fetal anomalies v0.3635 FARS2 Zornitza Stark Mode of inheritance for gene: FARS2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3634 FARS2 Zornitza Stark edited their review of gene: FARS2: Changed rating: RED
Fetal anomalies v0.3634 ERCC6L2 Zornitza Stark Marked gene: ERCC6L2 as ready
Fetal anomalies v0.3634 ERCC6L2 Zornitza Stark Phenotypes for gene: ERCC6L2 were changed from BONE MARROW FAILURE SYNDROME 2 to Bone marrow failure syndrome 2, MIM# 615715
Fetal anomalies v0.3631 ERCC6L2 Zornitza Stark reviewed gene: ERCC6L2: Rating: AMBER; Mode of pathogenicity: None; Publications: 24507776, 27185855; Phenotypes: Bone marrow failure syndrome 2, MIM# 615715; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3630 ENPP1 Zornitza Stark Marked gene: ENPP1 as ready
Fetal anomalies v0.3630 ENPP1 Zornitza Stark Phenotypes for gene: ENPP1 were changed from HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL RECESSIVE, 2; ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1 to Arterial calcification, generalized, of infancy, 1, MIM3 208000; Hypophosphatemic rickets, autosomal recessive, 2, MIM# 613312
Fetal anomalies v0.3627 ENPP1 Zornitza Stark reviewed gene: ENPP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19521093; Phenotypes: Arterial calcification, generalized, of infancy, 1, MIM3 208000, Hypophosphatemic rickets, autosomal recessive, 2, MIM# 613312; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3627 EGR2 Zornitza Stark Marked gene: EGR2 as ready
Fetal anomalies v0.3627 EGR2 Zornitza Stark Phenotypes for gene: EGR2 were changed from NEUROPATHY, CONGENITAL HYPOMYELINATING, 1 to Charcot-Marie-Tooth disease, type 1D, MIM# 607678; Dejerine-Sottas disease, MIM# 145900; Hypomyelinating neuropathy, congenital, 1, MIM# 605253
Fetal anomalies v0.3625 EGR2 Zornitza Stark reviewed gene: EGR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, type 1D, MIM# 607678, Dejerine-Sottas disease, MIM# 145900, Hypomyelinating neuropathy, congenital, 1, MIM# 605253; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.3625 DUSP6 Zornitza Stark Marked gene: DUSP6 as ready
Fetal anomalies v0.3623 DMP1 Zornitza Stark Marked gene: DMP1 as ready
Fetal anomalies v0.3623 DMP1 Zornitza Stark Phenotypes for gene: DMP1 were changed from HYPOPHOSPHATEMIC RICKETS, AR to Hypophosphatemic rickets, AR MIM#241520
Fetal anomalies v0.3621 DLG3 Zornitza Stark Marked gene: DLG3 as ready
Fetal anomalies v0.3621 DLG3 Zornitza Stark Phenotypes for gene: DLG3 were changed from MENTAL RETARDATION X-LINKED TYPE 90 to Mental retardation, X-linked 90, MIM#300850
Fetal anomalies v0.3619 DLAT Zornitza Stark Marked gene: DLAT as ready
Fetal anomalies v0.3617 DLAT Zornitza Stark changed review comment from: Only two families with ID reported; third individual had paroxysmal dyskinesia.; to: Clinical presentation is typically post-natal.
Fetal anomalies v0.3617 DEAF1 Zornitza Stark Marked gene: DEAF1 as ready
Fetal anomalies v0.3617 DEAF1 Zornitza Stark Phenotypes for gene: DEAF1 were changed from Autism, intellectual disability, basal ganglia dysfunction and epilepsy; MENTAL RETARDATION, AUTOSOMAL DOMINANT 24 to Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures 617171; Vulto-van Silfout-de Vries syndrome 615828
Fetal anomalies v0.3613 DEAF1 Zornitza Stark changed review comment from: Bi-allelic disease is through LOF mechanism (PTVs and missense). Mono-allelic disease described in association with de novo missense variants only.

LOF and Dominant-negative
- De novo missense in the SAND domain tend to have a dominant-negative effect
- Biallelic variants in the SAND domain lead to partial loss of function - missense (reduced function), NMD (haploinsufficiency)
- Heterozygous deletions have no phenotype.; to: Bi-allelic disease is through LOF mechanism (PTVs and missense). Mono-allelic disease described in association with de novo missense variants only.

LOF and Dominant-negative
- De novo missense in the SAND domain tend to have a dominant-negative effect
- Biallelic variants in the SAND domain lead to partial loss of function - missense (reduced function), NMD (haploinsufficiency)
- Heterozygous deletions have no phenotype.

Brain abnormalities on imaging, particularly with AD disorder.
Fetal anomalies v0.3613 ST3GAL5 Zornitza Stark Marked gene: ST3GAL5 as ready
Fetal anomalies v0.3610 ST3GAL5 Zornitza Stark changed review comment from: Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterised by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss. Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood. Although initially reported in the Amish (founder variant p.Arg288Ter), families from other ethnicities have also been reported.; to: Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterised by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss. Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood. Although initially reported in the Amish (founder variant p.Arg288Ter), families from other ethnicities have also been reported.

Clinical presentation is typically post-natal.
Fetal anomalies v0.3610 RSPRY1 Zornitza Stark Marked gene: RSPRY1 as ready
Fetal anomalies v0.3608 RSPRY1 Zornitza Stark changed review comment from: Two unrelated individuals reported, some functional evidence. Dev delay/autism part of the phenotype.
Sources: Expert list; to: Two unrelated individuals reported, some functional evidence. Multiple skeletal anomalies.
Sources: Expert list
Fetal anomalies v0.3608 RSPH9 Zornitza Stark Marked gene: RSPH9 as ready
Fetal anomalies v0.3608 RSPH9 Zornitza Stark Phenotypes for gene: RSPH9 were changed from Ciliary dyskinesia, primary 612650 to Ciliary dyskinesia, primary, MIM# 612650
Fetal anomalies v0.3605 RSPH4A Zornitza Stark Marked gene: RSPH4A as ready
Fetal anomalies v0.3603 RRAS2 Zornitza Stark Marked gene: RRAS2 as ready
Fetal anomalies v0.3600 RRAS Zornitza Stark Marked gene: RRAS as ready
Fetal anomalies v0.3597 RPS7 Zornitza Stark Marked gene: RPS7 as ready
Fetal anomalies v0.3594 RPS24 Zornitza Stark Marked gene: RPS24 as ready
Fetal anomalies v0.3592 RPS23 Zornitza Stark Marked gene: RPS23 as ready
Fetal anomalies v0.3592 RPS23 Zornitza Stark Phenotypes for gene: RPS23 were changed from Microcephaly, hearing loss, and dysmorphic features to Brachycephaly, trichomegaly, and developmental delay, MIM# 617412
Fetal anomalies v0.3588 MYH3 Zornitza Stark reviewed gene: MYH3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Arthrogryposis, distal, type 2A (Freeman-Sheldon), OMIM #193700, Arthrogryposis, distal, type 2B3 (Sheldon-Hall), OMIM #618436, Contractures, pterygia, and variable skeletal fusions syndrome 1A, OMIM #178110, Contractures, pterygia, and variable skeletal fusions syndrome 1B, OMIM #618469; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.3587 MYH3 Alison Yeung Marked gene: MYH3 as ready
Fetal anomalies v0.3587 MYH3 Alison Yeung Phenotypes for gene: MYH3 were changed from DISTAL ARTHROGRYPOSIS TYPE 2A; DISTAL ARTHROGRYPOSIS TYPE 2B to Arthrogryposis, distal, type 2A (Freeman-Sheldon) MIM# 193700; Arthrogryposis, distal, type 2B3 (Sheldon-Hall) MIM# 618436; Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A, MIM#178110; Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B, MIM# 618469
Fetal anomalies v0.3585 RPL35A Zornitza Stark Marked gene: RPL35A as ready
Fetal anomalies v0.3582 RPL10 Zornitza Stark Marked gene: RPL10 as ready
Fetal anomalies v0.3580 RPL10 Zornitza Stark changed review comment from: At least three families reported. Progressive microcephaly, up to -9.6 SD described.
Sources: Expert list; to: At least three families reported. Progressive microcephaly, up to -9.6 SD described. IUGR, congenital heart disease.

Sources: Expert list
Fetal anomalies v0.3580 RORA Zornitza Stark Marked gene: RORA as ready
Fetal anomalies v0.3580 RORA Zornitza Stark Phenotypes for gene: RORA were changed from INTELLECTUAL DISABILITY to Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, MIM#618060
Fetal anomalies v0.3575 RORA Zornitza Stark changed review comment from: Eleven unrelated individuals with de novo variants in this gene; postulated that some variants exert dominant-negative effect resulting in a more severe phenotype than the LoF variants.
Sources: Expert list; to: Eleven unrelated individuals with de novo variants in this gene; postulated that some variants exert dominant-negative effect resulting in a more severe phenotype than the LoF variants.

Clinical presentation is generally post-natal, but pontocerebellar hypoplasia rarely reported.

Sources: Expert list
Fetal anomalies v0.3575 ROBO3 Zornitza Stark Marked gene: ROBO3 as ready
Fetal anomalies v0.3573 RMND1 Zornitza Stark Marked gene: RMND1 as ready
Fetal anomalies v0.3570 RLIM Zornitza Stark Marked gene: RLIM as ready
Fetal anomalies v0.3567 RIN2 Zornitza Stark Marked gene: RIN2 as ready
Fetal anomalies v0.3567 RIN2 Zornitza Stark Phenotypes for gene: RIN2 were changed from MACROCEPHALY, ALOPECIA, CUTIS LAXA, AND SCOLIOSIS TALL FOREHEAD, SPARSE HAIR, SKIN HYPEREXTENSIBILITY, AND SCOLIOSIS to Macrocephaly, alopecia, cutis laxa, and scoliosis, MIM#613075
Fetal anomalies v0.3564 RIN2 Zornitza Stark changed review comment from: Macrocephaly, subcortical cysts and other brain abnormalities are a feature.; to: Macrocephaly, subcortical cysts and other brain abnormalities are a feature. More than 5 unrelated families reported.
Fetal anomalies v0.3564 RIN2 Zornitza Stark changed review comment from: ID is not a key feature of this syndrome, most individuals described as having normal/borderline intellect.; to: Macrocephaly, subcortical cysts and other brain abnormalities are a feature.
Fetal anomalies v0.3564 RFT1 Zornitza Stark Marked gene: RFT1 as ready
Fetal anomalies v0.3563 RFT1 Zornitza Stark changed review comment from: Bi-allelic variants are associated with DD/ID, seizures, deafness. More than 10 unrelated families reported.; to: Bi-allelic variants are associated with DD/ID, seizures, deafness. More than 10 unrelated families reported.

Clinical presentation is typically post-natal, though age of onset of microcephaly is uncertain.
Fetal anomalies v0.3563 RBM10 Zornitza Stark Marked gene: RBM10 as ready
Fetal anomalies v0.3561 RBBP8 Zornitza Stark Marked gene: RBBP8 as ready
Fetal anomalies v0.3558 RAD51C Zornitza Stark Marked gene: RAD51C as ready
Fetal anomalies v0.3555 RAD51 Zornitza Stark Marked gene: RAD51 as ready
Fetal anomalies v0.3551 RAD51 Zornitza Stark changed review comment from: Three unrelated individuals reported with de novo variants in this gene and FA phenotype. However, only one had radial ray abnormalities.
Sources: Expert Review; to: Three unrelated individuals reported with de novo variants in this gene and FA phenotype.
Sources: Expert Review
Fetal anomalies v0.3551 RAB11B Zornitza Stark Marked gene: RAB11B as ready
Fetal anomalies v0.3547 RAB11A Zornitza Stark Marked gene: RAB11A as ready
Fetal anomalies v0.3544 RAB11A Zornitza Stark changed review comment from: Five individuals reported with DNMs and neurodevelopmental phenotypes as part of this paper; however, clinical details are sparse. Emerging gene, phenotype not yet clearly delineated.
Sources: Literature; to: Five individuals reported with DNMs and neurodevelopmental phenotypes as part of this paper; however, clinical details are sparse. Emerging gene, phenotype not yet clearly delineated.

Clinical presentation is post-natal.
Sources: Literature
Fetal anomalies v0.3544 DMP1 Belinda Chong reviewed gene: DMP1: Rating: RED; Mode of pathogenicity: None; Publications: 17033625, 17033621, 31843680; Phenotypes: Hypophosphatemic rickets, AR MIM#241520; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3544 DLD Zornitza Stark Marked gene: DLD as ready
Fetal anomalies v0.3542 WNT9B Zornitza Stark Marked gene: WNT9B as ready
Fetal anomalies v0.3541 WNT9B Krithika Murali gene: WNT9B was added
gene: WNT9B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WNT9B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WNT9B were set to 34145744
Phenotypes for gene: WNT9B were set to Renal agenesis/hypoplasia/dysplasia, no OMIM #
Review for gene: WNT9B was set to AMBER
Added comment: Now new publications since last PanelApp review Sept 2021

---

WNT9B plays a key role in the development of the mammalian urogenital system. It is essential for the induction of mesonephric and metanephric tubules, the regulation of renal tubule morphogenesis, and the regulation of renal progenitor cell expansion and differentiation. WNT9B−/− mice have renal agenesis/hypoplasia and reproductive tract abnormalities.

Lemire et al. (2021) report 4 individuals from 2 unrelated consanguineous families with bilateral renal agenesis/hypoplasia/dysplasia and homozygous variants in WNT9B. The proband from Family 1 had bilateral renal cystic dysplasia and chronic kidney disease, with 2 deceased siblings with bilateral renal hypoplasia/agenesis. The 3 affected family members were homozygous for a Gly317Arg missense variant in WNT9B. Proband from Family 2 had renal hypoplasia/dysplasia, chronic kidney disease, and was homozygous for a Pro5Alafs*52 nonsense variant in WNT9B. The proband's unaffected brother is also homozygous for the nonsense variant in WNT9B, suggesting nonpenetrance.
Sources: Literature
Fetal anomalies v0.3541 TBCK Zornitza Stark Marked gene: TBCK as ready
Fetal anomalies v0.3541 TBCK Zornitza Stark Phenotypes for gene: TBCK were changed from Severe Infantile Syndromic Encephalopathy to Hypotonia, infantile, with psychomotor retardation and characteristic facies 3, MIM# 616900
Fetal anomalies v0.3539 TBCK Zornitza Stark reviewed gene: TBCK: Rating: GREEN; Mode of pathogenicity: None; Publications: 27040692, 30103036, 27040691; Phenotypes: Hypotonia, infantile, with psychomotor retardation and characteristic facies 3, MIM# 616900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3539 TBL1XR1 Zornitza Stark Marked gene: TBL1XR1 as ready
Fetal anomalies v0.3539 TBL1XR1 Zornitza Stark Phenotypes for gene: TBL1XR1 were changed from Intellectual disability with autism spectrum disorder; Pierpont syndrome to Mental retardation, autosomal dominant 41, MIM# 616944; Pierpont syndrome, MIM# 602342
Fetal anomalies v0.3537 TBL1XR1 Zornitza Stark reviewed gene: TBL1XR1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal dominant 41, MIM# 616944, Pierpont syndrome, MIM# 602342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3537 TBX15 Zornitza Stark Marked gene: TBX15 as ready
Fetal anomalies v0.3535 TBX18 Zornitza Stark Marked gene: TBX18 as ready
Fetal anomalies v0.3535 TBX18 Zornitza Stark Phenotypes for gene: TBX18 were changed from CONGENITAL ANOMALIES OF KIDNEY AND URINARY TRACT 2 to Congenital anomalies of kidney and urinary tract 2, MIM# 143400
Fetal anomalies v0.3532 TBX18 Zornitza Stark reviewed gene: TBX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 26235987; Phenotypes: Congenital anomalies of kidney and urinary tract 2, MIM# 143400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3532 TBX20 Zornitza Stark Marked gene: TBX20 as ready
Fetal anomalies v0.3529 TBX4 Zornitza Stark Marked gene: TBX4 as ready
Fetal anomalies v0.3529 TBX4 Zornitza Stark Phenotypes for gene: TBX4 were changed from Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, OMIM:147891 to Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome, MIM# 601360; Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, MIM# 147891
Fetal anomalies v0.3526 TBX4 Zornitza Stark reviewed gene: TBX4: Rating: GREEN; Mode of pathogenicity: None; Publications: 23592887, 31151956, 31761294, 31965066; Phenotypes: Amelia, posterior, with pelvic and pulmonary hypoplasia syndrome, MIM# 601360, Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, MIM# 147891; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3526 TCF12 Zornitza Stark Marked gene: TCF12 as ready
Fetal anomalies v0.3523 TBX6 Zornitza Stark Marked gene: TBX6 as ready
Fetal anomalies v0.3520 TCOF1 Zornitza Stark Marked gene: TCOF1 as ready
Fetal anomalies v0.3518 TGDS Zornitza Stark Marked gene: TGDS as ready
Fetal anomalies v0.3516 TGFB2 Zornitza Stark Marked gene: TGFB2 as ready
Fetal anomalies v0.3514 TGFB3 Zornitza Stark Marked gene: TGFB3 as ready
Fetal anomalies v0.3512 THOC6 Zornitza Stark Marked gene: THOC6 as ready
Fetal anomalies v0.3510 TBC1D1 Krithika Murali gene: TBC1D1 was added
gene: TBC1D1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TBC1D1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBC1D1 were set to 26572137
Phenotypes for gene: TBC1D1 were set to CAKUT
Review for gene: TBC1D1 was set to GREEN
Added comment: No new publications since last PanelApp review included below

---
1 heterozygous de novo frameshift variant in TBC1D1 in 1 CAKUT.
3 further CAKUT cases with three novel or rare inherited heterozygous TBC1D1 missense variants predicted to be pathogenic. TBC1D1 mutations affected Ser237-phosphorylation or protein stability and thereby act as hypomorphs. Tbc1d1 showed widespread expression in the developing murine urogenital system. A mild CAKUT spectrum phenotype, including anomalies observed in patients carrying TBC1D1 mutations, was found in kidneys of some Tbc1d1 (-/-) mice. Significantly reduced Glut4 levels were detected in kidneys of Tbc1d1 (-/-) mice and the dysplastic kidney of a TBC1D1 mutation carrier versus controls. TBC1D1 and SLC2A4 encoding GLUT4 were highly expressed in human fetal kidney. These data demonstrate heterozygous deactivating TBC1D1 mutations in CAKUT patients with a similar renal and ureteral phenotype, and provide evidence that TBC1D1 mutations may contribute to CAKUT pathogenesis, possibly via a role in glucose homeostasis.
Sources: Literature
Fetal anomalies v0.3510 THRA Zornitza Stark Marked gene: THRA as ready
Fetal anomalies v0.3508 SRGAP1 Krithika Murali gene: SRGAP1 was added
gene: SRGAP1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SRGAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRGAP1 were set to 26026792
Phenotypes for gene: SRGAP1 were set to congenital anomalies of the kidney and urinary tract
Review for gene: SRGAP1 was set to AMBER
Added comment: PMID 26026792 Hwang et al report 2 unrelated families with heterozygous SRGAP1 variants.
- Family 1 - proband with prenatally diagnosed multicystic dysplastic kidney, affected mother with right duplex kidney
- Family 2 - proband with horseshoe kidney with a multicystic dysplastic right upper pole. Variant paternally inherited, father not available for renal ultrasound

Supportive mouse models
Sources: Literature
Fetal anomalies v0.3507 TMCO1 Zornitza Stark Marked gene: TMCO1 as ready
Fetal anomalies v0.3507 TMCO1 Zornitza Stark Phenotypes for gene: TMCO1 were changed from CRANIOFACIAL DYSMORPHISM, SKELETAL ANOMALIES, AND MENTAL RETARDATION SYNDROME to Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome, MIM# 213980
Fetal anomalies v0.3505 TMCO1 Zornitza Stark changed review comment from: Multiple families reported. Although some have the same recurrent founder variants, sufficient number of families from different ethnicities and with different variants reported for Green rating.; to: Multiple families reported. Although some have the same recurrent founder variants, sufficient number of families from different ethnicities and with different variants reported for Green rating.

Skeletal abnormalities are pertinent to this panel.
Fetal anomalies v0.3505 TMCO1 Zornitza Stark reviewed gene: TMCO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20018682, 23320496, 24194475, 30556256, 31102500; Phenotypes: Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome, MIM# 213980; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3505 TPM3 Zornitza Stark Marked gene: TPM3 as ready
Fetal anomalies v0.3504 TREX1 Zornitza Stark Marked gene: TREX1 as ready
Fetal anomalies v0.3504 TREX1 Zornitza Stark Phenotypes for gene: TREX1 were changed from AICARDI-GOUTIERES SYNDROME 1, DOMINANT AND RECESSIVE to Aicardi-Goutieres syndrome 1, dominant and recessive, MIM# 225750
Fetal anomalies v0.3502 TREX1 Zornitza Stark reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33527515; Phenotypes: Aicardi-Goutieres syndrome 1, dominant and recessive, MIM# 225750; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.3502 SLIT2 Krithika Murali gene: SLIT2 was added
gene: SLIT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SLIT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLIT2 were set to 26026792; 15130495
Phenotypes for gene: SLIT2 were set to CAKUT; vesicoureteric reflux
Review for gene: SLIT2 was set to AMBER
Added comment: PMID 26026792 Hwang et al 2019 - identified three unrelated individuals with CAKUT and different heterozygous SLIT2 missense mutations.
- 1 patient presented with multiple bilateral subcortical renal cysts
- 1 patient presented with multicystic dysplastic kidneys
- 1 patient had right renal agenesis

Authors provide supportive variant-specific mouse models.

PMID: 34059960 Liu et al 2021 - 3 unrelated children from a Chinese Kidney Disease Database with vesicoureteric reflux had SLIT3 VUS identified

PMID 19350278 Zu et al 2009 - x2 unrelated individuals with SLIT2 variants - not segregating with disease in either family
Sources: Literature
Fetal anomalies v0.3502 NEK9 Zornitza Stark Marked gene: NEK9 as ready
Fetal anomalies v0.3502 NEK9 Zornitza Stark Phenotypes for gene: NEK9 were changed from Arthrogryposis, Perthes disease, and upward gaze palsy, MONDO:0013660; NEK9-related lethal skeletal dysplasia, MONDO:0014870; Lethal congenital contracture syndrome 10, OMIM:617022; ?Arthrogryposis, Perthes disease, and upward gaze palsy, OMIM:614262 to Arthrogryposis, Perthes disease, and upward gaze palsy, MONDO:0013660; NEK9-related lethal skeletal dysplasia, MONDO:0014870; Lethal congenital contracture syndrome 10, OMIM:617022; Arthrogryposis, Perthes disease, and upward gaze palsy, OMIM:614262
Fetal anomalies v0.3501 NEK8 Zornitza Stark Marked gene: NEK8 as ready
Fetal anomalies v0.3499 NEDD4L Zornitza Stark Marked gene: NEDD4L as ready
Fetal anomalies v0.3496 NDUFAF2 Zornitza Stark Marked gene: NDUFAF2 as ready
Fetal anomalies v0.3496 NDUFAF2 Zornitza Stark Phenotypes for gene: NDUFAF2 were changed from LEIGH SYNDROME to Mitochondrial complex I deficiency, nuclear type 10, MIM#618233
Fetal anomalies v0.3493 NDUFA10 Zornitza Stark Marked gene: NDUFA10 as ready
Fetal anomalies v0.3493 NDUFA10 Zornitza Stark Phenotypes for gene: NDUFA10 were changed from LEIGH SYNDROME DUP to Mitochondrial complex I deficiency, nuclear type 22, MIM#618243
Fetal anomalies v0.3491 NDUFA10 Zornitza Stark changed review comment from: Two families, functional data, but phenotypic description only available for one (DD/ID part of the phenotype).; to: Two families, functional data, but phenotypic description only available for one, IUGR reported.
Fetal anomalies v0.3491 NAA15 Zornitza Stark Marked gene: NAA15 as ready
Fetal anomalies v0.3491 NAA15 Zornitza Stark Phenotypes for gene: NAA15 were changed from CONGENITAL HEART DISEASE and NEURODEVELOPMENTAL DISORDER to Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities, MIM 617787
Fetal anomalies v0.3486 SEMA3A Zornitza Stark Phenotypes for gene: SEMA3A were changed from {Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897; congenital heart disease to {Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897; congenital heart disease; skeletal anomalies
Fetal anomalies v0.3484 SEMA3A Krithika Murali gene: SEMA3A was added
gene: SEMA3A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SEMA3A was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: SEMA3A were set to 28075028; 33369061; 20301509; 21059704; 24124006; 22927827
Phenotypes for gene: SEMA3A were set to {Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897; congenital heart disease
Review for gene: SEMA3A was set to GREEN
Added comment: Heterozygous variants associated with isolated GnRH deficiency with or without anosmia (Kallman syndrome like). Anomalies such as unilateral renal aplasia which can be detected antenatally reported with Kallman syndrome but not published with heterozygous SEMA3A variants.

More severe phenotype with biallelic SEMA3A variants reported with features detectable antenatally.

PMID 33369061 Gileta et al 2021 - report x1 patient. Female proband was compound heterozygote for a nonsense variant and a multiexonic deletion of SEMA3A. Presents with postnatal short stature, congenital cardiac anomalies, dysmorphic features, hypogonadotrophic hypogonadism and anosmia.

PMID 28075028 Baumann et al 2017 - report x1 patient. Homozygous LoF variants identified in a proband from a consanguineous Turkish family. Noted at birth to have a high-positioned scapulae, deformed ribs and a lateral clavicular hook. The patient also had upper/lower limb contractures and aberrant right subclavian artery. Mild facial dysmorphism, micropenis and hypogonadotrophic hypogonadism also noted in the first week of life. Postnatal short stature (length 50cm at term birth)

PMID 24124006 Hofmann et al 2013 - first reported biallelic variants in a proband with postnatal short stature, skeletal anomalies of the thorax, congenital heart
defect and camptodactyly
Sources: Literature
Fetal anomalies v0.3484 ROBO2 Zornitza Stark Marked gene: ROBO2 as ready
Fetal anomalies v0.3483 HOXB6 Zornitza Stark Marked gene: HOXB6 as ready
Fetal anomalies v0.3482 COQ7 Zornitza Stark Marked gene: COQ7 as ready
Fetal anomalies v0.3481 CDX2 Zornitza Stark Marked gene: CDX2 as ready
Fetal anomalies v0.3480 TLK2 Zornitza Stark Marked gene: TLK2 as ready
Fetal anomalies v0.3479 STAT3 Zornitza Stark Marked gene: STAT3 as ready
Fetal anomalies v0.3478 RNU12 Zornitza Stark Marked gene: RNU12 as ready
Fetal anomalies v0.3477 PJA1 Zornitza Stark Marked gene: PJA1 as ready
Fetal anomalies v0.3476 PHEX Zornitza Stark Marked gene: PHEX as ready
Fetal anomalies v0.3475 LTBP1 Zornitza Stark Marked gene: LTBP1 as ready
Fetal anomalies v0.3474 EFNA4 Zornitza Stark Marked gene: EFNA4 as ready
Fetal anomalies v0.3473 DHH Zornitza Stark Marked gene: DHH as ready
Fetal anomalies v0.3473 DHH Zornitza Stark Phenotypes for gene: DHH were changed from 46XY partial gonadal dysgenesis, with minifascicular neuropathy; 46XY sex reversal 7 to 46XY gonadal dysgenesis with minifascicular neuropathy MIM#607080
Fetal anomalies v0.3471 DEPDC5 Zornitza Stark Marked gene: DEPDC5 as ready
Fetal anomalies v0.3471 DEPDC5 Zornitza Stark Phenotypes for gene: DEPDC5 were changed from FAMILIAL FOCAL EPILEPSY WITH VARIABLE FOCI to Epilepsy, familial focal, with variable foci 1 MIM#604364
Fetal anomalies v0.3468 DDHD2 Zornitza Stark Marked gene: DDHD2 as ready
Fetal anomalies v0.3468 DDHD2 Zornitza Stark Phenotypes for gene: DDHD2 were changed from COMPLEX HEREDITARY SPASTIC PARAPLEGIA to Spastic paraplegia 54, autosomal recessive, MIM# 615033; MONDO:0014018
Fetal anomalies v0.3466 DDHD1 Zornitza Stark Marked gene: DDHD1 as ready
Fetal anomalies v0.3466 DDHD1 Zornitza Stark Phenotypes for gene: DDHD1 were changed from HEREDITARY SPASTIC PARAPLEGIA to Spastic paraplegia 28, autosomal recessive, 609340; MONDO:0012256
Fetal anomalies v0.3464 ROBO2 Krithika Murali gene: ROBO2 was added
gene: ROBO2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ROBO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ROBO2 were set to 18235093; 19350278; 24429398; 17357069; 26026792; 29194579; 34059960
Phenotypes for gene: ROBO2 were set to Vesicoureteral reflux 2 - MIM#610878; CAKUT
Review for gene: ROBO2 was set to GREEN
Added comment: Known association with familial vesicoureteral reflux and congenital anomalies of the kidney and urinary tract.
Sources: Literature
Fetal anomalies v0.3464 HOXB6 Krithika Murali gene: HOXB6 was added
gene: HOXB6 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: HOXB6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HOXB6 were set to 17003840; 22371315
Phenotypes for gene: HOXB6 were set to Hypospadias
Review for gene: HOXB6 was set to RED
Added comment: PMID 17003840 Chen et al 2007 report 2 babies with hypospadias and heterozygous HOXB6 variants. Cohort of 90 unrelated Chinese patients with hypospadias and 380 controls.

x1 patient - heterozygous, maternally inherited HOXB6 c.124C>A p.P42T in a child with scrotal, micropenis, bifid scrotum, cryptorchidism. Baby also has maternally inherited SRD5A2 and de novo MID1 variant. The HOXB6 variant is absent from gnomad v2, v3, not previously reported in ClinVar, minor GS change (38), moderately conserved (change in non-placental mammals), not in a region of missense constraint.

x1 patient - penile hypospadias, heterozygous HOXB6 c.367T>C p.C123R. No segregation information. 5 hets (East Asian, gnomad v2), 2 hets (East Asian, gnomad v3). GS 180, conserved in mammals (changed in birds), not in a region of missense constraint, not previously reported in ClinVar, predicted to escape NMD.

x2 patients with hypospadias from a single study, variants of uncertain significance.
Sources: Literature
Fetal anomalies v0.3464 DDC Zornitza Stark Marked gene: DDC as ready
Fetal anomalies v0.3463 DDB2 Zornitza Stark Marked gene: DDB2 as ready
Fetal anomalies v0.3461 FUZ Zornitza Stark Marked gene: FUZ as ready
Fetal anomalies v0.3459 DBT Zornitza Stark Marked gene: DBT as ready
Fetal anomalies v0.3457 DARS2 Zornitza Stark Marked gene: DARS2 as ready
Fetal anomalies v0.3457 DARS2 Zornitza Stark Gene: dars2 has been classified as Red List (Low Evidence).
Fetal anomalies v0.3457 DARS2 Zornitza Stark Phenotypes for gene: DARS2 were changed from LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION to Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, MIM# 611105
Fetal anomalies v0.3456 DARS2 Zornitza Stark Publications for gene: DARS2 were set to
Fetal anomalies v0.3455 TTC19 Zornitza Stark Marked gene: TTC19 as ready
Fetal anomalies v0.3455 TTC19 Zornitza Stark Phenotypes for gene: TTC19 were changed from MITOCHONDRIAL COMPLEX III DEFICIENCY to Mitochondrial complex III deficiency, nuclear type 2 (MIM#615157)
Fetal anomalies v0.3453 CYP19A1 Zornitza Stark Marked gene: CYP19A1 as ready
Fetal anomalies v0.3453 CYP19A1 Zornitza Stark Phenotypes for gene: CYP19A1 were changed from Aromatase deficiency 613546; Aromatase excess syndrome 139300 to Aromatase deficiency (MIM#613546), AR; Aromatase excess syndrome (MIM#139300), AD
Fetal anomalies v0.3450 TNXB Zornitza Stark Marked gene: TNXB as ready
Fetal anomalies v0.3449 FLRT3 Zornitza Stark Marked gene: FLRT3 as ready
Fetal anomalies v0.3446 TMEM126B Zornitza Stark Marked gene: TMEM126B as ready
Fetal anomalies v0.3446 TMEM126B Zornitza Stark Phenotypes for gene: TMEM126B were changed from Muscle Weakness and Isolated Complex I Deficiency to Mitochondrial complex I deficiency, nuclear type 29 (MIM#618250)
Fetal anomalies v0.3443 FLAD1 Zornitza Stark Marked gene: FLAD1 as ready
Fetal anomalies v0.3441 TK2 Zornitza Stark Marked gene: TK2 as ready
Fetal anomalies v0.3440 FGF20 Zornitza Stark Marked gene: FGF20 as ready
Fetal anomalies v0.3438 FGF17 Zornitza Stark Marked gene: FGF17 as ready
Fetal anomalies v0.3436 TEK Zornitza Stark Marked gene: TEK as ready
Fetal anomalies v0.3436 TEK Zornitza Stark Phenotypes for gene: TEK were changed from VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL to Glaucoma 3, primary congenital, E (MIM#617272); Venous malformations, multiple cutaneous and mucosal (MIM#600195)
Fetal anomalies v0.3433 TBXAS1 Zornitza Stark Marked gene: TBXAS1 as ready
Fetal anomalies v0.3432 TANGO2 Zornitza Stark Marked gene: TANGO2 as ready
Fetal anomalies v0.3432 TANGO2 Zornitza Stark Phenotypes for gene: TANGO2 were changed from Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MIM#616878)
Fetal anomalies v0.3430 TANGO2 Zornitza Stark reviewed gene: TANGO2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MIM#616878); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3430 ZFYVE26 Zornitza Stark Marked gene: ZFYVE26 as ready
Fetal anomalies v0.3430 ZFYVE26 Zornitza Stark Phenotypes for gene: ZFYVE26 were changed from SPASTIC PARAPLEGIA AUTOSOMAL RECESSIVE TYPE 15 to Spastic paraplegia 15, autosomal recessive MIM#270700
Fetal anomalies v0.3428 ZFYVE26 Zornitza Stark reviewed gene: ZFYVE26: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 15, autosomal recessive MIM#270700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3428 SYP Zornitza Stark Marked gene: SYP as ready
Fetal anomalies v0.3428 SYP Zornitza Stark Phenotypes for gene: SYP were changed from MENTAL RETARDATION X-LINKED SYP-RELATED to Intellectual developmental disorder, X-linked 96 (MIM#300802)
Fetal anomalies v0.3426 CYC1 Zornitza Stark Marked gene: CYC1 as ready
Fetal anomalies v0.3426 CYC1 Zornitza Stark Phenotypes for gene: CYC1 were changed from MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 6 to Mitochondrial complex III deficiency, nuclear type 6, MIM# 615453
Fetal anomalies v0.3424 SURF1 Zornitza Stark Marked gene: SURF1 as ready
Fetal anomalies v0.3424 SURF1 Zornitza Stark Phenotypes for gene: SURF1 were changed from LEIGH SYNDROME; COMPLEX IV DEFICIENCY to Mitochondrial complex IV deficiency, nuclear type 1 (MIM#220110)
Fetal anomalies v0.3422 ZDHHC9 Zornitza Stark Marked gene: ZDHHC9 as ready
Fetal anomalies v0.3422 ZDHHC9 Zornitza Stark Phenotypes for gene: ZDHHC9 were changed from MENTAL RETARDATION SYNDROMIC X-LINKED ZDHHC9-RELATED to Mental retardation, X-linked syndromic, Raymond type, MIM# 300799
Fetal anomalies v0.3420 ZDHHC9 Zornitza Stark reviewed gene: ZDHHC9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, X-linked syndromic, Raymond type, MIM# 300799; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v0.3420 STXBP1 Zornitza Stark Marked gene: STXBP1 as ready
Fetal anomalies v0.3420 STXBP1 Zornitza Stark Phenotypes for gene: STXBP1 were changed from ANGELMAN/PITT HOPKINS SYNDROME-LIKE DISORDER; EPILEPTIC ENCEPHALOPATHY EARLY INFANTILE TYPE 4 to Developmental and epileptic encephalopathy 4 (MIM#612164)
Fetal anomalies v0.3417 XPC Zornitza Stark Marked gene: XPC as ready
Fetal anomalies v0.3415 WDR45 Zornitza Stark Marked gene: WDR45 as ready
Fetal anomalies v0.3413 COQ7 Krithika Murali gene: COQ7 was added
gene: COQ7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: COQ7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ7 were set to 33215859; 28125198; 31240163; 28409910; 26084283
Phenotypes for gene: COQ7 were set to Coenzyme Q10 deficiency, primary, 8 - MIM#616733
Review for gene: COQ7 was set to GREEN
Added comment: Biallelic variants associated with primary coenzyme Q10 (CoQ10) deficiency, a heterogeneous multi-system disorder including early-postnatal features such as neonatal encephalopathy, contractures. Antenatal features reported include IUGR, oligohydramnios, feetal lung hypoplasia, dysplastic kidneys.

Specifically for COQ7-related CoQ10 deficiency:

PMID 33215859 Hashemi et al 2020 - report two affected individuals from a consanguineous Iranian family with homozygous COQ7 variants progressive spastic paraparesis diagnosed at age 1.5-2 with normal antenatal history.

PMID 31240163 Kwong et al 2019 - report a patient with compound hetereozygous COQ7 variants, encephalo‐myo‐nephro‐cardiopathy, persistent lactic acidosis, and basal ganglia lesions resulting in early infantile death. Skin fibroblast studies showed decreased combined complex II + III activity and reduction in CoQ10 level. The proband was a DCDA twin, noted to have IUGR, oligohydramnios, cardiomegaly and tricuspid regurgitation antenatally.

PMID 28409910 Wang et al 2017 - no antenatal features reported in their proband

PMID 26084283 Freyer et al 2015 - report x1 patient with homozygous COQ7 variant. The pregnancy was complicated by oligohydramniosis, fetal lung hypoplasia and growth retardation.
Sources: Literature
Fetal anomalies v0.3413 SPTBN5 Zornitza Stark Marked gene: SPTBN5 as ready
Fetal anomalies v0.3412 SPTBN2 Zornitza Stark Marked gene: SPTBN2 as ready
Fetal anomalies v0.3412 SPTBN2 Zornitza Stark Phenotypes for gene: SPTBN2 were changed from Infantile ataxia with oculomotor and pyramidal signs; SCA14; Spinocerebellar ataxia, autosomal recessive 14, 615386 to Spinocerebellar ataxia 5 (MIM#600224); Spinocerebellar ataxia, autosomal recessive 14 (MIM#615386)
Fetal anomalies v0.3409 SMARCAL1 Zornitza Stark Marked gene: SMARCAL1 as ready
Fetal anomalies v0.3409 SMARCAL1 Zornitza Stark Gene: smarcal1 has been classified as Green List (High Evidence).
Fetal anomalies v0.3409 SMARCAL1 Zornitza Stark Phenotypes for gene: SMARCAL1 were changed from SCHIMKE IMMUNOOSSEOUS DYSPLASIA to Schimke immunoosseous dysplasia (MIM#242900)
Fetal anomalies v0.3408 SMARCAL1 Zornitza Stark Publications for gene: SMARCAL1 were set to
Fetal anomalies v0.3407 SMARCAL1 Zornitza Stark Classified gene: SMARCAL1 as Green List (high evidence)
Fetal anomalies v0.3407 SMARCAL1 Zornitza Stark Gene: smarcal1 has been classified as Green List (High Evidence).
Fetal anomalies v0.3406 SP110 Zornitza Stark Marked gene: SP110 as ready
Fetal anomalies v0.3405 SLC6A8 Zornitza Stark Marked gene: SLC6A8 as ready
Fetal anomalies v0.3402 SLC52A3 Zornitza Stark Marked gene: SLC52A3 as ready
Fetal anomalies v0.3400 CDX2 Krithika Murali gene: CDX2 was added
gene: CDX2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CDX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDX2 were set to 29177441
Phenotypes for gene: CDX2 were set to Persistent cloaca
Review for gene: CDX2 was set to AMBER
Added comment: De novo heterozygous variants detected in 2 patients with persistent cloaca. This condition. can rarely be detected antenatally.
Sources: Literature
Fetal anomalies v0.3400 TLK2 Krithika Murali gene: TLK2 was added
gene: TLK2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TLK2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: TLK2 were set to 29861108; 31558842; 34821460
Phenotypes for gene: TLK2 were set to Intellectual developmental disorder, autosomal dominant 57 - MIM#618050
Review for gene: TLK2 was set to GREEN
Added comment: Associated with syndromic ID. Potential to detect reported phenotypic features of microcephaly, IUGR, craniosynostosis (rare) antenatally.
Sources: Literature
Fetal anomalies v0.3400 STAT3 Krithika Murali gene: STAT3 was added
gene: STAT3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: STAT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STAT3 were set to 30617622; 31771449; 34366294
Phenotypes for gene: STAT3 were set to Hyper-IgE recurrent infection syndrome - MIM#147060; Autoimmune disease, multisystem, infantile-onset, 1 - MIM#615952
Added comment: Well known association with Hyper IgE syndrome and multisystem autoimmune disease. Early post-natal diagnosis reported. Prenatally detectable features include craniosynostosis and IUGR.

31771449 Terry et al 2020 report a baby with a de novo heterozygous likely pathogenic STAT3 variant. Severe IUGR and oligohydramnios was noted on USS at 21 weeks gestation.
Sources: Literature
Fetal anomalies v0.3400 RNU12 Krithika Murali gene: RNU12 was added
gene: RNU12 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU12 were set to 34085356
Phenotypes for gene: RNU12 were set to CDAGS syndrome MIM#603116; Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations
Review for gene: RNU12 was set to GREEN
Added comment: No new publications since last PanelApp review July 2021

---

5 CDAGS syndrome families with biallelic variants all including NC_000022.10:g.43011402C>T and another variant on the second allele. Whole transcriptome sequencing analysis of patient lymphoblastoid cells identified differentially expressed genes, and differential alternative splicing analysis indicated there was an enrichment of alternative splicing events.
Sources: Literature
Fetal anomalies v0.3400 PJA1 Krithika Murali gene: PJA1 was added
gene: PJA1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PJA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PJA1 were set to 32530565
Phenotypes for gene: PJA1 were set to Trigonocephaly, intellectual disability
Review for gene: PJA1 was set to AMBER
Added comment: No new publications since last PanelApp review August 2020

--

Recurrent variant, p.Arg376Cys, reported in 7 Japanese individuals, supportive mouse model. Individuals shared a common haplotype, suggestive of founder effect.
Sources: Literature
Fetal anomalies v0.3400 PHEX Krithika Murali gene: PHEX was added
gene: PHEX was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PHEX was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: PHEX were set to 29791829; 16055933; 19219621; 9106524
Phenotypes for gene: PHEX were set to Hypophosphatemic rickets, X-linked dominant - MIM#307800
Review for gene: PHEX was set to GREEN
Added comment: Well-known association with hypophosphataemic rickets with some phenotypic features potentially detectable antenatally (skeletal, craniosynostosis). Early therapeutic interventions available.
Sources: Literature
Fetal anomalies v0.3400 LTBP1 Krithika Murali gene: LTBP1 was added
gene: LTBP1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to 33991472
Phenotypes for gene: LTBP1 were set to Cutis laxa, autosomal recessive, type IIE - MIM#619451
Review for gene: LTBP1 was set to GREEN
Added comment: Homozygous premature truncating LTBP1 variants in eight affected individuals from four unrelated consanguineous families reported associated with autosomal recessive cutis laxa type IIE. Phenotypic features relevant in the prenatal setting include:
- Congenital diaphragmatic hernia (1 individual)
- Cleft palate (2 individuals)
- Congenital heart defects
- Renal anomalies (1 individual)
- Microretrognathia (1 individual)
- Hydrocephalus (1 individual)
- Skeletal anomalies (craniosynostosis, short stature, brachydactyly, and syndactyly).

Supportive patient-derived fibroblast and zebrafish studies.
Sources: Literature
Fetal anomalies v0.3400 EFNA4 Krithika Murali gene: EFNA4 was added
gene: EFNA4 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: EFNA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EFNA4 were set to 29215649; 29168297; 16540516
Phenotypes for gene: EFNA4 were set to Craniosynostosis
Review for gene: EFNA4 was set to AMBER
Added comment: PMID 29215649 Lee et al 2018 - Cohort of 309 individuals with craniosynostosis tested with a 20-gene panel. Report 1 individual with unicoronal CS with a likely pathogenic EFNA4 variant.

PMID 29168297 Clarke et al 2018 - Study enrolled 397 probands with single suture CS. Report one maternally inherited EFNA4 VUS NM_005227.2:c.550C>T; p.(Leu184Phe) with metopic CS, x1 het in gnomad (v2), variant predicted to escape NMD, not reported in ClinVar/Decipher.

PMID 16540516 Merrill et al 2006 - Tested 81 patients with non-syndromic coronal CS. 3 heterozygous EFNA4 variants detected - x2 missense variants:
- c.178C>T p.H60Y -- 361 hets gnomad
- c.349 C>A p.P117T - 337 hets
- novel frameshift delin 471_472delCCinsA.

All 3 variants inherited from unaffected parent. Functional studies on fibroblast cells from the proband with the frameshift delin variant demonstrated an alternatively spliced minor isoform of EFNA4.
Sources: Literature
Fetal anomalies v0.3400 DHH Belinda Chong reviewed gene: DHH: Rating: ; Mode of pathogenicity: None; Publications: 31018998, 29471294, 11017805; Phenotypes: 46XY gonadal dysgenesis with minifascicular neuropathy MIM#607080; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3400 DEPDC5 Belinda Chong reviewed gene: DEPDC5: Rating: RED; Mode of pathogenicity: None; Publications: 23542697, 23542701, 24814846, 24585383, 26505888, 27173016, 31444548; Phenotypes: Epilepsy, familial focal, with variable foci 1 MIM#604364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v0.3400 DDHD2 Belinda Chong reviewed gene: DDHD2: Rating: RED; Mode of pathogenicity: None; Publications: 23486545, 24482476, 23176823, 31302745; Phenotypes: Spastic paraplegia 54, autosomal recessive, MIM# 615033, MONDO:0014018; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3400 DDHD1 Belinda Chong reviewed gene: DDHD1: Rating: RED; Mode of pathogenicity: None; Publications: 23176821; Phenotypes: Spastic paraplegia 28, autosomal recessive, 609340, MONDO:0012256; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3400 DDC Belinda Chong reviewed gene: DDC: Rating: RED; Mode of pathogenicity: None; Publications: 20505134, 33528536, 30799092, 33996177; Phenotypes: Aromatic L-amino acid decarboxylase deficiency MIM#608643; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3400 DARS2 Belinda Chong edited their review of gene: DARS2: Set current diagnostic: yes
Fetal anomalies v0.3400 DARS2 Belinda Chong reviewed gene: DARS2: Rating: RED; Mode of pathogenicity: None; Publications: 17384640, 15002045, 16788019, 30352563; Phenotypes: Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, MIM# 611105; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3400 TTC19 Daniel Flanagan reviewed gene: TTC19: Rating: RED; Mode of pathogenicity: None; Publications: 23532514, 24368687; Phenotypes: Mitochondrial complex III deficiency, nuclear type 2 (MIM#615157); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3400 CYP19A1 Belinda Chong reviewed gene: CYP19A1: Rating: RED; Mode of pathogenicity: None; Publications: 17164303, 25264451; Phenotypes: Aromatase deficiency (MIM#613546), AR, Aromatase excess syndrome (MIM#139300), AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3400 MYOCD Zornitza Stark Marked gene: MYOCD as ready
Fetal anomalies v0.3399 MYO9A Zornitza Stark Marked gene: MYO9A as ready
Fetal anomalies v0.3398 MYMK Zornitza Stark Marked gene: MYMK as ready
Fetal anomalies v0.3397 MYL1 Zornitza Stark Marked gene: MYL1 as ready
Fetal anomalies v0.3396 TMEM126B Daniel Flanagan reviewed gene: TMEM126B: Rating: AMBER; Mode of pathogenicity: None; Publications: 27374774, 27374773; Phenotypes: Mitochondrial complex I deficiency, nuclear type 29 (MIM#618250); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3396 TEK Daniel Flanagan reviewed gene: TEK: Rating: RED; Mode of pathogenicity: None; Publications: 19888299; Phenotypes: Glaucoma 3, primary congenital, E (MIM#617272), Venous malformations, multiple cutaneous and mucosal (MIM#600195); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3396 TANGO2 Daniel Flanagan reviewed gene: TANGO2: Rating: RED; Mode of pathogenicity: None; Publications: 26805781, 26805782, 30245509; Phenotypes: Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MIM#616878); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3396 ZFYVE26 Ain Roesley reviewed gene: ZFYVE26: Rating: RED; Mode of pathogenicity: None; Publications: 34057829; Phenotypes: Spastic paraplegia 15, autosomal recessive MIM#270700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3396 CYC1 Belinda Chong reviewed gene: CYC1: Rating: RED; Mode of pathogenicity: None; Publications: 23910460; Phenotypes: Mitochondrial complex III deficiency, nuclear type 6, MIM# 615453; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3396 SURF1 Daniel Flanagan reviewed gene: SURF1: Rating: RED; Mode of pathogenicity: None; Publications: 23829769; Phenotypes: Charcot-Marie-Tooth disease, type 4K (MIM#616684), Mitochondrial complex IV deficiency, nuclear type 1 (MIM#220110); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3396 ZDHHC9 Ain Roesley reviewed gene: ZDHHC9: Rating: RED; Mode of pathogenicity: None; Publications: Mental retardation, X-linked syndromic, Raymond typeMIM# 300799; Phenotypes: Mental retardation, X-linked syndromic, Raymond typeMIM# 300799; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Fetal anomalies v0.3396 MYH7 Zornitza Stark Marked gene: MYH7 as ready
Fetal anomalies v0.3396 MYH7 Zornitza Stark Phenotypes for gene: MYH7 were changed from Cardiomyopathy, hypertrophic, 1, OMIM:192600; Laing early-onset distal myopathy, MONDO:0008050; Left ventricular noncompaction 5, OMIM:613426; Cardiomyopathy, dilated, 1S, OMIM:613426; Hypertrophic cardiomyopathy 1, MONDO:0008647; Laing distal myopathy, OMIM:160500; Dilated cardiomyopathy 1S, MONDO:0013262 to Ebstein anomaly; Laing distal myopathy, MIM# 160500
Fetal anomalies v0.3392 MYH2 Zornitza Stark Marked gene: MYH2 as ready
Fetal anomalies v0.3390 MSMO1 Zornitza Stark Marked gene: MSMO1 as ready
Fetal anomalies v0.3388 MRPS34 Zornitza Stark Marked gene: MRPS34 as ready
Fetal anomalies v0.3386 MRPS34 Zornitza Stark changed review comment from: Six individuals from 4 unrelated families; clinical presentation is with developmental delay/regression. More variable features include movement disorders, microcephaly, strabismus, nystagmus, optic atrophy.
Sources: Expert list; to: Six individuals from 4 unrelated families; clinical presentation is with developmental delay/regression. More variable features include movement disorders, microcephaly, strabismus, nystagmus, optic atrophy.

Onset of microcephaly uncertain, other clinical features present post-natally.

Sources: Expert list
Fetal anomalies v0.3386 MRAS Zornitza Stark Marked gene: MRAS as ready
Fetal anomalies v0.3384 MOGS Zornitza Stark Marked gene: MOGS as ready
Fetal anomalies v0.3382 MN1 Zornitza Stark Marked gene: MN1 as ready
Fetal anomalies v0.3380 MN1 Zornitza Stark changed review comment from: Over 20 individuals described with de novo truncating variants in this gene; these cluster in the C-terminal and the authors postulate that that syndrome is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein.
Sources: Literature; to: Over 20 individuals described with de novo truncating variants in this gene; these cluster in the C-terminal and the authors postulate that that syndrome is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein.

Diaphragmatic hernia, craniosynostosis and brain abnormalities reported.

Sources: Literature
Fetal anomalies v0.3380 MITF Zornitza Stark Marked gene: MITF as ready
Fetal anomalies v0.3380 MITF Zornitza Stark Phenotypes for gene: MITF were changed from Tietz albinism-deafness syndrome, 103500; Waardenburg syndrome/ocular albinism, digenic, 103470; TIETZ SYNDROME; Waardenburg syndrome, type 2A, 193510; Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness; WAARDENBURG SYNDROME TYPE 2A; COMMAD syndrome, 617306; WAARDENBURG SYNDROME TYPE 2 WITH OCULAR ALBINISM to COMMAD syndrome, MIM# 617306
Fetal anomalies v0.3377 MIR17HG Zornitza Stark Marked gene: MIR17HG as ready
Fetal anomalies v0.3374 MANBA Zornitza Stark Marked gene: MANBA as ready
Fetal anomalies v0.3372 MANBA Zornitza Stark changed review comment from: Variable severity. Well established gene-disease association.; to: Well established gene-disease association but clinical presentation is typically post-natal.
Fetal anomalies v0.3372 SMARCAL1 Daniel Flanagan changed review comment from: Well-established gene-disease association; over 40 patients with biallelic mutations in SMARCAL1; Zebrafish and mouse models that recapitulates phenotype have been reported.

This disorder combines abnormality of the immune and skeletal systems. Primary features include growth retardation (IUGR in 50%), renal failure, cerebral infarcts, skin pigmentation and CID (lymphocytopaenia, recurrent infections and/or T-cell immunodeficiency) beginning in childhood.

GeneReviews: Short stature (99% of individuals) that typically manifests as a short neck and trunk with lumbar lordosis and a protruding abdomen.; to: Well-established gene-disease association; over 40 patients with biallelic mutations in SMARCAL1; Zebrafish and mouse models that recapitulates phenotype have been reported.

This disorder combines abnormality of the immune and skeletal systems. Primary features include growth retardation (IUGR in 50%), renal failure, cerebral infarcts, skin pigmentation and CID (lymphocytopaenia, recurrent infections and/or T-cell immunodeficiency) beginning in childhood.

GeneReviews: Short stature (99% of individuals) that typically manifests as a short neck and trunk with lumbar lordosis and a protruding abdomen. Most affected children have prenatal and postnatal disproportionate growth failure. A few have normal intrauterine growth followed by postnatal growth failure.
Fetal anomalies v0.3372 SPTBN2 Daniel Flanagan reviewed gene: SPTBN2: Rating: RED; Mode of pathogenicity: None; Publications: 23236289, 23838597, 22781464, 31617442, 31066025; Phenotypes: Spinocerebellar ataxia 5 (MIM#600224), Spinocerebellar ataxia, autosomal recessive 14 (MIM#615386); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.3372 SMARCAL1 Daniel Flanagan reviewed gene: SMARCAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15523612, 20301550, 20301550, 17089404, 20036229; Phenotypes: Schimke immunoosseous dysplasia (MIM#242900); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3372 MAN1B1 Zornitza Stark Marked gene: MAN1B1 as ready
Fetal anomalies v0.3372 MAN1B1 Zornitza Stark Phenotypes for gene: MAN1B1 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Rafiq syndrome, MIM# 614202
Fetal anomalies v0.3370 MACF1 Zornitza Stark Marked gene: MACF1 as ready
Fetal anomalies v0.3370 MACF1 Zornitza Stark Mode of pathogenicity for gene: MACF1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.3367 LRRC56 Zornitza Stark Marked gene: LRRC56 as ready
Fetal anomalies v0.3366 LRBA Zornitza Stark Marked gene: LRBA as ready
Fetal anomalies v0.3366 LRBA Zornitza Stark Phenotypes for gene: LRBA were changed from CHILDHOOD-ONSET HYPOGAMMAGLOBULINEMIA to Immunodeficiency, common variable, 8, with autoimmunity MIM#614700
Fetal anomalies v0.3364 LRBA Zornitza Stark reviewed gene: LRBA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency, common variable, 8, with autoimmunity MIM#614700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3364 LONP1 Zornitza Stark Marked gene: LONP1 as ready
Fetal anomalies v0.3362 LONP1 Zornitza Stark changed review comment from: At least three unrelated cases described in the literature, ID is part of the phenotype.; to: At least three unrelated cases described in the literature, multiple congenital anomalies are part of the phenotype.
Fetal anomalies v0.3362 LIPT2 Zornitza Stark Marked gene: LIPT2 as ready
Fetal anomalies v0.3359 LIPT1 Zornitza Stark Marked gene: LIPT1 as ready
Fetal anomalies v0.3359 LIPT1 Zornitza Stark Phenotypes for gene: LIPT1 were changed from Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. to Lipoyltransferase 1 deficiency, MIM#616299
Fetal anomalies v0.3356 LIAS Zornitza Stark Marked gene: LIAS as ready
Fetal anomalies v0.3353 LIAS Zornitza Stark changed review comment from: At least three families reported, severe ID is part of the phenotype.; to: At least three families reported, clinical presentation is typically post-natal.
Fetal anomalies v0.3353 LARS2 Zornitza Stark Marked gene: LARS2 as ready
Fetal anomalies v0.3353 LARS2 Zornitza Stark Gene: lars2 has been classified as Green List (High Evidence).
Fetal anomalies v0.3353 LARS2 Zornitza Stark Classified gene: LARS2 as Green List (high evidence)
Fetal anomalies v0.3353 LARS2 Zornitza Stark Gene: lars2 has been classified as Green List (High Evidence).
Fetal anomalies v0.3352 LAMB1 Zornitza Stark Marked gene: LAMB1 as ready
Fetal anomalies v0.3351 KPTN Zornitza Stark Marked gene: KPTN as ready
Fetal anomalies v0.3351 KPTN Zornitza Stark Phenotypes for gene: KPTN were changed from MACROCEPHALY, NEURODEVELOPMENTAL DELAY, AND SEIZURES to Mental retardation, autosomal recessive 41 (MIM#615637)
Fetal anomalies v0.3349 KPTN Zornitza Stark changed review comment from: 15 patients (9 from Amish families) reported with macrocephaly and intellectual disability with hom or chet variants in KPTN (PMID: 32808430).; to: 15 patients (9 from Amish families) reported with macrocephaly and intellectual disability with hom or chet variants in KPTN (PMID: 32808430). Age of onset of macrocephaly uncertain.
Fetal anomalies v0.3349 KNL1 Zornitza Stark Marked gene: KNL1 as ready
Fetal anomalies v0.3347 KMT2B Zornitza Stark Marked gene: KMT2B as ready
Fetal anomalies v0.3347 KMT2B Zornitza Stark Phenotypes for gene: KMT2B were changed from Complex early-onset dystonia to Dystonia 28, childhood-onset, MIM#617284
Fetal anomalies v0.3344 KMT2B Zornitza Stark changed review comment from: ID described as part of the phenotype in some patients.; to: Clinical presentation is typically post-natal.
Fetal anomalies v0.3344 KLHL7 Zornitza Stark Marked gene: KLHL7 as ready
Fetal anomalies v0.3342 KLHL7 Zornitza Stark changed review comment from: Overall IUGR rather than microcephaly, head sizes when reported appear to be in the -1-2SD range.; to: IUGR and contractures.
Fetal anomalies v0.3342 KIF5C Zornitza Stark Marked gene: KIF5C as ready
Fetal anomalies v0.3339 KIF2A Zornitza Stark Marked gene: KIF2A as ready
Fetal anomalies v0.3336 KIF14 Zornitza Stark Marked gene: KIF14 as ready
Fetal anomalies v0.3334 SPRED2 Zornitza Stark Phenotypes for gene: SPRED2 were changed from cardiac defects; skeletal anomalies to Noonan syndrome 14, MIM# 619745
Fetal anomalies v0.3333 NEXMIF Zornitza Stark Marked gene: NEXMIF as ready
Fetal anomalies v0.3333 NEXMIF Zornitza Stark Phenotypes for gene: NEXMIF were changed from Intellectual disability and epilepsy; KIAA2022 to Mental retardation, X-linked 98 300912
Fetal anomalies v0.3330 NEXMIF Zornitza Stark changed review comment from: Females have been described as both asymptomatic carriers or affected. Given only PTCs have been reported, there is no genotype-phenotype correlation. OMIM describes that a phenotype manifests depending on X-inactivation skewing No reported pathogenic missense to date except for the one LP hemizygous in DDD that is maternally inherited (Decipher) Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy.; to: Females have been described as both asymptomatic carriers or affected. Given only PTCs have been reported, there is no genotype-phenotype correlation. OMIM describes that a phenotype manifests depending on X-inactivation skewing No reported pathogenic missense to date except for the one LP hemizygous in DDD that is maternally inherited (Decipher) Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy.

Typically presents post-natally.
Fetal anomalies v0.3330 NHP2 Zornitza Stark Marked gene: NHP2 as ready
Fetal anomalies v0.3330 NHP2 Zornitza Stark Phenotypes for gene: NHP2 were changed from DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 2 to Dyskeratosis congenita, autosomal recessive 2, MIM# 613987; Høyeraal-Hreidarsson syndrome
Fetal anomalies v0.3327 NONO Zornitza Stark Marked gene: NONO as ready
Fetal anomalies v0.3327 NONO Zornitza Stark Phenotypes for gene: NONO were changed from Atresia; Ventricular septal defect (VSD); Pulmonary stenosis; Ebstein s anomaly; Left ventricular non-compaction cardiomyopathy (LVNC) to Mental retardation, X-linked, syndromic 34, MIM# 300967; Ventricular septal defect (VSD); Pulmonary stenosis; Ebstein s anomaly; Left ventricular non-compaction cardiomyopathy (LVNC)
Fetal anomalies v0.3324 KIAA0753 Zornitza Stark Marked gene: KIAA0753 as ready
Fetal anomalies v0.3321 KDM1A Zornitza Stark Marked gene: KDM1A as ready
Fetal anomalies v0.3321 KDM1A Zornitza Stark Phenotypes for gene: KDM1A were changed from Developmental delay and distinctive facial features to Cleft palate, psychomotor retardation, and distinctive facial features 616728
Fetal anomalies v0.3317 KDM1A Zornitza Stark changed review comment from: Three unrelated individuals with de novo missense variants in this gene and a neurodevelopmental phenotype. Note one of the individuals also had a de novo indel in ANKRD11. Some data published subsequently demonstrating functional impact of all three variants.; to: Three unrelated individuals with de novo missense variants in this gene and a neurodevelopmental phenotype. Note one of the individuals also had a de novo indel in ANKRD11. Some data published subsequently demonstrating functional impact of all three variants.

LGA, cleft palate, brain abnormalities reported.
Fetal anomalies v0.3317 KCNQ5 Zornitza Stark Marked gene: KCNQ5 as ready
Fetal anomalies v0.3317 KCNQ5 Zornitza Stark Phenotypes for gene: KCNQ5 were changed from Intellectual Disability with or without Epileptic Encephalopathy to Mental retardation, autosomal dominant 46, MIM# 617601
Fetal anomalies v0.3313 KCNQ5 Zornitza Stark changed review comment from: Four unrelated individuals reported with de novo missense variants in this gene and a neurodevelopmental disorder, including epileptic encephalopathy in some. Three of the variants demonstrated to be LoF and one GoF. Further individual reported in PMID 30359776 with mild ID and absence epilepsy and an intragenic duplication causing likely LoF.; to: Four unrelated individuals reported with de novo missense variants in this gene and a neurodevelopmental disorder, including epileptic encephalopathy in some. Three of the variants demonstrated to be LoF and one GoF. Further individual reported in PMID 30359776 with mild ID and absence epilepsy and an intragenic duplication causing likely LoF.

Clinical presentation is typically post-natal.
Fetal anomalies v0.3313 KCNJ6 Zornitza Stark Marked gene: KCNJ6 as ready
Fetal anomalies v0.3309 KCNJ6 Zornitza Stark changed review comment from: Keppen-Lubinsky syndrome characterised by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth.

Four unrelated individuals reported with de novo variants in this gene (one recurred in 2), mouse model. One of the individuals did not have lipodystrophy but had a prominent hyperkinetic movement disorder.; to: Keppen-Lubinsky syndrome characterised by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth.

Four unrelated individuals reported with de novo variants in this gene (one recurred in 2), mouse model. One of the individuals did not have lipodystrophy but had a prominent hyperkinetic movement disorder.

Clinical presentation is typically post-natal, with normal growth parameters at birth.
Fetal anomalies v0.3309 KCNH1 Zornitza Stark Marked gene: KCNH1 as ready
Fetal anomalies v0.3309 KCNH1 Zornitza Stark Phenotypes for gene: KCNH1 were changed from TEMPLE BARRAISTER SYNDROME to Zimmermann-Laband syndrome 1, OMIM:135500
Fetal anomalies v0.3305 KCNC3 Zornitza Stark Marked gene: KCNC3 as ready
Fetal anomalies v0.3305 KCNC3 Zornitza Stark Phenotypes for gene: KCNC3 were changed from SPINOCEREBELLAR ATAXIA TYPE 13 to Spinocerebellar ataxia 13, MIM#605259
Fetal anomalies v0.3302 KATNB1 Zornitza Stark Marked gene: KATNB1 as ready
Fetal anomalies v0.3301 JAM3 Zornitza Stark Marked gene: JAM3 as ready
Fetal anomalies v0.3301 JAM3 Zornitza Stark Phenotypes for gene: JAM3 were changed from HEMORRHAGIC DESTRUCTION OF THE BRAIN, SUBEPENDYMAL CALCIFICATION, AND CATARACTS to Haemorrhagic destruction of the brain, subependymal calcification, and cataracts, MIM# 613730
Fetal anomalies v0.3298 JAM3 Zornitza Stark changed review comment from: Autosomal recessive disorder with a distinctive phenotype comprising haemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Affected individuals have a catastrophic neurologic clinical course resulting in death in infancy. Four unrelated families reported.; to: Autosomal recessive disorder with a distinctive phenotype comprising haemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Affected individuals have a catastrophic neurologic clinical course resulting in death in infancy. Four unrelated families reported.

Perinatal presentation.
Fetal anomalies v0.3298 ITCH Zornitza Stark Marked gene: ITCH as ready
Fetal anomalies v0.3295 ITCH Zornitza Stark changed review comment from: Multiple affected individuals reported from Amish community, however, single variant, founder effect.; to: Multiple affected individuals reported from Amish community, however, single variant, founder effect. Short stature but age of onset uncertain.
Fetal anomalies v0.3295 IRX5 Zornitza Stark Marked gene: IRX5 as ready
Fetal anomalies v0.3295 IRX5 Zornitza Stark Phenotypes for gene: IRX5 were changed from HYPERTELORISM, SEVERE, WITH MIDFACE PROMINENCE, MYOPIA, MENTAL RETARDATION, AND BONE FRAGILITY to Hamamy syndrome, MIM# 611174
Fetal anomalies v0.3293 IFT81 Zornitza Stark Marked gene: IFT81 as ready
Fetal anomalies v0.3293 IFT52 Zornitza Stark Marked gene: IFT52 as ready
Fetal anomalies v0.3292 ICK Zornitza Stark Marked gene: ICK as ready
Fetal anomalies v0.3290 CTNS Zornitza Stark Marked gene: CTNS as ready
Fetal anomalies v0.3290 CTNS Zornitza Stark Phenotypes for gene: CTNS were changed from CYSTINOSIS NEPHROPATHIC TYPE; CYSTINOSIS LATE-ONSET JUVENILE OR ADOLESCENT NEPHROPATHIC TYPE; CYSTINOSIS ADULT NON-NEPHROPATHIC TYPE to Cystinosis, late-onset juvenile or adolescent nephropathic MIM#219900; Cystinosis, nephropathic MIM#219800; Cystinosis, ocular nonnephropathic MIM#219750
Fetal anomalies v0.3288 SLC52A2 Zornitza Stark Marked gene: SLC52A2 as ready
Fetal anomalies v0.3286 SLC4A4 Zornitza Stark Marked gene: SLC4A4 as ready
Fetal anomalies v0.3286 SLC4A4 Zornitza Stark Phenotypes for gene: SLC4A4 were changed from PROXIMAL RENAL TUBULAR ACIDOSIS WITH OCULAR ABNORMALITIES to Renal tubular acidosis, proximal, with ocular abnormalities (MIM#604278)
Fetal anomalies v0.3285 SLC39A13 Zornitza Stark Marked gene: SLC39A13 as ready
Fetal anomalies v0.3283 ZBTB24 Zornitza Stark Marked gene: ZBTB24 as ready
Fetal anomalies v0.3282 SLC25A26 Zornitza Stark Marked gene: SLC25A26 as ready
Fetal anomalies v0.3279 CTNS Belinda Chong reviewed gene: CTNS: Rating: RED; Mode of pathogenicity: None; Publications: 32564281, 20301574, 9537412, 31068690; Phenotypes: Cystinosis, late-onset juvenile or adolescent nephropathic MIM#219900, Cystinosis, nephropathic MIM#219800, Cystinosis, ocular nonnephropathic MIM#219750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3279 SLC4A4 Daniel Flanagan reviewed gene: SLC4A4: Rating: RED; Mode of pathogenicity: None; Publications: 10545938, 11274232; Phenotypes: Renal tubular acidosis, proximal, with ocular abnormalities (MIM#604278); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3279 ZBTB24 Krithika Murali gene: ZBTB24 was added
gene: ZBTB24 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ZBTB24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZBTB24 were set to 32865561; 21596365; 29023266; 32061411; 21906047; 28128455; 23739126; 22786748
Phenotypes for gene: ZBTB24 were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 2 - MIM#614069
Review for gene: ZBTB24 was set to GREEN
Added comment: Well reported association with ICF2 (immunodeficiency-centromeric instability facial anomalies syndrome 2). Patients have immunodeficiency (mainly hypo/agammaglobulinemia in the presence of B cells), recurrent infections (namely respiratory and gastrointestinal) and dysmorphic facies.

Although antenatal features not thoroughly described for published cases, low birth weight has been a reported feature as well as hypertelorism and micrognathia/retrognathia - these have the potential to be detected prenatally.

PMID 32865561 Helfricht et al 2020 - "loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance".

PMID 32061411 Banday. et al 2020 - report a patient with this condition and granulomatous hepatitis. Review phenotype of previously reported patients, low birth weight and facial dysmorphism including micrognathia noted in other cases.

PMID 29023266 Conrad et al 2017 - describe a 17 month old boy with recurrent infections, growth failure, facial anomalies (including hyperterlorism/low set ears), and inflammatory bowel disease. No antenatal information.

PMID 28128455 van den Boogaard 2017 - 5 new patients described

PMID 23739126 Nitta et al 2013 - report 3 unrelated patients, x1 patient - lower birth weight and head circumference. At age 5 had macrocephaly, hyperterlorism. Noted to have bilateral hydronephrosis. x1 patient BW 2660g, micrognathia, hyperterlorism.

PMID 21906047 Chouery et al 2012 - 3 siblings from a Lebanese family with novel homozygous LoF variant. Apparently normal pregnancies, at time of diagnostic assessment HC between the 5th and 15th centiles, height below the 5th percentile. Dysmorphic features including high arched palate, small chin, retrognathism and everted lower lips.

PMID 22786748 Cerbone et al 2012 - report an 8 year old M of consanguineous Moroccan ancestry with ID, dysmorphic features, cafe au last macules and a large arachnoid cyst in the right temporal region, causing compression of the temporal lobe and lateral ventricle

PMID 21596365 de Greef et al 2011 - report 4 new unrelated patients, no antenatal information
Sources: Literature
Fetal anomalies v0.3279 SLC19A3 Zornitza Stark Marked gene: SLC19A3 as ready
Fetal anomalies v0.3277 SIX1 Zornitza Stark Marked gene: SIX1 as ready
Fetal anomalies v0.3275 SIM1 Zornitza Stark Marked gene: SIM1 as ready
Fetal anomalies v0.3274 SIK1 Zornitza Stark Marked gene: SIK1 as ready
Fetal anomalies v0.3271 SDHA Zornitza Stark Marked gene: SDHA as ready
Fetal anomalies v0.3271 SDHA Zornitza Stark Phenotypes for gene: SDHA were changed from LEIGH SYNDROME to Cardiomyopathy, dilated, 1GG (MIM#613642); Mitochondrial complex II deficiency, nuclear type 1 (MIM#252011)
Fetal anomalies v0.3268 HMX1 Zornitza Stark Marked gene: HMX1 as ready
Fetal anomalies v0.3268 HMX1 Zornitza Stark Phenotypes for gene: HMX1 were changed from OCULOAURICULAR SYNDROME to Oculoauricular syndrome, MIM#612109
Fetal anomalies v0.3266 HIST1H4C Zornitza Stark Marked gene: HIST1H4C as ready
Fetal anomalies v0.3262 HIST1H1E Zornitza Stark Marked gene: HIST1H1E as ready
Fetal anomalies v0.3259 HGSNAT Zornitza Stark Marked gene: HGSNAT as ready
Fetal anomalies v0.3259 HGSNAT Zornitza Stark Phenotypes for gene: HGSNAT were changed from MUCOPOLYSACCHARIDOSIS TYPE 3C to Mucopolysaccharidosis type IIIC (Sanfilippo C), MIM# 252930; MONDO:0009657
Fetal anomalies v0.3256 HESX1 Zornitza Stark Marked gene: HESX1 as ready
Fetal anomalies v0.3254 HESX1 Zornitza Stark changed review comment from: Variants in this gene are associated with a spectrum of abnormalities: isolated pituitary deficiency through to septo-optic dysplasia. Optic nerve hypoplasia reported as part of this rather than AMC.; to: Variants in this gene are associated with a spectrum of abnormalities including corpus callosum abnormalities and hand abnormalities.
Fetal anomalies v0.3254 HESX1 Zornitza Stark edited their review of gene: HESX1: Changed rating: GREEN; Changed phenotypes: Septooptic dysplasia, MIM# 182230, Pituitary hormone deficiency, combined, 5, MIM# 182230
Fetal anomalies v0.3254 HADHB Zornitza Stark Marked gene: HADHB as ready
Fetal anomalies v0.3253 HADHB Zornitza Stark changed review comment from: ID is part of the phenotype.; to: SGA and cardiomyopathy reported.
Fetal anomalies v0.3253 GTF2E2 Zornitza Stark Marked gene: GTF2E2 as ready
Fetal anomalies v0.3250 GSPT2 Zornitza Stark Marked gene: GSPT2 as ready
Fetal anomalies v0.3247 SDHA Daniel Flanagan reviewed gene: SDHA: Rating: AMBER; Mode of pathogenicity: None; Publications: 20551992, 22972948, 12794685; Phenotypes: Cardiomyopathy, dilated, 1GG (MIM#613642), Mitochondrial complex II deficiency, nuclear type 1 (MIM#252011); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3247 GRIN2D Zornitza Stark Marked gene: GRIN2D as ready
Fetal anomalies v0.3247 GRIN2D Zornitza Stark Phenotypes for gene: GRIN2D were changed from Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers to Epileptic encephalopathy, early infantile, 46, MIM# 617162; intellectual disability
Fetal anomalies v0.3243 GRIN2D Zornitza Stark changed review comment from: Five unrelated individuals reported, two with recurrent variant (NM_000836.2:c.1999G>A or p.Val667Ile). GoF postulated as mechanism.
Sources: Expert list; to: Five unrelated individuals reported, two with recurrent variant (NM_000836.2:c.1999G>A or p.Val667Ile). GoF postulated as mechanism.

Clinical presentation is typically post-natal.

Sources: Expert list
Fetal anomalies v0.3243 GRHL2 Zornitza Stark Marked gene: GRHL2 as ready
Fetal anomalies v0.3241 GPAA1 Zornitza Stark Marked gene: GPAA1 as ready
Fetal anomalies v0.3241 GPAA1 Zornitza Stark Phenotypes for gene: GPAA1 were changed from Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia to Glycosylphosphatidylinositol biosynthesis defect 15, MIM# 617810
Fetal anomalies v0.3238 GPAA1 Zornitza Stark changed review comment from: At least 5 unrelated families reported with bi-allelic variants in this gene and delayed psychomotor development, variable intellectual disability, hypotonia, early-onset seizures in most, and cerebellar atrophy, resulting in cerebellar signs including gait ataxia and dysarthria. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.; to: At least 5 unrelated families reported with bi-allelic variants in this gene and delayed psychomotor development, variable intellectual disability, hypotonia, early-onset seizures in most, and cerebellar atrophy, resulting in cerebellar signs including gait ataxia and dysarthria. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.

Clinical presentation is typically post-natal.
Fetal anomalies v0.3238 UQCC2 Zornitza Stark Marked gene: UQCC2 as ready
Fetal anomalies v0.3237 CPS1 Zornitza Stark Marked gene: CPS1 as ready
Fetal anomalies v0.3237 CPS1 Zornitza Stark Phenotypes for gene: CPS1 were changed from CARBAMOYL PHOSPHATE SYNTHETASE 1 DEFICIENCY to Carbamoylphosphate synthetase I deficiency MIM#237300
Fetal anomalies v0.3235 CPS1 Zornitza Stark reviewed gene: CPS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Carbamoylphosphate synthetase I deficiency MIM#237300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3235 UQCC2 Krithika Murali gene: UQCC2 was added
gene: UQCC2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: UQCC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UQCC2 were set to 24385928; 28804536
Phenotypes for gene: UQCC2 were set to Mitochondrial complex III deficiency, nuclear type 7 - MIM#615824
Review for gene: UQCC2 was set to GREEN
Added comment: Biallelic variants associated with mitochondrial complex III deficiency. 2 unrelated families and variant-specific functional evidence/segregation information provided.

PMID 24385928 Tucker et al 2013 - report a patient with homozygous splice site UQCC2 variants. Presented with severe intrauterine growth retardation, neonatal lactic acidosis and renal tubular dysfunction of consanguineous Lebanese ancestry. Supportive functional studies including using patient fibroblasts.

PMID: 28804536 Feichtinger et al 2017 - report a second unrelated patient of consanguineous Turkish ancestry with UQCC2 deficiency, a female infant born at 32 weeks gestation after a a pregnancy complicated by IUGR and oligohydramnios. Followed by a fulminant postnatal course including respiratory distress syndrome, developed epileptic seizures progressing to status epilepticus, profound lactic acidosis with elevated urinary pyruvate and death at day 33 of life. Homozygous missense UQCC2 variants identified leading to a severe reduction of UQCC2 protein in patient's muscle and fibroblast cells.
Sources: Literature
Fetal anomalies v0.3235 CPS1 Belinda Chong reviewed gene: CPS1: Rating: RED; Mode of pathogenicity: None; Publications: 8486760, 17310273, 21120950; Phenotypes: Carbamoylphosphate synthetase I deficiency MIM#237300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3235 GNB5 Zornitza Stark Marked gene: GNB5 as ready
Fetal anomalies v0.3235 GNB5 Zornitza Stark Phenotypes for gene: GNB5 were changed from Sinus Bradycardia and Cognitive Disability to Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; Early infantile epileptic encephalopathy (EIEE)
Fetal anomalies v0.3232 GNAQ Zornitza Stark Marked gene: GNAQ as ready
Fetal anomalies v0.3229 GNAQ Zornitza Stark changed review comment from: ID can be part of the phenotype; however this condition is due to somatic mosaic gain of function variants so there may be issues with detection depending on tissue used and sequencing depth.; to: This condition is due to somatic mosaic gain of function variants so there may be issues with detection depending on tissue used and sequencing depth.
Fetal anomalies v0.3229 GNAI1 Zornitza Stark Marked gene: GNAI1 as ready
Fetal anomalies v0.3225 GNAI1 Zornitza Stark changed review comment from: 7 de novo missense and 1 PTV variants reported in the DDD paper Table 1.; to: 7 de novo missense and 1 PTV variants reported in the DDD paper Table 1. Typically presents post-natally.
Fetal anomalies v0.3225 GNA14 Zornitza Stark Marked gene: GNA14 as ready
Fetal anomalies v0.3224 GMNN Zornitza Stark Marked gene: GMNN as ready
Fetal anomalies v0.3221 GLIS2 Zornitza Stark Marked gene: GLIS2 as ready
Fetal anomalies v0.3219 GFPT1 Zornitza Stark Marked gene: GFPT1 as ready
Fetal anomalies v0.3217 GFPT1 Zornitza Stark changed review comment from: 15 unrelated families reported with bi-allelic variants and a congenital myasthenic syndrome. Two families with leukoencephalopathy as well as CMS.

The GFPT1 gene encodes an isoform of glutamine:fructose-6-phosphate amidotransferase (GFAT), which catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine 6-phosphate and glutamate. It is the first and rate-limiting enzyme of the hexosamine biosynthetic pathway. Hexosamine is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans. Muscle samples from several patients showed decreased protein glycosylation, suggesting this is a disorder of glycosylation. However, there is also some data put forward in PMID 30635494 that this may be a mitochondrial condition.; to: 15 unrelated families reported with bi-allelic variants and a congenital myasthenic syndrome. Two families with leukoencephalopathy as well as CMS.

Presentation typically in childhood/adolescence.
Fetal anomalies v0.3217 GALNT2 Zornitza Stark Marked gene: GALNT2 as ready
Fetal anomalies v0.3217 GALNT2 Zornitza Stark changed review comment from: Seven individuals from four families reported with bi-allelic LOF variants and global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities.
Sources: Literature; to: Seven individuals from four families reported with bi-allelic LOF variants and global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities.

Microcephaly and poor growth but age of onset of these features is uncertain.

Sources: Literature
Fetal anomalies v0.3217 GABRG2 Zornitza Stark Marked gene: GABRG2 as ready
Fetal anomalies v0.3217 GABRG2 Zornitza Stark Phenotypes for gene: GABRG2 were changed from EPILEPSY, GENERALIZED, WITH FEBRILE SEIZURES PLUS, TYPE 3; GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 3 to Epileptic encephalopathy, early infantile, 74 618396; Epilepsy, generalized, with febrile seizures plus, type 3, 607681
Fetal anomalies v0.3213 GABRG2 Zornitza Stark changed review comment from: Multiple unrelated families reported, variable severity of both seizures and ID.; to: Multiple unrelated families reported, variable severity of both seizures and ID. Typically presents post-natally.
Fetal anomalies v0.3213 GABRA1 Zornitza Stark Marked gene: GABRA1 as ready
Fetal anomalies v0.3213 GABRA1 Zornitza Stark Phenotypes for gene: GABRA1 were changed from JUVENILE MYOCLONIC EPILEPSY; EPILEPTIC ENCEPHALOPATHY to Epileptic encephalopathy, early infantile, 19 615744; Rett syndrome; Rett-like phenotypes; idiopathic generalized Epilepsy; Dravet syndrome
Fetal anomalies v0.3209 GABRA1 Zornitza Stark changed review comment from: PMID: 11992121; 1 large family with Juvenile Myoclonic Epilepsy PMID: 21714819; 2 probands with idiopathic generalized epilepsy PMID: 24623842; 4 patients with Dravet syndrome PMID: 30842224; non-MECP2 probands with Rett-like syndromes categorised into 1) typical RTT, 2) atypical RTT, 3) RTT-like phenotype. Total of 1 family with SNV in GABRA1 in Rett-like cohort.; to: PMID: 11992121; 1 large family with Juvenile Myoclonic Epilepsy PMID: 21714819; 2 probands with idiopathic generalized epilepsy PMID: 24623842; 4 patients with Dravet syndrome PMID: 30842224; non-MECP2 probands with Rett-like syndromes categorised into 1) typical RTT, 2) atypical RTT, 3) RTT-like phenotype. Total of 1 family with SNV in GABRA1 in Rett-like cohort.

Typically presents post-natally.
Fetal anomalies v0.3209 FZD5 Zornitza Stark Marked gene: FZD5 as ready
Fetal anomalies v0.3207 FUT8 Zornitza Stark Marked gene: FUT8 as ready
Fetal anomalies v0.3205 FUT8 Zornitza Stark changed review comment from: Three unrelated individuals reported with bi-allelic variants in this gene.
Sources: Expert list; to: Three unrelated individuals reported with bi-allelic variants in this gene. IUGR and congenital anomalies reported.
Sources: Expert list
Fetal anomalies v0.3205 FUCA1 Zornitza Stark Marked gene: FUCA1 as ready
Fetal anomalies v0.3203 FRRS1L Zornitza Stark Marked gene: FRRS1L as ready
Fetal anomalies v0.3203 FRRS1L Zornitza Stark Phenotypes for gene: FRRS1L were changed from Epileptic encephalopathy with continuous spike-and-wave during sleep to Epileptic encephalopathy, early infantile, 37, MIM#616981
Fetal anomalies v0.3200 FRMPD4 Zornitza Stark Marked gene: FRMPD4 as ready
Fetal anomalies v0.3197 FOXP4 Zornitza Stark Marked gene: FOXP4 as ready
Fetal anomalies v0.3196 FOXP2 Zornitza Stark Marked gene: FOXP2 as ready
Fetal anomalies v0.3192 FIG4 Zornitza Stark Marked gene: FIG4 as ready
Fetal anomalies v0.3192 FIG4 Zornitza Stark Phenotypes for gene: FIG4 were changed from Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Charcot-Marie-Tooth disease type 4J, MONDO:0012640; Yunis-Varon syndrome, OMIM:216340; Yunis-Varon syndrome, MONDO:0008995; ?Polymicrogyria, bilateral temporooccipital, OMIM:612691; Bilateral parasagittal parieto-occipital polymicrogyria, MONDO:0012986 to Yunis-Varon syndrome, OMIM:216340; Yunis-Varon syndrome, MONDO:0008995; ?Polymicrogyria, bilateral temporooccipital, OMIM:612691; Bilateral parasagittal parieto-occipital polymicrogyria, MONDO:0012986
Fetal anomalies v0.3189 FANCM Zornitza Stark Marked gene: FANCM as ready
Fetal anomalies v0.3187 FANCL Zornitza Stark Marked gene: FANCL as ready
Fetal anomalies v0.3185 SF3B2 Zornitza Stark Marked gene: SF3B2 as ready
Fetal anomalies v0.3184 SEPT9 Zornitza Stark Marked gene: SEPT9 as ready
Fetal anomalies v0.3183 PLCH1 Zornitza Stark Marked gene: PLCH1 as ready
Fetal anomalies v0.3182 PLEKHA5 Zornitza Stark Marked gene: PLEKHA5 as ready
Fetal anomalies v0.3181 PLEKHA7 Zornitza Stark Marked gene: PLEKHA7 as ready
Fetal anomalies v0.3180 PPP1R13L Zornitza Stark Marked gene: PPP1R13L as ready
Fetal anomalies v0.3179 METTL23 Zornitza Stark Marked gene: METTL23 as ready
Fetal anomalies v0.3178 LRRC32 Zornitza Stark Marked gene: LRRC32 as ready
Fetal anomalies v0.3177 SCN8A Zornitza Stark Marked gene: SCN8A as ready
Fetal anomalies v0.3177 SCN8A Zornitza Stark Phenotypes for gene: SCN8A were changed from EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 13; COGNITIVE IMPAIRMENT WITH OR WITHOUT CEREBELLAR ATAXIA to Developmental and epileptic encephalopathy 13, MIM#614558, dominant and recessive; Myoclonus, familial, 2, MIM# 618364; paroxysmal kinesigenic dyskinesias; Cognitive impairment with or without cerebellar ataxia, MIM# 614306
Fetal anomalies v0.3176 RFWD3 Zornitza Stark Marked gene: RFWD3 as ready
Fetal anomalies v0.3175 RAB39B Zornitza Stark Marked gene: RAB39B as ready
Fetal anomalies v0.3175 RAB39B Zornitza Stark Phenotypes for gene: RAB39B were changed from MENTAL RETARDATION X-LINKED TYPE 72 (MRX72) +/- PARKINSONS to Intellectual developmental disorder, X-linked 72 MIM#300271; Waisman syndrome MIM#311510
Fetal anomalies v0.3173 LRP6 Zornitza Stark Marked gene: LRP6 as ready
Fetal anomalies v0.3172 PTCHD1 Zornitza Stark Marked gene: PTCHD1 as ready
Fetal anomalies v0.3170 PSMB8 Zornitza Stark Marked gene: PSMB8 as ready
Fetal anomalies v0.3168 PRSS12 Zornitza Stark Marked gene: PRSS12 as ready
Fetal anomalies v0.3168 PRSS12 Zornitza Stark Phenotypes for gene: PRSS12 were changed from MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 1 to Intellectual disability, PRSS12 related MIM#249500
Fetal anomalies v0.3166 PRPS1 Zornitza Stark Marked gene: PRPS1 as ready
Fetal anomalies v0.3166 PRPS1 Zornitza Stark Phenotypes for gene: PRPS1 were changed from DEAFNESS X-LINKED TYPE 1; PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY; CHARCOT-MARIE-TOOTH DISEASE X-LINKED RECESSIVE TYPE 5; ARTS SYNDROME to Arts syndrome MIM#301835
Fetal anomalies v0.3163 PPP3CA Zornitza Stark changed review comment from: The mono-allelic condition is relevant antenatally. However, only 2 individuals reported.

DEE tends to present post-natally.; to: Condition causing multiple congenital anomalies is postulated to be due to GoF variants. However, only 2 individuals reported.

DEE postulated to be due to LoF variants, and presents post-natally.
Fetal anomalies v0.3163 PPT1 Zornitza Stark Marked gene: PPT1 as ready
Fetal anomalies v0.3161 PPA2 Zornitza Stark Marked gene: PPA2 as ready
Fetal anomalies v0.3161 PPA2 Zornitza Stark Phenotypes for gene: PPA2 were changed from Sudden arrhythmic cardiac death after infectious or alcohol trigger to Sudden cardiac failure, alcohol-induced, 617223; Sudden cardiac failure, infantile, 617222
Fetal anomalies v0.3159 PLP1 Zornitza Stark Marked gene: PLP1 as ready
Fetal anomalies v0.3159 PLP1 Zornitza Stark Phenotypes for gene: PLP1 were changed from LEUKODYSTROPHY HYPOMYELINATING TYPE 1; SPASTIC PARAPLEGIA X-LINKED TYPE 2 to Pelizaeus-Merzbacher disease MIM#312080; Spastic paraplegia 2, X-linked MIM#312920
Fetal anomalies v0.3157 LDB3 Zornitza Stark Marked gene: LDB3 as ready
Fetal anomalies v0.3157 LDB3 Zornitza Stark Phenotypes for gene: LDB3 were changed from MYOPATHY MYOFIBRILLAR TYPE 4; LEFT VENTRICULAR NON-COMPACTION TYPE 3; CARDIOMYOPATHY DILATED TYPE 1C to Cardiomyopathy, dilated, 1C, with or without LVNC MIM#601493; Cardiomyopathy, hypertrophic, 24 MIM#601493; Left ventricular noncompaction 3 MIM#601493; Myopathy, myofibrillar, 4 MIM#609452
Fetal anomalies v0.3153 IGSF1 Zornitza Stark Marked gene: IGSF1 as ready
Fetal anomalies v0.3153 IGSF1 Zornitza Stark Added comment: Comment when marking as ready: Not LGA, unlikely to present antenatally
Fetal anomalies v0.3153 IGSF1 Zornitza Stark Phenotypes for gene: IGSF1 were changed from CENTRAL HYPOTHYROIDISM AND TESTICULAR ENLARGEMENT to Hypothyroidism, central, and testicular enlargement MIM#300888
Fetal anomalies v0.3151 SF3B2 Krithika Murali gene: SF3B2 was added
gene: SF3B2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SF3B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF3B2 were set to 34344887
Phenotypes for gene: SF3B2 were set to Craniofacial microsomia
Review for gene: SF3B2 was set to GREEN
Added comment: No new relevant published evidence since PanelApp review Aug 2021

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Twenty individuals from seven families reported with de novo or transmitted haploinsufficient variants in SF3B2. Affected individuals had mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities.

Targeted morpholino knockdown of SF3B2 in Xenopus resulted in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease.

The families were ascertained from a cohort and the authors suggest that haploinsufficient variants in SF3B2 are the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.
Sources: Literature
Fetal anomalies v0.3151 SEPT9 Krithika Murali gene: SEPT9 was added
gene: SEPT9 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SEPT9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEPT9 were set to 16186812; 19451530; 19939853; 19139049; 18492087
Phenotypes for gene: SEPT9 were set to Amyotrophy, hereditary neuralgic, MIM# 162100
Review for gene: SEPT9 was set to AMBER
Added comment: No new relevant published evidence since last PanelApp review May 2021

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Only one report identified from 2008 of dysmorphic features including cleft palate co-occurring with HNA.

New gene name is SEPTIN9, also note founder variants as well as 5'UTR variants and intragenic duplications reported.
Sources: Literature
Fetal anomalies v0.3151 PLCH1 Krithika Murali gene: PLCH1 was added
gene: PLCH1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLCH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLCH1 were set to 33820834
Phenotypes for gene: PLCH1 were set to Holoprosencephaly spectrum; Severe developmental delay; Brain malformations
Review for gene: PLCH1 was set to AMBER
Added comment: No new published evidence since last PanelApp review April 2021

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PMID: 33820834 (2021) - Two sibling pairs from two unrelated families with a holoprosencephaly spectrum phenotype and different homozygous PLCH1 variants (c.2065C>T, p.Arg689* and c.4235delA, p.Cys1079ValfsTer16, respectively). One family presented with congenital hydrocephalus, epilepsy, significant developmental delay and a monoventricle or fused thalami; while sibs from the second family had alobar holoprosencephaly and cyclopia. 3/4 individuals also displayed a cleft palate and congenital heart disease. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome.
Sources: Literature
Fetal anomalies v0.3151 PLEKHA5 Krithika Murali gene: PLEKHA5 was added
gene: PLEKHA5 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: PLEKHA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLEKHA5 were set to 29805042
Phenotypes for gene: PLEKHA5 were set to cleft lip; cleft palate
Review for gene: PLEKHA5 was set to AMBER
Added comment: No new published evidence since last PanelApp review April 2020

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One de novo variant reported, another 5 '3C' rare variants reported in 6 families in this cohort; unclear if monogenic or polygenic contribution to CL/P.
Sources: Literature, Expert list
Fetal anomalies v0.3151 PLEKHA7 Krithika Murali gene: PLEKHA7 was added
gene: PLEKHA7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLEKHA7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLEKHA7 were set to 29805042
Phenotypes for gene: PLEKHA7 were set to Cleft palate
Review for gene: PLEKHA7 was set to AMBER
Added comment: No new evidence since last PanelApp review in Jan 2021

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Six rare variants identified in 4 individuals in a CL/P cohort, however, only one of these classified as likely pathogenic. One individual had bi-allelic variants. Some supportive functional data
Sources: Literature
Fetal anomalies v0.3151 PPP1R13L Krithika Murali gene: PPP1R13L was added
gene: PPP1R13L was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PPP1R13L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP1R13L were set to 32666529; 28864777
Phenotypes for gene: PPP1R13L were set to Dilated cardiomyopathy, onset in infancy; Cleft lip and palate
Review for gene: PPP1R13L was set to GREEN
Added comment: No new information since last PanelApp review June 2021

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At least 6 unrelated families. NMD-predicted, missense and stop-loss (extension) variants have been reported in individuals with autosomal recessive PPP1R13L-related syndrome. Patients described with biallelic pathogenic variants in PPP1R13L all had severe infantile-onset dilated cardiomyopathy, with additional features including cleft lip and palate, wedge-shaped teeth, and sparse, dry, woolly hair described in several individuals. Death due to HF progression before 5yo reported in cases that didn't receive a heart transplant. Cognitive delay also reported in two unrelated individuals (PMID: 28069640, PMID: 32666529).
Sources: Literature
Fetal anomalies v0.3151 METTL23 Krithika Murali gene: METTL23 was added
gene: METTL23 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: METTL23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: METTL23 were set to 32878022; 32439618; 32067349; 24626631; 24501276
Phenotypes for gene: METTL23 were set to Mental retardation, autosomal recessive 44 - #615942
Review for gene: METTL23 was set to RED
Added comment: Biallelic variants associated with syndromic ID. Published studies provide no or limited antenatal information with no consistent prenatal phenotype described.

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PMID: 32878022 – Khan et al 2020 - homozygous missense variants identified in consanguineous Pakistani family with 3 affected siblings having ID, epilepsy, behavioural issues, hypotonia and dysmorphic features (prominent large-size eyes, eyebrows, ears, short upturned nose with flat nasal bridge, and thin upper lip). Authors report that prenatal, perinatal and neonatal medical records of all patients were normal.

PMID 32439618 – Smaili et al 2020 report two Moroccan siblings presenting with mild intellectual disability and dysmorphic features. WES identified homozygous METTL23 gene variants. Describe uneventful pregnancies and postnatal course. Macrocephaly reported in both siblings (HC 52cm in a 7 year old M and 50cm in 6 yo F) - no information regarding HC of parents provided, macrocephaly not a consistently reported feature of this condition.

PMID: 32067349 – Almannai et al 2020 - 6 individuals from 4 families - 2 families unrelated, 2 families come from same Saudi tribe and are therefore likely to be distantly related with same homozygous METTL23 variant identified in both. No prenatal features or immediate postnatal issues described related to this condtion. One subject reported to have an MRI-B showing mild ventriculomegaly at a later age which may reflect mild white matter volume loss. This subject also had a 618 Kilobases duplication at 7p11.2 (57,261,112-57,878,853) identified on CGH array.

PMID: 24626631 – Bernkopf 2014 - describe 2 unrelated families. Provide no antenatal information or report no issues antenatally/at birth apart from one baby being large and cyanosed postnatally

PMID: 24501276 – Reiff et al 2014 - report 7 affected members of a large, consanguineous Arab family with ID and mild dysmorphic features. X1 patient had cleft uvula and submucosal cleft palate.
Sources: Literature
Fetal anomalies v0.3151 LRRC32 Krithika Murali gene: LRRC32 was added
gene: LRRC32 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: LRRC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC32 were set to 30976112
Phenotypes for gene: LRRC32 were set to Cleft palate, proliferative retinopathy, and developmental delay - MIM#619074
Review for gene: LRRC32 was set to AMBER
Added comment: Gene previously reviewed for PanelApp Feb 2021 - no new relevant publications since

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Three individuals from two consanguineous families with cleft palate, proliferative retinopathy, and developmental delay had the same homozygous biallelic variant, c.1630C>T; p.(Arg544Ter), segregated and shared haplotype indicative of founder effect. Mouse model has cleft palate and neonatal death.
Sources: Literature
Fetal anomalies v0.3151 SCN8A Ain Roesley reviewed gene: SCN8A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 13, MIM#614558, dominant and recessive, Myoclonus, familial, 2, MIM# 618364, paroxysmal kinesigenic dyskinesias, Cognitive impairment with or without cerebellar ataxia, MIM# 614306; Mode of inheritance: None; Current diagnostic: yes
Fetal anomalies v0.3151 LRP6 Krithika Murali gene: LRP6 was added
gene: LRP6 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: LRP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRP6 were set to 16126904; 30950205; 26387593; 26963285; 28813618; 29500247; 33164649; 34306029
Phenotypes for gene: LRP6 were set to Tooth agenesis, selective, 7 - MIM#616724; cleft lip/palate
Review for gene: LRP6 was set to AMBER
Added comment: LoF variants known to be associated with tooth agenesis. In addition, x2 unrelated families from 2 different studies with heterozygous LRP6 variant had tooth agenesis and cleft lip/palate (PMID 29500247; 26963285). Growth failure reported in some individuals but unclear if prenatal in onset (PMID 26963285). Minor finger/ear anomalies reported in x2 patients (PMID 26387593; 30950205)- unlikely to be detected antenatally and one of the reported patients (30950205) had x2 chromosome deletions, one of which involved LRP6 and multiple other genes.

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PMID: 34306029 Huang et al 2021 - Heterozygous LRP6: c.2570G > A (p.R857H), harbored by six members of a Chinese family, including 4 with tooth agenesis. Sparse hair another phenotypic feature.

PMID: 33164649 Yu et al 2021 - identified 4 novel LRP6 heterozygous mutations in 4 of 77 oligodontia patients. One patient with a nonsense paternally inherited variant had a hypohidrotic ectodermal dysplasia phenotype - no antenatal features, father had oligodontia. Supportive functional evidence

PMID: 29500247 Basha et al 2018 - Nonsense LRP6 variant identified in a family with cleft lip/palate. Proband had bilateral cleft lip and palate with missing upper lateral incisors, mother had bilateral cleft lip. x1 unaffected brother but family members not reassessed for oligodontia after variant identified.

PMID: 28813618 Dinckan et al 2018 - heterozygous splice site LRP6 variant identified in 1 family with isolated tooth agenesis. Affected family members also had mild periocular hyperpigmentation and hypoplastic alae nasi - thought to be unrelated to phenotype

PMID: 26963285 Ockeloen et al 2016 - frameshift variant identified in patient with tooth agenesis and orofacial clefting - boy born with bilateral cleft lip, L) sided cleft of the alveolus and complete cleft of the hard and soft palate. Also noted to have growth retardation, hypermetropia and small median alveolar manibular cleft. Maternal relatives with variant had severe tooth agenesis but no clefting. Canonical splice site variant identified in a patient with isolated severe tooth agenesis. Targeted resequencing showed statistically significant enrichment of unique LRP6 variants in tooth agenesis patients (7/67 versus 13/706 controls), not orofacial clefting cohort. 4/7 of these patients required growth hormone therapy and 3/7 had clinodactyly in addition to dental anomalies.

PMID: 26387593 – Massink et al 2015 - x4 LoF heterozygous LRP6 variants identified in 4 unrelated families with isolated severe tooth agenesis. All affected members of one family showed minor anatomical variation of the ear and underdevelopment of the thumb

PMID: 30950205 Ross et al 2019 - Proband with oligodontia and thrombocytopenia, also had mild finger and ear anomalies. Array revealed an interstitial loss of 150 kb in 8p23.1 encompassing MCPH1 and ANGPT2 and an interstitial loss of 290 kb in 12p13.2 encompassing ETV6, BCL2L14 and LRP6.
Sources: Literature
Fetal anomalies v0.3151 PRPS1 Ain Roesley reviewed gene: PRPS1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32781272, 24961627; Phenotypes: Arts syndrome MIM#301835; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Fetal anomalies v0.3151 PPA2 Ain Roesley reviewed gene: PPA2: Rating: RED; Mode of pathogenicity: None; Publications: 27523598, 34400813; Phenotypes: Sudden cardiac failure, alcohol-induced, 617223, Sudden cardiac failure, infantile, 617222; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3151 PLP1 Ain Roesley reviewed gene: PLP1: Rating: RED; Mode of pathogenicity: None; Publications: 20301361; Phenotypes: Pelizaeus-Merzbacher disease MIM#312080, Spastic paraplegia 2, X-linked MIM#312920; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Fetal anomalies v0.3151 LDB3 Ain Roesley reviewed gene: LDB3: Rating: RED; Mode of pathogenicity: None; Publications: 26419279, 16427346, 14660611, 14662268, 27546599, 25911362; Phenotypes: Cardiomyopathy, dilated, 1C, with or without LVNC MIM#601493, Cardiomyopathy, hypertrophic, 24 MIM#601493, Left ventricular noncompaction 3 MIM#601493, Myopathy, myofibrillar, 4 MIM#609452; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v0.3151 IGSF1 Ain Roesley reviewed gene: IGSF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26840047; Phenotypes: Hypothyroidism, central, and testicular enlargement MIM#300888; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Fetal anomalies v0.3151 KAT5 Zornitza Stark Marked gene: KAT5 as ready
Fetal anomalies v0.3150 INTS1 Zornitza Stark Marked gene: INTS1 as ready
Fetal anomalies v0.3149 COL25A1 Zornitza Stark Marked gene: COL25A1 as ready
Fetal anomalies v0.3148 COL25A1 Zornitza Stark gene: COL25A1 was added
gene: COL25A1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: COL25A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COL25A1 were set to 35077597; 26437029
Phenotypes for gene: COL25A1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Review for gene: COL25A1 was set to GREEN
Added comment: 6 cases from 4 unrelated families with AMC as a feature of the phenotype PMID: 35077597 - 5 patients from 3 unrelated families with biallelic missense and splice site COL25A1 variants presenting with arthrogryposis multiplex congenita with or without an ocular congenital cranial dysinnervation disorder phenotype PMID: 26437029 - Patient: 273182 in DECIPHER with compound het missense variants. Phenotype includes Congenital finger flexion contractures, Contracture of the distal interphalangeal joint of the 2nd finger, Duane anomaly
Sources: Literature
Fetal anomalies v0.3147 HYAL2 Zornitza Stark Marked gene: HYAL2 as ready
Fetal anomalies v0.3146 HOXA2 Zornitza Stark Marked gene: HOXA2 as ready
Fetal anomalies v0.3145 ESRP2 Zornitza Stark Marked gene: ESRP2 as ready
Fetal anomalies v0.3144 EIF3F Zornitza Stark Marked gene: EIF3F as ready
Fetal anomalies v0.3142 COL9A3 Zornitza Stark Marked gene: COL9A3 as ready
Fetal anomalies v0.3141 FTO Zornitza Stark Marked gene: FTO as ready
Fetal anomalies v0.3141 FTO Zornitza Stark Marked gene: FTO as ready
Fetal anomalies v0.3140 KAT5 Krithika Murali gene: KAT5 was added
gene: KAT5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: KAT5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KAT5 were set to 32822602
Phenotypes for gene: KAT5 were set to Neurodevelopmental disorder wtih dysmorphic facies, sleep disturbance, and brain abnormalities- MIM#619103
Review for gene: KAT5 was set to GREEN
Added comment: PMID: 32822602 Humbert et al 2020 - single study reporting 3 individuals with syndromic ID and de novo heterozygous missense variants in KAT5, supportive functional data

Individual 1 – diagnosed as an adult, syndromic ID, brachydactyly, partial agenesis of the corpus callosum

Indidual 2 – 13 yo M with ID and multiple malformations – born at 38 weeks with a unilateral CL/P, horshoe kidney, progressive cerebellar atrophy, dysgenesis of the corpus callosum

Individual 3 – presented with congenital microcephay, short stature, VSD, dysplastic pulmonary valve with supravalvular and valvular stenosis, submucous cleft, hypospadias, MRI B PMG R) sylvian fissure, cystic dilation of 4th ventricle and inferior cerebellar vermis atrophy
Sources: Literature
Fetal anomalies v0.3140 INTS1 Krithika Murali gene: INTS1 was added
gene: INTS1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: INTS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS1 were set to 28542170; 30622326; 31428919
Phenotypes for gene: INTS1 were set to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies - MIM#618571
Review for gene: INTS1 was set to GREEN
Added comment: PMID: 28542170 Oegema et al 2017 - 3 unrelated individuals with syndromic ID of Dutch ancestry showed the same homozygous truncating INTS1 mutation - 1/3 Cleft palate/lip, 1/3 renal malformation

PMID: 30622326 – Krall et al 2019 - 5 patients from 4 families with biallelic sequence variants in INTS1. The patients manifested absent or severely limited speech, an abnormal gait, hypotonia and cataracts. Other phenotypic features included:
o Micropthalmia – 2/5
o Frontal bossing 2/5
o Hypertelorism – 5/5
o Microretrognathia – 4/5
o Renal malformation 2/5


PMID: 31428919 – Zhang et al 2020 - 2 Chinese siblings with ID found to have INTST1 compound het variants, both had cataracts, facial dysmorphism, short stature, severe ID and anomalous genitalia
Sources: Literature
Fetal anomalies v0.3140 HYAL2 Krithika Murali gene: HYAL2 was added
gene: HYAL2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: HYAL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HYAL2 were set to 34906488; 28081210; 23172227; 26515055
Phenotypes for gene: HYAL2 were set to Cleft lip and palate; cor triatriatum; congenital cardiac malformations
Review for gene: HYAL2 was set to GREEN
Added comment: PMID 28081210 Muggenthaler et al 2017 - 2 unrelated consanguineous extended families (Amish and Arab) with an orofacial clefting phenotype with cardiac anomalies

PMID 34906488 Fasham et al 2021 - report 10 additional individuals from 6 unrelated families (Amish x2 - same founder variant as in previous study, Romanian, Italian, Northern European ancestry)

Combined reported phenotypic features of 17 individuals from both studies most relevant in the prenatal setting include:
• Hyperterlorism 13/16
• External ear anomalies – 11/14
• Cleft lip/palate – 10/17
• Micrognathia – 9/14
• Cardiac anomalies 12/17
Sources: Literature
Fetal anomalies v0.3140 HOXA2 Krithika Murali gene: HOXA2 was added
gene: HOXA2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: HOXA2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: HOXA2 were set to 18394579; 23775976; 27503514; 28109504; 31567444; 32649979
Phenotypes for gene: HOXA2 were set to Microtia with or without hearing impairment (AD) - MIM#612290
Review for gene: HOXA2 was set to GREEN
Added comment: Heterozygous variants associated with non-syndromic microtia and hearing loss reported in over 5 families

Homozygous variant associated with severe microtia, hearing loss and partial cleft palate reported in 3 affected individuals in 1 family.

Supportive mouse models

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PMID: 18394579 Alasti et al 2008 - first identified 3 affected individuals from one consanguineous Persian family also had partial cleft palate with homozygous HOXA2 variant. Only family with AR inheritance reported so far.

PMID: 23775976 Brown et al 2013 – multiple affected individuals from one family with non-syndromic bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing identified heterozygous protein truncating HOXA2 nonsense change (c.703C>T, p.Q235*).

PMID: 27503514 Piceci et al 2017 – reported one family with isolated bilateral microtia segregating as an autosomal dominant trait. Heterozygous protein truncating nonsense variant identified [c.670G>T, p.(Glu224*)] segregating in all affected individuals

PMID: 28109504 Hao et al 2017 - 2 novel variants in the 5’ UTR of HOXA2 identified in a screen of patients with microtia, limited phenotypic information

PMID: 31567444 Meddaugh et al 2020 - reported heterozygous variant in 4-year-old Caucasian male with bilateral dysplastic ears and conductive hearing loss.

PMID: 32649979 Si et al 2020 – reported two Chinese families with non-syndromic bilateral microtia identifying two separate heterozygous nonsense HOXA2 variants
Sources: Literature
Fetal anomalies v0.3140 FTO Krithika Murali gene: FTO was added
gene: FTO was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FTO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FTO were set to 19559399; 26378117
Phenotypes for gene: FTO were set to Growth retardation, developmental delay, facial dysmorphism - MIM#612938; multiple congenital malformations
Review for gene: FTO was set to AMBER
Added comment: Biallelic variants associated with syndromic ID reported in 2 unrelated families.

PMID: 26378117 Daoud et al 2016 - homozygous missense variant identified in a female proband. 3rd child to consanguineous Tunisian parents. Proband also carried a paternally inherited balanced translocation. Antenatal USS identified IUGR. Postnatal Echo showed PDA and hypertrabeculation of LV apex.

PMID 19559399 Boissel et al 2009 - homozygous missense variant identified in 9 affected individuals from a consanguineous Palestinian Arab family. Phenotypic features identified most pertinent to the prenatal setting include: 3/7 IUGR, 7/7 retrognathia, congenital heart disease 6/8, lissencephaly 3/8, hypertrophic cardiomyopathy 4/8, hydrocephalus 4/8, cleft palate/bifid uvula 3/6.
Sources: Literature
Fetal anomalies v0.3140 ESRP2 Krithika Murali gene: ESRP2 was added
gene: ESRP2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ESRP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ESRP2 were set to 29805042
Phenotypes for gene: ESRP2 were set to Cleft lip
Review for gene: ESRP2 was set to AMBER
Added comment: No new publications since last PanelApp review Feb 2021

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PMID: 29805042 Cox et al. Identified ESRP2 as a potential gene in a cohort of 72 multi generational families with cleft lip with or without cleft palate. 1 likely pathogenic variant (chr16:g.68266284C>T;p.Arg315) was identified in one family. Further analysis of 497 individuals identified a further likely pathogenic variant (chr16:g.68265234G>A;p.Arg520*) in another family.
Sources: Literature
Fetal anomalies v0.3140 EIF3F Krithika Murali gene: EIF3F was added
gene: EIF3F was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: EIF3F was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF3F were set to 33736665
Phenotypes for gene: EIF3F were set to ntellectual developmental disorder, autosomal recessive 67- MIM#618295
Review for gene: EIF3F was set to GREEN
Added comment: No new publications since PanelApp review Oct 2021

Hüffmeier et al (2021) reported 21 patients who were homozygous/compound heterozygous for Phe232Val variant in EIF3F. All affected individuals had developmental delay and speech delay. About half had behavioural problems, altered muscular tone, hearing loss, and short stature (3/7 from birth). The study suggests that microcephaly (4/10 from birth), reduced sensitivity to pain, cleft lip/palate (1/21), congenital heart defect (1/21), gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum.
Sources: Literature
Fetal anomalies v0.3140 COL9A3 Krithika Murali gene: COL9A3 was added
gene: COL9A3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: COL9A3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: COL9A3 were set to 33570243; 31090205; 30450842; 25381065; 24273071; 15551337
Phenotypes for gene: COL9A3 were set to Epiphyseal dysplasia, multiple, 3, with or without myopathy - MIM#600969; Stickler syndrome
Review for gene: COL9A3 was set to GREEN
Added comment: 6 patients from 4 families reported with biallelic variants associated with a Stickler syndrome like phenotype. All of these cases characterised by the absence of cleft palate, which is noted more commonly in other autosomal dominant forms of Stickler syndrome.

Potential antenatally detectable features described with biallelic COL9A3 variants include fetal growth restriction (1/6), midface hypoplasia (6/6), tibial and femoral bowing (1/6)

PMID 33570243 Markova et al 2021 - report a patient with novel Class 4 compound heterozygous COL9A3 variants confirmed to be in trans. Antenatal USS identified fetal growth restriction in the third trimester. Examination findings by clinical geneticist aged 2 provided, including dysmorphic facial features noted - slightly flattened nasal bridge, small nose, mild mid-facial hypoplasia, high palate.

PMID 31090205 – Nixon et al 2019 - homozygous COL9A3 variant identified in proband, consanguineous family. Antenatal phenotype not provided, mid-facial hypoplasia noted.

PMID: 30450842 – Hanson-Kahn et al 2018 - proband homozygous for LoF COL9A3 variants.
Phenotypic features included moderate to severe sensorineural hearing loss, high myopia, mid-face hypoplasia and both tibial and femoral bowing at birth.

PMID 24273071 Faletra et al 2014 - first reported family with AR COL9A3 associated Stickler syndrome due to homozygous LoF variants. 3 siblings with hearing loss, midface hypoplasia, high myopia, variable severity ID from consanguineous Moroccan family.

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Variants in COL9A3 have previously been associated with autosomal dominant multiple epiphyseal dysplasia, susceptibility to an intervertebral disc disease, and hearing loss. Generally milder phenotype than individuals with biallelic variants. However, PMID 33633367 Nash et al 2021 - report 2 families with heterozygous COL9A3 variants with a more severe Stickler-like phenotype including severe peripheral lattice vitreoretinal abnormalities and mild/moderate sensorineural hearing loss in some cases. No antenatal information provided
Sources: Literature
Fetal anomalies v0.3140 ANKRD17 Krithika Murali gene: ANKRD17 was added
gene: ANKRD17 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ANKRD17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKRD17 were set to 33909992
Phenotypes for gene: ANKRD17 were set to Chopra-Amiel-Gordon syndrome - MIM#619504; multiple congenital malformations
Review for gene: ANKRD17 was set to GREEN
Added comment: 33909992 - Chopra et al 2021 reported 34 individuals from 33 families with a syndromic ID

Multiple cases with antenatal anomalies or features detectable antenatally reported
- 3/34 with cleft lip and/or palate (including 2 with Pierre Robin sequence)
- 1/34 retrognathia
- 5/34 renal anomalies including 3 with unilateral renal agenesis and 1 with antenatal diagnosis of horseshoe kidney
- 2/34 microcephaly
- 4/34 macrocephaly (1 noted on 37/40 antenatal USS to have macrocephaly and enlarged cisterna magna, 1 also had NSD1 variant)
- 5/34 IUGR/fetal growth concerns
-1/34 with VSD
Sources: Literature
Fetal anomalies v0.3140 ACBD5 Krithika Murali gene: ACBD5 was added
gene: ACBD5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ACBD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD5 were set to 27799409; 23105016; 33427402; 34668366
Phenotypes for gene: ACBD5 were set to Retinal dystrophy with leukodystrophy - MIM#618863
Review for gene: ACBD5 was set to RED
Added comment: Biallelic ACBD5 variants cause impairment of very long-chain fatty acid metabolism. Patients have retinal dystrophy and leukodystrophy. Other features include ataxia, spastic paraparesis, developmental delay and facial dysmorphism. One patient with cleft palate reported but this may be an incidental finding and not related to this condition. No other antenatal features reported.

--

PMID 27799409 Ferdinandusse et al 2017 - patient born full-term with cleft palate, progressive leukodystrophy, ataxia, retinal dystrophy and facial dysmorphism

PMID 23105016 Abu-Safieh et al 2013 - limited phenotypic information, reported 3 siblings with homozygous splice site ACBD5 variants with spastic paraparesis and leukodystrophy.

PMID: 33427402 Bartlett et al 2020 - 36 year old F proband born at term after an uncomplicated pregnancy, normal growth parameters.

PMID: 34668366 Gorukmez et al 2021 - x2 siblings with homozygous variant – no antenatal features reported
Sources: Literature
Fetal anomalies v0.3140 CFAP74 Zornitza Stark Marked gene: CFAP74 as ready
Fetal anomalies v0.3139 HAND2 Zornitza Stark Marked gene: HAND2 as ready
Fetal anomalies v0.3138 QRICH1 Zornitza Stark Marked gene: QRICH1 as ready
Fetal anomalies v0.3136 QARS Zornitza Stark Marked gene: QARS as ready
Fetal anomalies v0.3136 QARS Zornitza Stark Gene: qars has been classified as Green List (High Evidence).
Fetal anomalies v0.3136 QARS Zornitza Stark Phenotypes for gene: QARS were changed from MICROCEPHALY, PROGRESSIVE, SEIZURES, AND CEREBRAL AND CEREBELLAR ATROPHY to Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, MIM# 615760
Fetal anomalies v0.3135 QARS Zornitza Stark Publications for gene: QARS were set to
Fetal anomalies v0.3134 QARS Zornitza Stark Classified gene: QARS as Green List (high evidence)
Fetal anomalies v0.3134 QARS Zornitza Stark Gene: qars has been classified as Green List (High Evidence).
Fetal anomalies v0.3133 PXDN Zornitza Stark Marked gene: PXDN as ready
Fetal anomalies v0.3133 PXDN Zornitza Stark Phenotypes for gene: PXDN were changed from CONGENITAL CATARACT, CORNEAL OPACITY, AND DEVELOPMENTAL GLAUCOMA to Anterior segment dysgenesis 7, with sclerocornea, MIM# 269400
Fetal anomalies v0.3130 PSAT1 Zornitza Stark Marked gene: PSAT1 as ready
Fetal anomalies v0.3128 PSAT1 Zornitza Stark changed review comment from: Neu-Laxova syndrome: severe perinatal presentation with high mortality, not relevant to this panel. PSAT1 deficiency: single family described, ID is part of the phenotype. There is probably a spectrum of disorders related to this gene, downgrade to Amber on this panel for now.; to: Neu-Laxova syndrome: severe perinatal presentation with high mortality.
Fetal anomalies v0.3128 PRUNE1 Zornitza Stark Marked gene: PRUNE1 as ready
Fetal anomalies v0.3127 PREPL Zornitza Stark Marked gene: PREPL as ready
Fetal anomalies v0.3125 PREPL Zornitza Stark edited their review of gene: PREPL: Added comment: At least six unrelated individuals and bi-allelic variants of this gene; however, several are said to have normal EMG/nerve conduction studies, therefore uncertain if this is truly a myasthenic syndrome.

In addition, different recessive contiguous gene deletion syndromes involving PREPL and a variable combination of SLC3A1 (hypotonia-cystinuria syndrome), CAMKMT (atypical hypotonia-cystinuria syndrome), and PPM1B (2p21 deletion syndrome) have been described. Presentation for these is post-natal.; Changed rating: AMBER; Changed publications: 29483676, 28726805, 24610330, 27472506
Fetal anomalies v0.3125 POP1 Zornitza Stark Marked gene: POP1 as ready
Fetal anomalies v0.3123 POP1 Zornitza Stark changed review comment from: Anauxetic dysplasia is a spondyloepimetaphyseal dysplasia characterized by severe short stature of prenatal onset, very short adult height (less than 1 meter), hypodontia, midface hypoplasia, and mild intellectual disability.; to: Anauxetic dysplasia is a spondyloepimetaphyseal dysplasia characterized by severe short stature of prenatal onset, very short adult height (less than 1 meter), hypodontia, midface hypoplasia, and mild intellectual disability.

At least 4 unrelated families reported.
Fetal anomalies v0.3123 POP1 Zornitza Stark changed review comment from: Primarily a skeletal dysplasia, mild LD described in some but overall I don't think this is the right panel.; to: Anauxetic dysplasia is a spondyloepimetaphyseal dysplasia characterized by severe short stature of prenatal onset, very short adult height (less than 1 meter), hypodontia, midface hypoplasia, and mild intellectual disability.
Fetal anomalies v0.3123 POLE Zornitza Stark Marked gene: POLE as ready
Fetal anomalies v0.3120 PLPBP Zornitza Stark Marked gene: PLPBP as ready
Fetal anomalies v0.3120 PLPBP Zornitza Stark Phenotypes for gene: PLPBP were changed from Vitamin-B6-Dependent Epilepsy to Epilepsy, early-onset, vitamin B6-dependent, MIM# 617290
Fetal anomalies v0.3117 PLPBP Zornitza Stark changed review comment from: Over 20 individuals reported. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding.; to: Over 20 individuals reported. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding.

Abnormal fetal movements reported.
Fetal anomalies v0.3117 PLG Zornitza Stark Marked gene: PLG as ready
Fetal anomalies v0.3114 PLD1 Zornitza Stark Marked gene: PLD1 as ready
Fetal anomalies v0.3113 TOPORS Zornitza Stark Marked gene: TOPORS as ready
Fetal anomalies v0.3112 SPINT2 Zornitza Stark Phenotypes for gene: SPINT2 were changed from Diarrhea 3, secretory sodium, congenital, syndromic - MIM#270420; congenital secretory sodium diarrhea 3 - MONDO0010036 to Diarrhoea 3, secretory sodium, congenital, syndromic - MIM#270420; congenital secretory sodium diarrhea 3 - MONDO#0010036
Fetal anomalies v0.3111 SPINT2 Zornitza Stark reviewed gene: SPINT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diarrhoea 3, secretory sodium, congenital, syndromic - MIM#270420, congenital secretory sodium diarrhea 3 - MONDO#0010036; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3111 SPINT2 Zornitza Stark Marked gene: SPINT2 as ready
Fetal anomalies v0.3110 RPS29 Zornitza Stark Marked gene: RPS29 as ready
Fetal anomalies v0.3109 RPS28 Zornitza Stark Marked gene: RPS28 as ready
Fetal anomalies v0.3108 RPL15 Zornitza Stark Marked gene: RPL15 as ready
Fetal anomalies v0.3107 PNPLA6 Zornitza Stark Marked gene: PNPLA6 as ready
Fetal anomalies v0.3106 TOPORS Krithika Murali gene: TOPORS was added
gene: TOPORS was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TOPORS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOPORS were set to 34132027
Phenotypes for gene: TOPORS were set to MONDO:0005308; ciliopathy; postaxial polydactyly; multiple lingual hamartomas; dysmorphic features
Review for gene: TOPORS was set to AMBER
Added comment: Gene recently reviewed, no new publications since

--

PMID:34132027 - Two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for the same missense variant (p.Pro10Gln). Suggested possible founder allele. Further search did not identify any additional publications.

Note mono-allelic variants associated with RP.
Sources: Literature
Fetal anomalies v0.3106 SPINT2 Krithika Murali reviewed gene: SPINT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33029133, 29575628, 28716867, 24142340, 30445423, 19185281, 20009592, 24142340; Phenotypes: Diarrhea 3, secretory sodium, congenital, syndromic - MIM#270420, congenital secretory sodium diarrhea 3 - MONDO#0010036; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3106 SPINT2 Krithika Murali gene: SPINT2 was added
gene: SPINT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SPINT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPINT2 were set to 19185281; 20009592; 24142340; 30445423; 33547739; 33374714; 33029133
Phenotypes for gene: SPINT2 were set to Diarrhea 3, secretory sodium, congenital, syndromic - MIM#270420; congenital secretory sodium diarrhea 3 - MONDO0010036
Fetal anomalies v0.3106 RPS28 Krithika Murali gene: RPS28 was added
gene: RPS28 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RPS28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPS28 were set to 24942156
Phenotypes for gene: RPS28 were set to Diamond Blackfan anemia 15 with mandibulofacial dysostosis - MIM#606164
Review for gene: RPS28 was set to AMBER
Added comment: 2 unrelated families reported in 2014. Antenatally detectable phenotypic features included cleft palate, micrognathia, cardiac, auricular and renal anomalies
Sources: Literature
Fetal anomalies v0.3106 PYROXD1 Zornitza Stark Marked gene: PYROXD1 as ready
Fetal anomalies v0.3106 PYROXD1 Zornitza Stark Phenotypes for gene: PYROXD1 were changed from Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization to Myopathy, myofibrillar, 8 (MIM#617258)
Fetal anomalies v0.3103 RPL15 Krithika Murali gene: RPL15 was added
gene: RPL15 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RPL15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPL15 were set to 20301769; 29599205; 23812780
Phenotypes for gene: RPL15 were set to Diamond-Blackfan anemia 12 - MIM#615550; multiple congenital malformations; hydrops
Review for gene: RPL15 was set to GREEN
Added comment: Known association with Diamond Blackfan anaemia (~1% of cases) which in turn is known to be associated with congenital malformations (craniofacial, upper limb, heart and genitourinary malformations). 3 of 4 patients with truncating RPL15 variants had severe non-immune hydrops fetalis and required intrauterine transfusions.
Sources: Literature
Fetal anomalies v0.3103 PYGM Zornitza Stark Marked gene: PYGM as ready
Fetal anomalies v0.3101 PTPN14 Zornitza Stark Marked gene: PTPN14 as ready
Fetal anomalies v0.3099 PRKAG2 Zornitza Stark Marked gene: PRKAG2 as ready
Fetal anomalies v0.3099 PRKAG2 Zornitza Stark Phenotypes for gene: PRKAG2 were changed from Glycogen storage disease of heart, lethal congenital, OMIM:261740; Cardiomyopathy, hypertrophic 6, OMIM:600858; Lethal congenital glycogen storage disease of heart, MONDO:0009867; Hypertrophic cardiomyopathy 6, MONDO:0010946 to Glycogen storage disease of heart, lethal congenital, OMIM:261740; Lethal congenital glycogen storage disease of heart, MONDO:0009867
Fetal anomalies v0.3096 PPP3CA Zornitza Stark Marked gene: PPP3CA as ready
Fetal anomalies v0.3096 PPP3CA Zornitza Stark Phenotypes for gene: PPP3CA were changed from Severe Neurodevelopmental Disease with Seizures to Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development MIM#618265
Fetal anomalies v0.3094 PPP3CA Zornitza Stark reviewed gene: PPP3CA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development MIM#618265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.3094 POLR1A Zornitza Stark Marked gene: POLR1A as ready
Fetal anomalies v0.3091 POLG2 Zornitza Stark Marked gene: POLG2 as ready
Fetal anomalies v0.3089 PLCB4 Zornitza Stark Marked gene: PLCB4 as ready
Fetal anomalies v0.3089 PLCB4 Zornitza Stark Phenotypes for gene: PLCB4 were changed from AURICULOCONDYLAR SYNDROME to Auriculocondylar syndrome 2, MIM# 614669
Fetal anomalies v0.3084 PNPLA6 Krithika Murali gene: PNPLA6 was added
gene: PNPLA6 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PNPLA6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA6 were set to 35069422; 33818269; 25299038; 33210227; 33141049; 32758583; 32586184
Phenotypes for gene: PNPLA6 were set to Oliver-McFarlane syndrome - MIM#275400
Review for gene: PNPLA6 was set to AMBER
Added comment: Heterogenous group of neurodegenerative conditions associated with biallelic PNPLA6 gene variants with childhood or adult onset symptoms. Oliver-McFarlane syndrome (OMFS) though is a rare congenital disorder characterised by trichomegaly, severe chorioretinal atrophy and multiple pituitary hormone deficiencies. Congenital hypogonadism is present in half of patients. Low birth weight, preterm delivery and being small for gestational age has been reported as a feature of OMFS. One case of microcephaly has been reported. Overall, limited prenatal phenotypic information for all reported cases of OMFS but associated growth restriction has the potential to be detected antenatally.

--

33818269 - report two unrelated patients with Oliver McFarlane syndrome with biallelic PNPLA6 variants who were born pre-term and small for gestational age.

32758583 Liu et al 2020 - report one boy with Oliver McFarlane syndrome diagnosed with microcephaly and small for gestational age after delivery at 35 weeks.
Sources: Literature
Fetal anomalies v0.3084 PDE6D Zornitza Stark Marked gene: PDE6D as ready
Fetal anomalies v0.3083 NPM1 Zornitza Stark Marked gene: NPM1 as ready
Fetal anomalies v0.3081 KIAA0825 Zornitza Stark Marked gene: KIAA0825 as ready
Fetal anomalies v0.3080 IQCE Zornitza Stark Marked gene: IQCE as ready
Fetal anomalies v0.3079 IFT27 Zornitza Stark Marked gene: IFT27 as ready
Fetal anomalies v0.3078 HMGB1 Zornitza Stark Marked gene: HMGB1 as ready
Fetal anomalies v0.3076 FAM92A Zornitza Stark Marked gene: FAM92A as ready
Fetal anomalies v0.3075 PDSS2 Zornitza Stark Marked gene: PDSS2 as ready
Fetal anomalies v0.3075 PDSS2 Zornitza Stark Phenotypes for gene: PDSS2 were changed from COENZYME Q10 DEFICIENCY, PRIMARY, 3 to Coenzyme Q10 deficiency, primary, 3 MIM#614652
Fetal anomalies v0.3073 PDHX Zornitza Stark Marked gene: PDHX as ready
Fetal anomalies v0.3070 TRRAP Zornitza Stark Marked gene: TRRAP as ready
Fetal anomalies v0.3069 G6PD Zornitza Stark Marked gene: G6PD as ready
Fetal anomalies v0.3068 NT5C3A Zornitza Stark Marked gene: NT5C3A as ready
Fetal anomalies v0.3066 NDUFV1 Zornitza Stark Marked gene: NDUFV1 as ready
Fetal anomalies v0.3066 NDUFV1 Zornitza Stark Phenotypes for gene: NDUFV1 were changed from MITOCHONDRIAL COMPLEX I DEFICIENCY to Mitochondrial complex I deficiency, nuclear type 4 MIM#618225
Fetal anomalies v0.3063 NDUFS8 Zornitza Stark Marked gene: NDUFS8 as ready
Fetal anomalies v0.3063 NDUFS8 Zornitza Stark Phenotypes for gene: NDUFS8 were changed from MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX I DEFICIENCY to Mitochondrial complex I deficiency, nuclear type 2 MIM#618222
Fetal anomalies v0.3057 NDUFA1 Zornitza Stark Marked gene: NDUFA1 as ready
Fetal anomalies v0.3057 NDUFA1 Zornitza Stark Phenotypes for gene: NDUFA1 were changed from MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX I DEFICIENCY to Mitochondrial complex I deficiency, nuclear type 12 MIM#301020
Fetal anomalies v0.3055 MYO5A Zornitza Stark Marked gene: MYO5A as ready
Fetal anomalies v0.3053 LTBP2 Zornitza Stark Marked gene: LTBP2 as ready
Fetal anomalies v0.3053 LTBP2 Zornitza Stark Phenotypes for gene: LTBP2 were changed from MICROSPHEROPHAKIA; PRIMARY CONGENITAL GLAUCOMA TYPE 3D to Glaucoma 3, primary congenital, D 613086; Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, MIM# 251750
Fetal anomalies v0.3050 LRPPRC Zornitza Stark Marked gene: LRPPRC as ready
Fetal anomalies v0.3050 LRPPRC Zornitza Stark Phenotypes for gene: LRPPRC were changed from LEIGH SYNDROME, FRENCH-CANADIAN TYPE to Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) MIM#220111
Fetal anomalies v0.3041 LMOD1 Zornitza Stark Marked gene: LMOD1 as ready
Fetal anomalies v0.3038 LEMD3 Zornitza Stark Marked gene: LEMD3 as ready
Fetal anomalies v0.3036 ITPR1 Zornitza Stark Marked gene: ITPR1 as ready
Fetal anomalies v0.3036 ITPR1 Zornitza Stark Phenotypes for gene: ITPR1 were changed from SPINOCEREBELLAR ATAXIA 29, CONGENITAL NONPROGRESSIVE; Gillespie Syndrome; SPINOCEREBELLAR ATAXIA TYPE15 to Spinocerebellar ataxia 15 MIM#606658; Spinocerebellar ataxia 29, congenital nonprogressive MIM#117360; Gillespie syndrome, MIM# 206700
Fetal anomalies v0.3034 UROS Zornitza Stark Marked gene: UROS as ready
Fetal anomalies v0.3033 MVK Zornitza Stark Marked gene: MVK as ready
Fetal anomalies v0.3032 LAMB2 Zornitza Stark Marked gene: LAMB2 as ready
Fetal anomalies v0.3031 PYROXD1 Belinda Chong reviewed gene: PYROXD1: Rating: RED; Mode of pathogenicity: None; Publications: 30345904, 30515627, 27745833; Phenotypes: Myopathy, myofibrillar, 8 (MIM#617258); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3031 PYGM Belinda Chong reviewed gene: PYGM: Rating: RED; Mode of pathogenicity: None; Publications: 1701414, 8316268, 17915571, 17994553, 21880526; Phenotypes: McArdle disease, MIM# 232600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3031 PRKAG2 Belinda Chong reviewed gene: PRKAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15877279, 17667862, 32646569; Phenotypes: Glycogen storage disease of heart, lethal congenital MIM#261740; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v0.3031 PPP3CA Belinda Chong reviewed gene: PPP3CA: Rating: AMBER; Mode of pathogenicity: None; Publications: 29432562, 28942967, 28942967; Phenotypes: Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development MIM#618265, Developmental and epileptic encephalopathy 91 617711; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v0.3031 PLCB4 Belinda Chong reviewed gene: PLCB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22560091, 23315542, 33131036, 32201334, 28328130, 27007857, 23913798; Phenotypes: Auriculocondylar syndrome 2, MIM# 614669; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3031 PLCB1 Zornitza Stark Marked gene: PLCB1 as ready
Fetal anomalies v0.3031 PLCB1 Zornitza Stark Phenotypes for gene: PLCB1 were changed from EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 12 to Epileptic encephalopathy, early infantile, 12 (MIM#613722)
Fetal anomalies v0.3028 PLCB1 Zornitza Stark reviewed gene: PLCB1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Epileptic encephalopathy, early infantile, 12 (MIM#613722); Mode of inheritance: None
Fetal anomalies v0.3028 PLAG1 Zornitza Stark Marked gene: PLAG1 as ready
Fetal anomalies v0.3025 PLAA Zornitza Stark Marked gene: PLAA as ready
Fetal anomalies v0.3022 PLAA Zornitza Stark changed review comment from: NDMSBA is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of progressive microcephaly and spasticity and severe global developmental delay resulting in profound mental retardation and severely impaired or absent motor function. More variable features include seizures and optic atrophy. Brain imaging may show myelinating abnormalities and white matter lesions consistent with a leukoencephalopathy, as well as structural anomalies, including thin corpus callosum, gyral abnormalities, and cerebral or cerebellar atrophy.

At least 5 families reported.; to: NDMSBA is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of progressive microcephaly and spasticity and severe global developmental delay resulting in profound mental retardation and severely impaired or absent motor function. More variable features include seizures and optic atrophy. Brain imaging may show myelinating abnormalities and white matter lesions consistent with a leukoencephalopathy, as well as structural anomalies, including thin corpus callosum, gyral abnormalities, and cerebral or cerebellar atrophy.

At least 5 families reported. Mouse model.
Fetal anomalies v0.3022 PIK3C2A Zornitza Stark Marked gene: PIK3C2A as ready
Fetal anomalies v0.3020 PIK3C2A Zornitza Stark changed review comment from: Three unrelated families, ID is part of the phenotype.
Sources: Expert list; to: Three unrelated families, cataracts and skeletal abnormalities are part of the phenotype.
Sources: Expert list
Fetal anomalies v0.3020 PIH1D3 Zornitza Stark Marked gene: PIH1D3 as ready
Fetal anomalies v0.3018 PIGY Zornitza Stark Marked gene: PIGY as ready
Fetal anomalies v0.3018 PIGY Zornitza Stark Phenotypes for gene: PIGY were changed from Glycosylphosphatidylinositol deficiency to Hyperphosphatasia with mental retardation syndrome 6, MIM# 616809
Fetal anomalies v0.3016 PIGY Zornitza Stark changed review comment from: Two unrelated families only; variable phenotype described. One family had a promoter region homozygous variant.; to: Two unrelated families only; variable phenotype described. One family had a promoter region homozygous variant.

Joint contractures, microcephaly, cataracts and other ultrasound-detectable abnormalities reported.
Fetal anomalies v0.3016 PIGN Zornitza Stark Marked gene: PIGN as ready
Fetal anomalies v0.3014 PIGG Zornitza Stark Marked gene: PIGG as ready
Fetal anomalies v0.3012 PIGG Zornitza Stark changed review comment from: Five patients from 3 unrelated families described with bi-allelic variants in this gene.
Sources: Expert Review; to: Five patients from 3 unrelated families described with bi-allelic variants in this gene.

Some had brain abnormalities (cerebellar atrophy and thin CC): uncertain if this is a consistent/prominent feature of this disorder at present. Otherwise, clinical presentation is typically post-natal.

Sources: Expert Review
Fetal anomalies v0.3012 PIBF1 Zornitza Stark Marked gene: PIBF1 as ready
Fetal anomalies v0.3010 PHF21A Zornitza Stark Marked gene: PHF21A as ready
Fetal anomalies v0.3006 PGM3 Zornitza Stark changed review comment from: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation.

Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity.

More than 10 unrelated families reported.

Typically presents post-natally.; to: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation.

Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity.

More than 10 unrelated families reported.

Typically presents post-natally. However, more severe presentations with skeletal abnormalities and congenital malformations reported in PMID 28543917 and 24931394.
Fetal anomalies v0.3005 PGM3 Zornitza Stark Marked gene: PGM3 as ready
Fetal anomalies v0.3003 PGM3 Zornitza Stark changed review comment from: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation.

Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity.

More than 10 unrelated families reported.; to: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation.

Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity.

More than 10 unrelated families reported.

Typically presents post-natally.
Fetal anomalies v0.3003 WDR26 Seb Lunke Marked gene: WDR26 as ready
Fetal anomalies v0.3003 WDR26 Seb Lunke Phenotypes for gene: WDR26 were changed from Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features to Skraban-Deardorff syndrome, MIM#617616; Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features
Fetal anomalies v0.3001 WDR26 Seb Lunke Added comment: Comment on list classification: Craniofacial features to subtle for US, brain abnormalities are not always present and also subtle.
Fetal anomalies v0.3000 WDR34 Seb Lunke Marked gene: WDR34 as ready
Fetal anomalies v0.2998 WDR35 Seb Lunke Marked gene: WDR35 as ready
Fetal anomalies v0.2996 WDR60 Seb Lunke Marked gene: WDR60 as ready
Fetal anomalies v0.2994 WDR62 Seb Lunke Marked gene: WDR62 as ready
Fetal anomalies v0.2994 WDR62 Seb Lunke Phenotypes for gene: WDR62 were changed from MICROCEPHALY CORTICAL MALFORMATIONS AND MENTAL RETARDATION to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317; MONDO:0011435
Fetal anomalies v0.2993 PDE6D Krithika Murali gene: PDE6D was added
gene: PDE6D was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PDE6D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE6D were set to 30423442; 24166846
Phenotypes for gene: PDE6D were set to Joubert syndrome 22 - MIM#615665
Review for gene: PDE6D was set to GREEN
Added comment: Biallelic variants associated with Joubert syndrome identified in 2 families. Antenatal detection possible.

30423442 Megarbane et al 2018
Report homozygous truncating PDE6D variant in a male infant with post-axial polydactyly noted at birth on all extremities. Brain MRI at 6 months of age showed cerebellar vermis agenesis, hypoplastic corpus callosum, cortical atrophy of the temporal lobes and molar tooth sign.

PMID 24166846 Thomas et al 2014 report a consanguineous family with three affected and 2 healthy sibs. Features noted in both liveborn children:
- 1/2 IUGR
- 1/2 facial dysmorphism
- 2/2 postaxial polydactyly
- 1/2 syndactyly
- 1/2 renal hypoplasia
- 2/2 microphthalmia
- 1/2 supportive MRI-B features
- 1/2 coloboma

3rd sibling is a male fetus terminated at 14 weeks gestation following findings of brain anomalies and polydactyly.

Supportive animal models
Sources: Literature
Fetal anomalies v0.2993 NPM1 Krithika Murali gene: NPM1 was added
gene: NPM1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NPM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPM1 were set to 31570891
Phenotypes for gene: NPM1 were set to Dyskeratosis congenita
Review for gene: NPM1 was set to AMBER
Added comment: Heterozygous variants identified in 2 patients with dyskeratosis congenita (DKC).

x1 patient with NPM1 missense mutation presented with severe growth defects at birth, thumb abnormalities and thrombocytopenia.

x1 patient with in-frame NPM1 deletion presented with skin pigmentation abnormalities, nail dystrophy, microcephaly, developmental delay, short stature, skeletal abnormalities in the
radius and bone marrow failure by age 6.

Some of these features may be amenable to antenatal detection.
Sources: Literature
Fetal anomalies v0.2993 PGAP1 Zornitza Stark Marked gene: PGAP1 as ready
Fetal anomalies v0.2990 PET100 Zornitza Stark Marked gene: PET100 as ready
Fetal anomalies v0.2990 PET100 Zornitza Stark Phenotypes for gene: PET100 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY to Mitochondrial complex IV deficiency, nuclear type 12, MIM# 619055
Fetal anomalies v0.2987 PET100 Zornitza Stark changed review comment from: Founder effect in 6 Australian families of Lebanese origin (M1?) reported originally; functional data. Second family with different variants also reported; and another 2 Lebanese families with same founder variant.; to: Founder effect in 6 Australian families of Lebanese origin (M1?) reported originally; functional data. Second family with different variants also reported; and another 2 Lebanese families with same founder variant.

IUGR is a feature.
Fetal anomalies v0.2987 PDSS1 Zornitza Stark Marked gene: PDSS1 as ready
Fetal anomalies v0.2987 PDSS1 Zornitza Stark Phenotypes for gene: PDSS1 were changed from COENZYME Q10 DEFICIENCY, PRIMARY, 2 to Coenzyme Q10 deficiency, primary, 2 MIM#614651
Fetal anomalies v0.2984 PDSS1 Zornitza Stark reviewed gene: PDSS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Coenzyme Q10 deficiency, primary, 2 MIM#614651; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2984 PDE10A Zornitza Stark Marked gene: PDE10A as ready
Fetal anomalies v0.2979 PAICS Zornitza Stark Marked gene: PAICS as ready
Fetal anomalies v0.2978 PACS1 Zornitza Stark Marked gene: PACS1 as ready
Fetal anomalies v0.2974 PACS1 Zornitza Stark changed review comment from: Multiple individuals reported with recurrent p.Arg203Trp variant; in vitro assays is suggestive of dominant-negative disease mechanism; to: Multiple individuals reported with recurrent p.Arg203Trp variant; in vitro assays is suggestive of dominant-negative disease mechanism

Brain, cardiac and renal abnormalities reported.
Fetal anomalies v0.2974 P4HB Zornitza Stark Marked gene: P4HB as ready
Fetal anomalies v0.2971 OTUD5 Zornitza Stark Marked gene: OTUD5 as ready
Fetal anomalies v0.2970 IFT27 Krithika Murali gene: IFT27 was added
gene: IFT27 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: IFT27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT27 were set to 24488770; 30761183; 26763875; 25443296
Phenotypes for gene: IFT27 were set to Bardet-Biedl syndrome 19-MIM#615996
Review for gene: IFT27 was set to GREEN
Added comment: Biallelic variants associated with Bardet-Biedl syndrome. Phenotypic features detectable antenatally include polydactyly, cardiac and brain anomalies also reported.
Sources: Literature
Fetal anomalies v0.2970 HMGB1 Krithika Murali gene: HMGB1 was added
gene: HMGB1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HMGB1 were set to 34164801
Phenotypes for gene: HMGB1 were set to microcephaly; intellectual disability
Review for gene: HMGB1 was set to GREEN
Added comment: 34164801 Uguen et al 2021 report 6 unrelated individuals with LoF HMGB1 variants associated with syndromic ID. 4 individuals reported to have microcephaly - majority noted to have microcephaly at birth +/- growth restriction.
Sources: Literature
Fetal anomalies v0.2970 FAM92A Krithika Murali gene: FAM92A was added
gene: FAM92A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FAM92A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM92A were set to 30395363
Phenotypes for gene: FAM92A were set to Polydactyly, postaxial, type A9 - MIM#618219
Review for gene: FAM92A was set to AMBER
Added comment: 30395363 - homozygous nonsense variants in FAM92A segregated with postaxial polydactyly in x1 consanguineous Parkistani family. Supportive mouse model reported.
Sources: Literature
Fetal anomalies v0.2970 OSGEP Zornitza Stark Marked gene: OSGEP as ready
Fetal anomalies v0.2968 OSGEP Zornitza Stark changed review comment from: 25 families reported.
Sources: Expert list; to: 25 families reported. IUGR and oligohydramnios are a feature.
Sources: Expert list
Fetal anomalies v0.2968 NUS1 Zornitza Stark Marked gene: NUS1 as ready
Fetal anomalies v0.2964 NUS1 Zornitza Stark edited their review of gene: NUS1: Added comment: The CDG disorder caused by bi-allelic variants in this gene has iUGR as a feature. Note limited reports (one published, one ClinVar).

The DEE disorder associated with mono-allelic variants typically presents post-natally.; Changed rating: AMBER; Changed phenotypes: Congenital disorder of glycosylation, type 1aa; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2964 NUP88 Zornitza Stark Marked gene: NUP88 as ready
Fetal anomalies v0.2963 NUP62 Zornitza Stark Marked gene: NUP62 as ready
Fetal anomalies v0.2961 NTRK2 Zornitza Stark Marked gene: NTRK2 as ready
Fetal anomalies v0.2957 NSUN2 Zornitza Stark Marked gene: NSUN2 as ready
Fetal anomalies v0.2957 NSUN2 Zornitza Stark Phenotypes for gene: NSUN2 were changed from AUTOSOMAL- RECESSIVE INTELLECTUAL DISABILITY MRT5 to Mental retardation, autosomal recessive 5, MIM# 611091
Fetal anomalies v0.2955 NSUN2 Zornitza Stark edited their review of gene: NSUN2: Added comment: Low birth weight reported. Microcephaly also reported, age of onset unclear.; Changed rating: AMBER; Changed publications: 22541559, 22541562, 22577224
Fetal anomalies v0.2955 NRXN2 Zornitza Stark Marked gene: NRXN2 as ready
Fetal anomalies v0.2951 PDSS2 Ain Roesley reviewed gene: PDSS2: Rating: RED; Mode of pathogenicity: None; Publications: 29032433, 25349199, 17186472, 21723727, 10972372; Phenotypes: Coenzyme Q10 deficiency, primary, 3 MIM#614652; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2951 TRRAP Krithika Murali gene: TRRAP was added
gene: TRRAP was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TRRAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRRAP were set to 30827496
Phenotypes for gene: TRRAP were set to Developmental delay with or without dysmorphic facies and autism- #618454; multiple congenital anomalies
Review for gene: TRRAP was set to GREEN
Added comment: 13 unrelated individuals reported with a complex syndromic neurodevelopmental disorder associated with malformations that can be detected antenatally. This includes, brain, heart, kidney, urogenital anomalies, abdominal wall hernias, cleft lip/palate
Sources: Literature
Fetal anomalies v0.2951 G6PD Krithika Murali gene: G6PD was added
gene: G6PD was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: G6PD was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: G6PD were set to 1316704; 26279483; 18177777; 17825683; 1127504; 7472841
Phenotypes for gene: G6PD were set to Haemolytic anaemia, G6PD deficient (300908)
Review for gene: G6PD was set to AMBER
Added comment: Well-known association with G6PD deficiency. Borderline red-amber gene for fetal anomalies. However, as features of anaemia can sometimes be detected in fetus antenatally and therapeutic/maternal trigger avoidance options available, I have favoured amber rating.

PMID: 26279483 Keller et al 2015 - report a mother who is a carrier for a G6PD variant (Guadalajara variant) with a family history of a brother and paternal uncle who died as neonates from severe hydrops. She was counselled to avoid substances that could precipitate oxidative stress from 22 weeks gestation onwards. During her first pregnancy, a male fetus was found to have mild cardiomegaly at 31 weeks with elevated MCAPSV - suggestive of anaemia. Intrauterine transfusion instituted. Presence of maternally inherited G6PD variant confirmed in the fetus.

There are other case reports of hydrops fetalis presumed secondary to G6PD deficiency but evidence is limited..

4999390; 1127504 - older studies, no genomic confirmation available.

4999390 Perkins et al 1971 - Mother presumed to be a carrier for G6PD deficiency and all 3 babies presumed to have the same
- 1st child neonatal jaundice with abnormal G6PD test result and death at 59 days of life from undetermined cause
- 2nd pregnancy - mother given sulfizoxazole for UTI during pregnancy, delivered stillborn infant at 36 weeks with hydrops fetalis and severe anaemia
- 3rd child - well, neonatal jaundice and abnormal G6PD test.

Mother O neg blood group, all three babies +ve blood group, DAT -ve and RhoGam given each pregnancy.

1127504 - Mentzer and Collier et al 1975
Male infant died at 2 hours of life with evidence of haemolysis and autopsy findings of hydrops. G6PD screening test in baby abnormal. Mother had low-normal G6PD activity, abnormal ascorbate cyanide test, abnormal MTT cytochemical however no abnormal migrating band of G6PD activity was present on electrophoresis. URTI episode during pregnancy, ascorbic acid consumption and fava bean consumption noted. G6PD deficiency presumed in mother and infant but not genomically confirmed.

23719252; 24999569 - Two case reports identified. However, a second diagnosis was present in both and the G6PD deficiency may have contributed to severity rather than being the primary factor.
Sources: Literature
Fetal anomalies v0.2951 NDUFV1 Ain Roesley reviewed gene: NDUFV1: Rating: ; Mode of pathogenicity: None; Publications: 34807224; Phenotypes: Mitochondrial complex I deficiency, nuclear type 4 MIM#618225; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2951 MYBPC1 Alison Yeung Marked gene: MYBPC1 as ready
Fetal anomalies v0.2951 MYBPC1 Alison Yeung Phenotypes for gene: MYBPC1 were changed from Arthrogryposis, distal, type 1B 614335; Lethal congenital contracture syndrome 4 614915 to Arthrogryposis, distal, type 1B 614335; Lethal congenital contracture syndrome 4, MIM# 614915
Fetal anomalies v0.2950 MYBPC1 Alison Yeung reviewed gene: MYBPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Arthrogryposis, distal, type 1B, MIM# 614335, Lethal congenital contracture syndrome 4, MIM# 614915; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.2950 NDUFS8 Ain Roesley reviewed gene: NDUFS8: Rating: RED; Mode of pathogenicity: None; Publications: 23430795, 9837812, 15159508, 22499348, 20818383, 20819849; Phenotypes: Mitochondrial complex I deficiency, nuclear type 2 MIM#618222; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2950 MUSK Alison Yeung Marked gene: MUSK as ready
Fetal anomalies v0.2949 MTOR Alison Yeung Marked gene: MTOR as ready
Fetal anomalies v0.2948 NDUFS7 Ain Roesley reviewed gene: NDUFS7: Rating: RED; Mode of pathogenicity: None; Publications: 17604671, 17275378, 10360771; Phenotypes: Mitochondrial complex I deficiency, nuclear type 3 MIM#618224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2948 NDUFS7 Ain Roesley reviewed gene: NDUFS7: Rating: RED; Mode of pathogenicity: None; Publications: 34797029; Phenotypes: Mitochondrial complex I deficiency, nuclear type 3 MIM#618224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2948 NDUFA1 Ain Roesley reviewed gene: NDUFA1: Rating: RED; Mode of pathogenicity: None; Publications: 29506883, 19185523, 17262856, 21596602; Phenotypes: Mitochondrial complex I deficiency, nuclear type 12 MIM#301020; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Fetal anomalies v0.2948 LTBP2 Ain Roesley reviewed gene: LTBP2: Rating: RED; Mode of pathogenicity: None; Publications: 19656777, 19361779, 20617341, 32165823, 30380740, 30565850; Phenotypes: Glaucoma 3, primary congenital, D 613086, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, MIM# 251750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2948 MTO1 Alison Yeung Marked gene: MTO1 as ready
Fetal anomalies v0.2948 MTO1 Alison Yeung Phenotypes for gene: MTO1 were changed from INFANTILE HYPERTROPHIC CARDIOMYOPATHY AND LACTIC ACIDOSIS to Combined oxidative phosphorylation deficiency 10, MIM# 61702
Fetal anomalies v0.2947 MSL3 Alison Yeung Marked gene: MSL3 as ready
Fetal anomalies v0.2947 MSL3 Alison Yeung Phenotypes for gene: MSL3 were changed from Basilicata-Akhtar syndrome, 301032; MSL3 syndrome to Basilicata-Akhtar syndrome, MIM# 301032
Fetal anomalies v0.2946 MSL3 Alison Yeung reviewed gene: MSL3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Basilicata-Akhtar syndrome, MIM# 301032; Mode of inheritance: None
Fetal anomalies v0.2946 LRPPRC Ain Roesley reviewed gene: LRPPRC: Rating: AMBER; Mode of pathogenicity: None; Publications: 32972427, 26510951, 21266382; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) MIM#220111; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2946 MOCS1 Alison Yeung Marked gene: MOCS1 as ready
Fetal anomalies v0.2946 MPLKIP Alison Yeung Marked gene: MPLKIP as ready
Fetal anomalies v0.2945 MPDU1 Alison Yeung Marked gene: MPDU1 as ready
Fetal anomalies v0.2942 MNX1 Alison Yeung Marked gene: MNX1 as ready
Fetal anomalies v0.2942 MNX1 Alison Yeung Phenotypes for gene: MNX1 were changed from CURRARINO SYNDROME to Currarino syndrome, MIM# 176450
Fetal anomalies v0.2941 MNX1 Alison Yeung reviewed gene: MNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Currarino syndrome, MIM# 176450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.2941 MMP21 Alison Yeung Marked gene: MMP21 as ready
Fetal anomalies v0.2940 MLYCD Alison Yeung Marked gene: MLYCD as ready
Fetal anomalies v0.2940 MLYCD Alison Yeung Phenotypes for gene: MLYCD were changed from MALONYL-COA DECARBOXYLASE DEFICIENCY to Malonyl-CoA decarboxylase deficiency, MIM# 248360
Fetal anomalies v0.2939 ITPR1 Ain Roesley reviewed gene: ITPR1: Rating: RED; Mode of pathogenicity: None; Publications: 27108797, 31340402, 30242502, 29169895; Phenotypes: Spinocerebellar ataxia 15 MIM#606658, Spinocerebellar ataxia 29, congenital nonprogressive MIM#117360, Gillespie syndrome, MIM# 206700; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2939 STAT5B Zornitza Stark Marked gene: STAT5B as ready
Fetal anomalies v0.2938 STAC3 Zornitza Stark Marked gene: STAC3 as ready
Fetal anomalies v0.2936 ST3GAL3 Zornitza Stark Marked gene: ST3GAL3 as ready
Fetal anomalies v0.2936 ST3GAL3 Zornitza Stark Phenotypes for gene: ST3GAL3 were changed from MENTAL RETARDATION, AUTOSOMAL RECESSIVE 12 to Mental retardation, autosomal recessive 12 MIM# 611090; Developmental and epileptic encephalopathy 15, MIM# 615006
Fetal anomalies v0.2933 ST3GAL3 Zornitza Stark edited their review of gene: ST3GAL3: Changed rating: RED; Changed phenotypes: Mental retardation, autosomal recessive 12 MIM# 611090, Developmental and epileptic encephalopathy 15, MIM# 615006
Fetal anomalies v0.2933 SPECC1L Zornitza Stark Marked gene: SPECC1L as ready
Fetal anomalies v0.2929 SP7 Zornitza Stark Marked gene: SP7 as ready
Fetal anomalies v0.2928 SOX6 Zornitza Stark Marked gene: SOX6 as ready
Fetal anomalies v0.2925 SOX6 Zornitza Stark changed review comment from: Comment when marking as ready: Most individuals had ID, ranging from mild to severe.; to: Comment when marking as ready: Congenital anomalies, in particular craniosynostosis.
Fetal anomalies v0.2925 SOX5 Zornitza Stark Marked gene: SOX5 as ready
Fetal anomalies v0.2921 SOX5 Zornitza Stark changed review comment from: Comment when marking as ready: Note many cases reported of intragenic deletion.; to: Comment when marking as ready: Note many cases reported of intragenic deletion.

Presentation is typically post-natal.
Fetal anomalies v0.2921 SOX18 Zornitza Stark Marked gene: SOX18 as ready
Fetal anomalies v0.2918 SNRPE Zornitza Stark Marked gene: SNRPE as ready
Fetal anomalies v0.2915 SNAP29 Zornitza Stark Marked gene: SNAP29 as ready
Fetal anomalies v0.2913 SNAP25 Zornitza Stark Marked gene: SNAP25 as ready
Fetal anomalies v0.2910 SMPD4 Zornitza Stark Marked gene: SMPD4 as ready
Fetal anomalies v0.2909 SMG9 Zornitza Stark Marked gene: SMG9 as ready
Fetal anomalies v0.2909 SMG9 Zornitza Stark Phenotypes for gene: SMG9 were changed from Heart and brain malformation syndrome, 616920; SMG9 Multiple Congenital Anomaly Syndrome to Heart and brain malformation syndrome, MIM# 616920
Fetal anomalies v0.2907 SMG9 Zornitza Stark changed review comment from: Three unrelated families reported, severe congenital malformation syndrome, ID is part of the phenotype in survivors.
Sources: Expert list; to: Three unrelated families reported, severe congenital malformation syndrome.
Sources: Expert list
Fetal anomalies v0.2907 SMARCC1 Zornitza Stark Marked gene: SMARCC1 as ready
Fetal anomalies v0.2907 SMARCC1 Zornitza Stark Gene: smarcc1 has been classified as Green List (High Evidence).
Fetal anomalies v0.2907 SMARCC1 Zornitza Stark Classified gene: SMARCC1 as Green List (high evidence)
Fetal anomalies v0.2907 SMARCC1 Zornitza Stark Gene: smarcc1 has been classified as Green List (High Evidence).
Fetal anomalies v0.2906 SLC5A7 Zornitza Stark Marked gene: SLC5A7 as ready
Fetal anomalies v0.2904 SLC29A3 Zornitza Stark Marked gene: SLC29A3 as ready
Fetal anomalies v0.2902 SLC25A4 Zornitza Stark Marked gene: SLC25A4 as ready
Fetal anomalies v0.2902 SLC25A4 Zornitza Stark Phenotypes for gene: SLC25A4 were changed from Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number to Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) AD, MIM#617184
Fetal anomalies v0.2898 SLC25A4 Zornitza Stark changed review comment from: Variants in this gene cause both dominant and recessive disease. MIM#617184 reported as causing profound hypotonia and frequent need for respiratory support; the other two conditions, one AR and the other AD, appear less severe. Not convinced ID is an intrinsic part of the phenotype.; to: Variants in this gene cause both dominant and recessive disease. MIM#617184 reported as causing profound hypotonia and frequent need for respiratory support; the other two conditions, one AR and the other AD, appear less severe.
Fetal anomalies v0.2898 SLC25A4 Zornitza Stark edited their review of gene: SLC25A4: Added comment: Hypertrophic cardiomyopathy is an early feature.; Changed rating: GREEN; Changed phenotypes: Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) AD, MIM#617184; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.2898 SLC1A2 Zornitza Stark Marked gene: SLC1A2 as ready
Fetal anomalies v0.2893 SLC18A3 Zornitza Stark Marked gene: SLC18A3 as ready
Fetal anomalies v0.2892 UROS Krithika Murali gene: UROS was added
gene: UROS was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: UROS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UROS were set to 34187847; 34828434; 15065102
Phenotypes for gene: UROS were set to Porphyria, congenital erythropoietic - MIM#263700; hydrops fetalis; multiple congenital anomalies
Review for gene: UROS was set to GREEN
Added comment: Biallelic variants associated with congenital erytropoietic porphyria (CEP).

PMID 34187847 Khalouaoui A et al 2021 report one infant with CEP secondary to homozygous UROS variants. Prenatal ultrasound at 25 weeks of gestation revealed an increased nuchal translucency and myocardial hypertrophy.

PMID: 34828434 Arnaud et al 2021 - report one fetus miscarried in the 2nd trimester with 22 weeks ultrasound showing hyperechogenic small intestine with short femurs. Subsequent pregnancy MTOP after antenatal USS showed hygroma coli, ascites, short femurs, double outlet right ventricle. Genomic sequencing on stored fetal DNA samples confirmed homozygous UROS p.Cys73Arg variants in both fetuses.

PMID 15065102 Lazebnik et al 2004 reported the prenatal findings of two siblings with CEP secondary to homozygous pathogenic C73R variants. 1st child - USS at 17.5 weeks gestation showed increased nuchal thickness (9.7mm) with mild ascites, pericardial effusion, and skin oedema which persisted on subsequent scans. 2nd child - 16 week USS showed increased nuchal thickness (8.7mm) with scalp oedema, ascites, pericardial effusion, skin oedema and hepatomegaly.

Other cases with antenatal features, particularly non-immune hydrops, secondary to suspected CEP reported but not confirmed molecularly.
Sources: Literature
Fetal anomalies v0.2892 MVK Krithika Murali gene: MVK was added
gene: MVK was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MVK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MVK were set to 27012807; 16722536
Phenotypes for gene: MVK were set to Mevalonic aciduria-#610377; Hyper-IgD syndrome - #260920
Review for gene: MVK was set to GREEN
Added comment: Biallelic MVK variants associated with mevalonate kinate deficiencies - an overlapping spectrum of phenotypes includes mevalonic aciduria (MVA) on the severe end and hyper-IgD syndrome (HIDS) generally having a less severe clinical course and later diagnosis.

Fetal manifestations of MVA reported include microcephaly and hydrops fetalis.
Sources: Literature
Fetal anomalies v0.2892 LAMB2 Krithika Murali gene: LAMB2 was added
gene: LAMB2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: LAMB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMB2 were set to 16450351
Phenotypes for gene: LAMB2 were set to Pierson syndrome-MIM#609049; Nephrotic syndrome, type 5, with or without ocular abnormalities-MIM#614199
Review for gene: LAMB2 was set to AMBER
Added comment: Biallelic variants associated with Pierson syndrome. Phenotypic features include congenital nephrotic syndrome, ocular anomalies including microcoria. Most affected individuals die early from renal disease with survivors tending to have ID/visual loss.

Prenatal features reported in 1 consanguineous Turkish family with 4 pregnancies affected by Pierson syndrome. Antenatal ultrasound features noted include:
- 2/4 homogenous hyperechogenicity of the kidneys similar to bone tissue
- 2/4 enlargement of fetal kidneys
- 2/4 bilateral pyelectasis
- 1/4 oligohydramnios --> anhydramnios
- 1/4 hydrops
- 1/4 ancencephaly

All 4 fetuses had ultrasound anomalies. Anencephaly seen in the 4th pregnancy noted at 11 weeks resulting in MTOP. Homozygosity for LAMB2 variant confirmed. PM showed that kidneys were appropriate for gestational age. I could not find another case report of anencephaly with Pierson syndrome, this may be an incidental finding.
Sources: Literature
Fetal anomalies v0.2892 HS2ST1 Zornitza Stark Marked gene: HS2ST1 as ready
Fetal anomalies v0.2891 FLNC Zornitza Stark Marked gene: FLNC as ready
Fetal anomalies v0.2891 FLNC Zornitza Stark Phenotypes for gene: FLNC were changed from Arthrogryposis; congenital myopathy; Cardiomyopathy, familial restrictive 5 - MIM #617047; Cardiomyopathy, familial hypertrophic, 26 -MIM# 617047; Myopathy, distal, 4 - #614065; Myopathy, myofibrillar, 5 - MIM#609524 to Arthrogryposis; congenital myopathy; Myopathy, myofibrillar, 5 - MIM#609524
Fetal anomalies v0.2885 IARS Zornitza Stark Publications for gene: IARS were set to 27426735
Fetal anomalies v0.2884 SIX6 Zornitza Stark Marked gene: SIX6 as ready
Fetal anomalies v0.2883 SHANK3 Zornitza Stark Marked gene: SHANK3 as ready
Fetal anomalies v0.2880 SHANK3 Zornitza Stark changed review comment from: Phelan-McDermid syndrome is a developmental disorder with variable features. Common features include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behaviour, and minor dysmorphic features. Well established gene-disease association, deletions are common.; to: Phelan-McDermid syndrome is a developmental disorder with variable features. Common features include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behaviour, and minor dysmorphic features. Well established gene-disease association, deletions are common.

Clinical presentation is typically post-natal.
Fetal anomalies v0.2880 SHANK1 Zornitza Stark Marked gene: SHANK1 as ready
Fetal anomalies v0.2876 SGSH Zornitza Stark Marked gene: SGSH as ready
Fetal anomalies v0.2876 SGSH Zornitza Stark Phenotypes for gene: SGSH were changed from MUCOPOLYSACCHARIDOSIS TYPE 3A to Mucopolysaccharidosis type IIIA (Sanfilippo A), MIM# 252900; MONDO:0009655
Fetal anomalies v0.2873 SETD2 Zornitza Stark Marked gene: SETD2 as ready
Fetal anomalies v0.2869 SETD2 Zornitza Stark changed review comment from: Multiple affected individuals with macrocephaly, intellectual disability, speech delay, low sociability, and behavioral problems. More variable features include postnatal overgrowth, obesity, advanced carpal ossification, developmental delay, and seizures; to: Multiple affected individuals with macrocephaly, intellectual disability, speech delay, low sociability, and behavioral problems. More variable features include postnatal overgrowth, obesity, advanced carpal ossification, developmental delay, and seizures.

Chiari malformation and ventriculomegaly reported.
Fetal anomalies v0.2869 SETD1A Zornitza Stark Marked gene: SETD1A as ready
Fetal anomalies v0.2869 SETD1A Zornitza Stark Phenotypes for gene: SETD1A were changed from INTELLECTUAL DISABILITY to Epilepsy, early-onset, with or without developmental delay, MIM# 618832; Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM# 619056
Fetal anomalies v0.2865 SETD1A Zornitza Stark changed review comment from: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 4 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; to: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 4 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.

Presentation of both disorders is typically post-natal.
Fetal anomalies v0.2865 SECISBP2 Zornitza Stark Marked gene: SECISBP2 as ready
Fetal anomalies v0.2862 SEC24D Zornitza Stark Marked gene: SEC24D as ready
Fetal anomalies v0.2862 SEC24D Zornitza Stark Phenotypes for gene: SEC24D were changed from SYNDROMIC OSTEOGENESIS IMPERFECTA to Cole-Carpenter syndrome 2, MIM# 616294
Fetal anomalies v0.2859 SCN3A Zornitza Stark Marked gene: SCN3A as ready
Fetal anomalies v0.2859 SCN3A Zornitza Stark Phenotypes for gene: SCN3A were changed from Focal epilepsy to Epilepsy, familial focal, with variable foci 4, MIM# 617935; Epileptic encephalopathy, early infantile, 62, MIM# 617938; Intellectual disability; Malformations of cortical development
Fetal anomalies v0.2854 SCLT1 Zornitza Stark Marked gene: SCLT1 as ready
Fetal anomalies v0.2854 SCLT1 Zornitza Stark Phenotypes for gene: SCLT1 were changed from Senior-L ken Syndrome; No OMIM phenotype; Oro-facio-digital syndrome type IX to Orofaciodigital syndrome type IX; Senior-Loken syndrome; Bardet-Biedl syndrome
Fetal anomalies v0.2851 SCLT1 Zornitza Stark changed review comment from: Established ciliopathy gene but no clear association with ciliopathy/JS-type structural brain abnormalities.; to: Established ciliopathy gene.
Fetal anomalies v0.2851 SASS6 Zornitza Stark Marked gene: SASS6 as ready
Fetal anomalies v0.2851 SASS6 Zornitza Stark Phenotypes for gene: SASS6 were changed from ?Microcephaly 14, primary, autosomal recessive 616402 to Microcephaly 14, primary, autosomal recessive, MIM# 616402
Fetal anomalies v0.2849 HS2ST1 Krithika Murali gene: HS2ST1 was added
gene: HS2ST1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Neurofacioskeletal syndrome with or without renal agenesis-MIM#619194; multiple congenital anomalies; arthrogryposis
Review for gene: HS2ST1 was set to GREEN
Added comment: PMID 33159882 - Scheenberger et al 2020

Biallelic HS2ST1 variants associated with disease reported in 4 affected individuals from 3 unrelated families, including one affected fetus with arthrogryposis, skeletal anomalies, bilateral renal agenesis. Other congenital anomalies reported include agenesis or hypoplasia of the corpus callosum.
Sources: Literature
Fetal anomalies v0.2849 SACS Zornitza Stark Marked gene: SACS as ready
Fetal anomalies v0.2849 SACS Zornitza Stark Phenotypes for gene: SACS were changed from SPASTIC ATAXIA, CHARLEVOIX-SAGUENAY TYPE to Spastic ataxia, Charlevoix-Saguenay type, MIM# 270550
Fetal anomalies v0.2846 FLNC Krithika Murali changed review comment from: ClinGen definitive gene-disease validation for myofibrillar myopathy type 5 and dilated cardiomyopathy. Predominantly adult onset phenotype, AD inheritance. 4 unrelated cases with likely de novo FLNC variants presenting with congenital myopathy and arthrogryposis have also been reported which are features amenable to antenatal detection.

PMID 29858533 Kiselev et al reported 4 unrelated patients with early onset myopathy and restrictive cardiomyopathy. 3/4 also presented with arthrogryposis.

x1 patient required delivery via CS due to breech presentation and at birth was noted to have arthrogryposis and hip dysplasia - de novo FLNC variant confirmed. RCM diagnosed age 2

x1 patient noted to have IUGR in a pregnancy complicated by pre-eclampsia. At birth was noted to have arthrogryposis, hip subluxation and abdominal wall weakness with herniation. RCM diagnosed age 6 months. Variant not present in unaffected mother, paternal DNA unavailable.

x1 patient required CS delivery due to insufficient rotation in birth canal. Noted to have arthrogryposis at birth. Variant confirmed to be de novo

x1 patient presented with muscle weakness first year of life, RCM age 3. Parents declined genetic testing.

---
Other cases of interest

PMID 30260051 Schubert et al 2018 - report two restrictive cardiomyopathy families with childhood onset disease with age 1 being the earliest age of diagnosis in a DCDA monozygotic twin who was also diagnosed with a small VSD perinatally. Both twins were also noted to have extra-cardiac manifestations at the time of diagnosis including developmental delay, hypotonia, dysmorphic facial features, and clasped thumbs with onset of kidney dysfunction age 3 post-cardiac transplant.

PMID: 32516863 – Kolbel et al 2020 report one neonate with homozygous FLNC variant c.1325C>G (p.Pro442Arg). Absent from gnomad. Presented with weak suck first month of life with subsequent motor development delay, generalised muscular hypotonia, contractures. Variant confirmed in both unaffected parents. Authors postulate this is a novel case of homozygous FLNC variants associated with congenital presentation. This is a single case report, only heterozygous variants reported so far including in congenital presentations, both parents with het variants unaffected. Possibility of an alternative genetic explanation for this patient's presentation not excluded.
Sources: Literature; to: ClinGen definitive gene-disease validation for myofibrillar myopathy type 5 and dilated cardiomyopathy. Predominantly adult onset phenotype, AD inheritance. 4 unrelated cases with likely de novo FLNC variants presenting with congenital myopathy and arthrogryposis have also been reported. These features/complications of these features are amenable to antenatal detection.

PMID 29858533 Kiselev et al reported 4 unrelated patients with early onset myopathy and restrictive cardiomyopathy. 3/4 also presented with arthrogryposis.

x1 patient required delivery via CS due to breech presentation and at birth was noted to have arthrogryposis and hip dysplasia - de novo FLNC variant confirmed. RCM diagnosed age 2

x1 patient noted to have IUGR in a pregnancy complicated by pre-eclampsia. At birth was noted to have arthrogryposis, hip subluxation and abdominal wall weakness with herniation. RCM diagnosed age 6 months. Variant not present in unaffected mother, paternal DNA unavailable.

x1 patient required CS delivery due to insufficient rotation in birth canal. Noted to have arthrogryposis at birth. Variant confirmed to be de novo

x1 patient presented with muscle weakness first year of life, RCM age 3. Parents declined genetic testing.

---
Other cases of interest

PMID 30260051 Schubert et al 2018 - report two restrictive cardiomyopathy families with childhood onset disease with age 1 being the earliest age of diagnosis in a DCDA monozygotic twin who was also diagnosed with a small VSD perinatally. Both twins were also noted to have extra-cardiac manifestations at the time of diagnosis including developmental delay, hypotonia, dysmorphic facial features, and clasped thumbs with onset of kidney dysfunction age 3 post-cardiac transplant.

PMID: 32516863 – Kolbel et al 2020 report one neonate with homozygous FLNC variant c.1325C>G (p.Pro442Arg). Absent from gnomad. Presented with weak suck first month of life with subsequent motor development delay, generalised muscular hypotonia, contractures. Variant confirmed in both unaffected parents. Authors postulate this is a novel case of homozygous FLNC variants associated with congenital presentation. This is a single case report, only heterozygous variants reported so far including in congenital presentations, both parents with het variants unaffected. Possibility of an alternative genetic explanation for this patient's presentation not excluded.
Sources: Literature
Fetal anomalies v0.2846 FLNC Krithika Murali gene: FLNC was added
gene: FLNC was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FLNC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FLNC were set to 29858533; 30260051; 32516863
Phenotypes for gene: FLNC were set to Arthrogryposis; congenital myopathy; Cardiomyopathy, familial restrictive 5 - MIM #617047; Cardiomyopathy, familial hypertrophic, 26 -MIM# 617047; Myopathy, distal, 4 - #614065; Myopathy, myofibrillar, 5 - MIM#609524
Review for gene: FLNC was set to GREEN
Added comment: ClinGen definitive gene-disease validation for myofibrillar myopathy type 5 and dilated cardiomyopathy. Predominantly adult onset phenotype, AD inheritance. 4 unrelated cases with likely de novo FLNC variants presenting with congenital myopathy and arthrogryposis have also been reported which are features amenable to antenatal detection.

PMID 29858533 Kiselev et al reported 4 unrelated patients with early onset myopathy and restrictive cardiomyopathy. 3/4 also presented with arthrogryposis.

x1 patient required delivery via CS due to breech presentation and at birth was noted to have arthrogryposis and hip dysplasia - de novo FLNC variant confirmed. RCM diagnosed age 2

x1 patient noted to have IUGR in a pregnancy complicated by pre-eclampsia. At birth was noted to have arthrogryposis, hip subluxation and abdominal wall weakness with herniation. RCM diagnosed age 6 months. Variant not present in unaffected mother, paternal DNA unavailable.

x1 patient required CS delivery due to insufficient rotation in birth canal. Noted to have arthrogryposis at birth. Variant confirmed to be de novo

x1 patient presented with muscle weakness first year of life, RCM age 3. Parents declined genetic testing.

---
Other cases of interest

PMID 30260051 Schubert et al 2018 - report two restrictive cardiomyopathy families with childhood onset disease with age 1 being the earliest age of diagnosis in a DCDA monozygotic twin who was also diagnosed with a small VSD perinatally. Both twins were also noted to have extra-cardiac manifestations at the time of diagnosis including developmental delay, hypotonia, dysmorphic facial features, and clasped thumbs with onset of kidney dysfunction age 3 post-cardiac transplant.

PMID: 32516863 – Kolbel et al 2020 report one neonate with homozygous FLNC variant c.1325C>G (p.Pro442Arg). Absent from gnomad. Presented with weak suck first month of life with subsequent motor development delay, generalised muscular hypotonia, contractures. Variant confirmed in both unaffected parents. Authors postulate this is a novel case of homozygous FLNC variants associated with congenital presentation. This is a single case report, only heterozygous variants reported so far including in congenital presentations, both parents with het variants unaffected. Possibility of an alternative genetic explanation for this patient's presentation not excluded.
Sources: Literature
Fetal anomalies v0.2846 MKS1 Alison Yeung Marked gene: MKS1 as ready
Fetal anomalies v0.2846 MKS1 Alison Yeung Phenotypes for gene: MKS1 were changed from MECKEL SYNDROME TYPE 1; BARDET-BIEDL SYNDROME TYPE 13 to Joubert syndrome 28, MIM# 617121; MONDO:0014928; Meckel syndrome 1, MIM# 249000; MONDO:0009571
Fetal anomalies v0.2845 MKKS Alison Yeung Marked gene: MKKS as ready
Fetal anomalies v0.2845 MKKS Alison Yeung Phenotypes for gene: MKKS were changed from BARDET-BIEDL SYNDROME TYPE 6; MCKUSICK-KAUFMAN SYNDROME to McKusick-Kaufman syndrome, MIM# 236700; Bardet-Biedl syndrome 6, MIM# 605231
Fetal anomalies v0.2844 MGP Alison Yeung Marked gene: MGP as ready
Fetal anomalies v0.2843 MTM1 Alison Yeung Marked gene: MTM1 as ready
Fetal anomalies v0.2843 MTM1 Alison Yeung Phenotypes for gene: MTM1 were changed from MYOTUBULAR MYOPATHY, X-LINKED to Myotubular myopathy, X-linked, MIM# 310400
Fetal anomalies v0.2842 MFSD2A Alison Yeung Marked gene: MFSD2A as ready
Fetal anomalies v0.2841 MFRP Alison Yeung Marked gene: MFRP as ready
Fetal anomalies v0.2841 MFRP Alison Yeung Added comment: Comment on list classification: Ocular anomalies not detectable on US. No extra-ocular fetal anomalies reported. Marked as Red for fetal anomalies gene panel
Fetal anomalies v0.2840 MFRP Alison Yeung changed review comment from: Bi-allelic variants in this gene associated with posterior microphthalmia with retinitis pigmentosa, foveoschisis, and optic disc drusen. Ocular abnormalities not detectable on fetal US and no association with extra-ocular fetal anomalies.; to: Bi-allelic variants in this gene associated with posterior microphthalmia with retinitis pigmentosa, foveoschisis, and optic disc drusen. Ocular abnormalities not detectable on fetal US and no association with extra-ocular fetal anomalies.
Fetal anomalies v0.2840 IQCB1 Alison Yeung Marked gene: IQCB1 as ready
Fetal anomalies v0.2840 IQCB1 Alison Yeung Added comment: Comment when marking as ready: Not associated with fetal anomalies. Marked as RED for fetal anomalies panel
Fetal anomalies v0.2839 IARS Alison Yeung Phenotypes for gene: IARS were changed from Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, 617093 to Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, OMIM# 617093
Fetal anomalies v0.2838 IARS Alison Yeung reviewed gene: IARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27426735, 27891590; Phenotypes: Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, MIM#617093; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2838 IARS Alison Yeung Marked gene: IARS as ready
Fetal anomalies v0.2838 IARS Alison Yeung Gene: iars has been classified as Green List (High Evidence).
Fetal anomalies v0.2838 CTU2 Alison Yeung Marked gene: CTU2 as ready
Fetal anomalies v0.2838 TNNI2 Zornitza Stark Marked gene: TNNI2 as ready
Fetal anomalies v0.2838 TNNI2 Zornitza Stark Phenotypes for gene: TNNI2 were changed from Arthrogryposis multiplex congenita, distal, type 2B 601680 to Arthrogryposis multiplex congenita, distal, type 2B MIM#601680
Fetal anomalies v0.2835 TNNI2 Zornitza Stark changed review comment from: Gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility demonstrated for at least two variants.; to: Gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility demonstrated for at least two variants.

Perinatal presentation.
Fetal anomalies v0.2835 TNNT1 Zornitza Stark Marked gene: TNNT1 as ready
Fetal anomalies v0.2832 ACAN Zornitza Stark Phenotypes for gene: ACAN were changed from SPONDYLOEPIMETAPHYSEAL DYSPLASIA AGGRECAN TYPE; SPONDYLOEPIPHYSEAL DYSPLASIA TYPE KIMBERLEY to Spondyloepimetaphyseal dysplasia, aggrecan type, OMIM# 612813; Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, OMIM# 165800
Fetal anomalies v0.2830 NOVA2 Zornitza Stark Marked gene: NOVA2 as ready
Fetal anomalies v0.2825 NOVA2 Zornitza Stark changed review comment from: Six individuals with de novo frameshift variants resulting in C-terminal extension suggesting partial LoF as mechanism.
Sources: Literature; to: Six individuals with de novo frameshift variants resulting in C-terminal extension suggesting partial LoF as mechanism.

Structural brain abnormalities reported.


Sources: Literature
Fetal anomalies v0.2825 KIF26B Zornitza Stark Marked gene: KIF26B as ready
Fetal anomalies v0.2825 KIF26B Zornitza Stark gene: KIF26B was added
gene: KIF26B was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: KIF26B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF26B were set to 30151950
Phenotypes for gene: KIF26B were set to Progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis
Review for gene: KIF26B was set to RED
Added comment: 1 report only of infant with progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis secondary to the involvement of anterior horn cells and ventral (motor) nerves. Whole exome sequencing on the trio identified a de novo KIF26B missense variant (p.Gly546Ser). Functional analysis of the variant protein in cultured cells revealed a reduction in the KIF26B protein's ability to promote cell adhesion, a defect that potentially contributes to its pathogenicity.
Sources: Expert Review
Fetal anomalies v0.2824 ACP5 Alison Yeung Marked gene: ACP5 as ready
Fetal anomalies v0.2823 ACAN Alison Yeung Marked gene: ACAN as ready
Fetal anomalies v0.2823 ACAN Alison Yeung reviewed gene: ACAN: Rating: GREEN; Mode of pathogenicity: None; Publications: 24762113, 27870580, 19110214, 30124491, 28331218, 20137779; Phenotypes: Spondyloepimetaphyseal dysplasia, aggrecan type, OMIM# 612813, Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, OMIM# 165800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2823 SLC45A1 Zornitza Stark Marked gene: SLC45A1 as ready
Fetal anomalies v0.2820 SLC45A1 Zornitza Stark changed review comment from: Intellectual developmental disorder with neuropsychiatric features is an autosomal recessive disorder characterized by moderate intellectual disability, relatively mild seizures, and neuropsychiatric abnormalities, such as anxiety, obsessive-compulsive behavior, and autistic features. Mild facial dysmorphic features may also be present.

Two families reported and some functional data.; to: Intellectual developmental disorder with neuropsychiatric features is an autosomal recessive disorder characterized by moderate intellectual disability, relatively mild seizures, and neuropsychiatric abnormalities, such as anxiety, obsessive-compulsive behavior, and autistic features. Mild facial dysmorphic features may also be present.

Two families reported and some functional data.

Clinical presentation is typically post-natal.
Fetal anomalies v0.2820 SLC35A1 Zornitza Stark Marked gene: SLC35A1 as ready
Fetal anomalies v0.2818 SLC35A1 Zornitza Stark changed review comment from: Three unrelated families reported.; to: Three unrelated families reported, variable severity, including onset. Microcephaly reported, but onset uncertain.
Fetal anomalies v0.2818 PAX7 Zornitza Stark Marked gene: PAX7 as ready
Fetal anomalies v0.2817 PAX7 Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: Progressive disorder, onset in infancy.
Fetal anomalies v0.2817 DNAH2 Zornitza Stark Marked gene: DNAH2 as ready
Fetal anomalies v0.2817 DNAH2 Zornitza Stark Phenotypes for gene: DNAH2 were changed from Hydrops; Complex cardiopathy to Hydrops; complex congenital heart disease; heterotaxy
Fetal anomalies v0.2816 TSPAN7 Zornitza Stark Marked gene: TSPAN7 as ready
Fetal anomalies v0.2816 TSPAN7 Zornitza Stark Phenotypes for gene: TSPAN7 were changed from MENTAL RETARDATION X-LINKED TYPE 58 to Intellectual developmental disorder, X-linked 58, MIM# 300210
Fetal anomalies v0.2813 TOGARAM1 Zornitza Stark Marked gene: TOGARAM1 as ready
Fetal anomalies v0.2813 TOGARAM1 Zornitza Stark Gene: togaram1 has been classified as Red List (Low Evidence).
Fetal anomalies v0.2810 MEGF8 Zornitza Stark Marked gene: MEGF8 as ready
Fetal anomalies v0.2810 MEGF8 Zornitza Stark Phenotypes for gene: MEGF8 were changed from CARPENTER SYNDROME to Carpenter syndrome 2, MIM #614976
Fetal anomalies v0.2808 MEF2C Zornitza Stark Marked gene: MEF2C as ready
Fetal anomalies v0.2808 MEF2C Zornitza Stark Phenotypes for gene: MEF2C were changed from MENTAL RETARDATION-STEREOTYPIC MOVEMENTS-EPILEPSY AND/OR CEREBRAL MALFORMATIONS to Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations, MIM# 613443; MONDO:0013266
Fetal anomalies v0.2805 MED12 Zornitza Stark Marked gene: MED12 as ready
Fetal anomalies v0.2803 MCPH1 Zornitza Stark Marked gene: MCPH1 as ready
Fetal anomalies v0.2803 MCPH1 Zornitza Stark Phenotypes for gene: MCPH1 were changed from MICROCEPHALY PRIMARY TYPE 1 to Microcephaly 1, primary, autosomal recessive, MIM# 251200
Fetal anomalies v0.2801 MCPH1 Zornitza Stark changed review comment from: Well established primary micorcephaly gene.

Sources: Literature; to: Well established primary microcephaly gene.

Sources: Literature
Fetal anomalies v0.2801 MCPH1 Zornitza Stark changed review comment from: Single individual reported as part of a CDH cohort.
Sources: Literature; to: Well established primary micorcephaly gene.

Sources: Literature
Fetal anomalies v0.2801 MCPH1 Zornitza Stark edited their review of gene: MCPH1: Changed rating: GREEN; Changed phenotypes: Microcephaly 1, primary, autosomal recessive, MIM# 251200
Fetal anomalies v0.2801 MCOLN1 Zornitza Stark Marked gene: MCOLN1 as ready
Fetal anomalies v0.2799 MATN3 Zornitza Stark Marked gene: MATN3 as ready
Fetal anomalies v0.2797 MASP1 Zornitza Stark Marked gene: MASP1 as ready
Fetal anomalies v0.2795 MAPRE2 Zornitza Stark Marked gene: MAPRE2 as ready
Fetal anomalies v0.2793 MAPRE2 Zornitza Stark changed review comment from: ID is part of the phenotype, more severe in those with bi-allelic variants.
Sources: Expert list; to: Cleft palate and microcephaly reported.

Sources: Expert list
Fetal anomalies v0.2793 MAP2K2 Zornitza Stark Marked gene: MAP2K2 as ready
Fetal anomalies v0.2793 MAP2K2 Zornitza Stark Phenotypes for gene: MAP2K2 were changed from CARDIOFACIOCUTANEOUS SYNDROME to Cardiofaciocutaneous syndrome 4, MIM# 615280
Fetal anomalies v0.2791 MAP2K2 Zornitza Stark Mode of pathogenicity for gene: MAP2K2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.2789 MAP2K1 Zornitza Stark Marked gene: MAP2K1 as ready
Fetal anomalies v0.2789 MAP2K1 Zornitza Stark Phenotypes for gene: MAP2K1 were changed from CARDIOFACIOCUTANEOUS SYNDROME to Cardiofaciocutaneous syndrome 3, MIM# 615279
Fetal anomalies v0.2787 MAP2K1 Zornitza Stark Mode of pathogenicity for gene: MAP2K1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.2785 MAGEL2 Zornitza Stark Marked gene: MAGEL2 as ready
Fetal anomalies v0.2785 MAGEL2 Zornitza Stark Phenotypes for gene: MAGEL2 were changed from ARTHROGRYPOSIS MULTIPLEX CONGENITA; Schaaf-Yang syndrome, 615547; Schaaf-Yang syndrome to Schaaf-Yang syndrome, MIM# 615547
Fetal anomalies v0.2783 MAB21L2 Zornitza Stark Marked gene: MAB21L2 as ready
Fetal anomalies v0.2781 LZTR1 Zornitza Stark Marked gene: LZTR1 as ready
Fetal anomalies v0.2778 LZTFL1 Zornitza Stark Marked gene: LZTFL1 as ready
Fetal anomalies v0.2778 LZTFL1 Zornitza Stark Phenotypes for gene: LZTFL1 were changed from Bardet-Biedl syndrome 17 615994 to Bardet-Biedl syndrome 17, MIM# 615994
Fetal anomalies v0.2776 LYST Zornitza Stark Marked gene: LYST as ready
Fetal anomalies v0.2774 LRRC6 Zornitza Stark Marked gene: LRRC6 as ready
Fetal anomalies v0.2774 LRRC6 Zornitza Stark Phenotypes for gene: LRRC6 were changed from PRIMARY CILIARY DISKINESIA to Ciliary dyskinesia, primary, 19, MIM# 614935
Fetal anomalies v0.2772 LRP5 Zornitza Stark Marked gene: LRP5 as ready
Fetal anomalies v0.2770 LRP5 Zornitza Stark changed review comment from: ID generally normal in all of these conditions.; to: Variants in this gene are associated with multiple disorders. Some have congenital anomalies as a feature.
Fetal anomalies v0.2770 LRP2 Zornitza Stark Marked gene: LRP2 as ready
Fetal anomalies v0.2770 LRP2 Zornitza Stark Phenotypes for gene: LRP2 were changed from DONNAI-BARROW SYNDROME to Donnai-Barrow syndrome, MIM# 222448
Fetal anomalies v0.2769 LMX1B Zornitza Stark Marked gene: LMX1B as ready
Fetal anomalies v0.2766 LMX1B Zornitza Stark changed review comment from: Nail-patella syndrome (NPS) is an autosomal-dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Varying degrees of proteinuria or hematuria are present, and can occasionally progress to chronic renal failure. >300 families reported.; to: Nail-patella syndrome (NPS) is an autosomal-dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Varying degrees of proteinuria or hematuria are present, and can occasionally progress to chronic renal failure. >300 families reported.

Prenatal presentations with abnormal limb movement reported.
Fetal anomalies v0.2766 LMOD3 Zornitza Stark Marked gene: LMOD3 as ready
Fetal anomalies v0.2764 LMNA Zornitza Stark Marked gene: LMNA as ready
Fetal anomalies v0.2764 LMNA Zornitza Stark Phenotypes for gene: LMNA were changed from LETHAL TIGHT SKIN CONTRACTURE SYNDROME; CARDIOMYOPATHY DILATED WITH HYPERGONADOTROPIC HYPOGONADISM; FAMILIAL PARTIAL LIPODYSTROPHY TYPE 2; HUTCHINSON-GILFORD PROGERIA SYNDROME; EMERY-DREIFUSS MUSCULAR DYSTROPHY TYPE 2; MUSCULAR DYSTROPHY CONGENITAL LMNA-RELATED; CHARCOT-MARIE-TOOTH DISEASE TYPE 2B1; MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY; HEART-HAND SYNDROME SLOVENIAN TYPE; CARDIOMYOPATHY DILATED TYPE 1A; LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 1B to Restrictive dermopathy, lethal, MIM# 275210; Mandibuloacral dysplasia, MIM# 248370
Fetal anomalies v0.2763 LMNA Zornitza Stark edited their review of gene: LMNA: Added comment: Variants in this gene are associated with multiple phenotypes. The more severe end of the spectrum may present antenatally.; Changed rating: GREEN; Changed phenotypes: Restrictive dermopathy, lethal, MIM# 275210, Mandibuloacral dysplasia, MIM# 248370; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2763 LMBRD1 Zornitza Stark Marked gene: LMBRD1 as ready
Fetal anomalies v0.2761 LMBR1 Zornitza Stark Marked gene: LMBR1 as ready
Fetal anomalies v0.2760 LMBR1 Zornitza Stark changed review comment from: Radial aplasia but with ulnar dimelia. Reported microduplications in LMBR1 associated with Laurin-Sandrow syndrome are in the SHH regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene. Duplications are >10kb.
Sources: Expert list; to: Variants are associated with multiple types of limb anomalies.

Note that the reported microduplications in LMBR1 associated with Laurin-Sandrow syndrome are in the SHH regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene. Duplications are >10kb.
Sources: Expert list
Fetal anomalies v0.2760 ISPD Zornitza Stark Marked gene: ISPD as ready
Fetal anomalies v0.2760 ISPD Zornitza Stark Phenotypes for gene: ISPD were changed from WALKER WARBURG SYNDROME to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7, MIM# 614643
Fetal anomalies v0.2758 ERGIC1 Zornitza Stark Marked gene: ERGIC1 as ready
Fetal anomalies v0.2757 ERBB3 Zornitza Stark Marked gene: ERBB3 as ready
Fetal anomalies v0.2756 ERGIC1 Krithika Murali gene: ERGIC1 was added
gene: ERGIC1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ERGIC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERGIC1 were set to 28317099; 34037256; 31230720
Phenotypes for gene: ERGIC1 were set to Arthrogryposis multiplex congenita 2, neurogenic type; OMIM # 208100
Review for gene: ERGIC1 was set to GREEN
Added comment: Recent Panelapp review by Z. Stark Oct 2021 - no new publications since

---

Pehlivan et al. 2019 (PMID:31230720) identified the third case of arthrogryposis in a child who harboured a previously unreported homozygous variant (c.782G>A; p.Gly261Asp) in this gene. Parents were heterozygous carriers. Functional studies were not performed.
Created: 14 Oct 2021, 7:23 a.m. | Last Modified: 14 Oct 2021, 7:23 a.m.
Panel Version: 0.9373

Reinstein et al. (2018) used WES in a large consanguineous Israeli Arab kindred consisting of 16 patients affected with the neurogenic type of arthrogryposis multiplex congenita. They identified a homozygous missense (V98E) mutation in ERGIC1 gene, which segregated with the disorder in the kindred, and was not found in the ExAC database or in 212 ethnically matched controls. Functional studies of the variant and studies of patient cells were not performed. ERGIC1 encodes a cycling membrane protein which has a possible role in transport between endoplasmic reticulum and Golgi.

Marconi et al (2021) used genome sequencing in a consanguineous family with 2 affected siblings presenting congenital arthrogryposis and some facial dysmorphism. They identified a homozygous 22.6 Kb deletion encompassing the promoter and first exon of ERGIC1. mRNA quantification showed the complete absence of ERGIC1 expression in the two affected siblings and a decrease in heterozygous parents.
Sources: Literature
Sources: Literature
Fetal anomalies v0.2756 ERBB3 Krithika Murali gene: ERBB3 was added
gene: ERBB3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ERBB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERBB3 were set to 31752936; 17701904; 33720042
Phenotypes for gene: ERBB3 were set to Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease (HSCR, aganglionic megacolon) MIM#142623
Review for gene: ERBB3 was set to GREEN
Added comment: Biallelic variants associated with multi-system disorder, including gut dysmotility/Hirschsprung disease; with or without contractures.
--

PMID 33497358: 6 individuals from 4 unrelated families reported with severe gut dysmotility and other features of neurocristinopathy including short-segment HSCR, progressive axonal peripheral neuropathy, dysautonomia, hypopigmentation, deafness. Note variants in this gene have also recently been linked to Hirschsprung's disease.

PMID 17701904: Lethal congenital contractual syndrome: Two families reported with contractures, positional approach used in gene discovery (2007).

PMID 33720042 - Seven variants (missense and frameshfit) from four independent families with Hirschsprung disease (HSCR) reported. All reported individuals variably associated with conditions such as HSCR, chronic intestinal pseudo-obstruction, peripheral neuropathy, and arthrogryposis. Functional study revealed mutant proteins reduced protein expression or altered phosphorylation of the mutant receptors.
Sources: Literature
Fetal anomalies v0.2756 INVS Zornitza Stark Marked gene: INVS as ready
Fetal anomalies v0.2754 INSR Zornitza Stark Marked gene: INSR as ready
Fetal anomalies v0.2753 INSR Zornitza Stark changed review comment from: ID is not part of the phenotype of Leprechaunism, and some of the individuals with Rabson-Mendenhall are described as 'mentally precocious'.; to: IUGR
Fetal anomalies v0.2753 INPP5E Zornitza Stark Marked gene: INPP5E as ready
Fetal anomalies v0.2753 INPP5E Zornitza Stark Phenotypes for gene: INPP5E were changed from MENTAL RETARDATION-TRUNCAL OBESITY-RETINAL DYSTROPHY-MICROPENIS; JOUBERT SYNDROME TYPE 1 to Joubert syndrome 1, MIM# 213300; MONDO:0008944
Fetal anomalies v0.2751 IKBKG Zornitza Stark Marked gene: IKBKG as ready
Fetal anomalies v0.2749 MED25 Zornitza Stark Marked gene: MED25 as ready
Fetal anomalies v0.2748 SHMT2 Zornitza Stark Marked gene: SHMT2 as ready
Fetal anomalies v0.2747 MAST1 Zornitza Stark Marked gene: MAST1 as ready
Fetal anomalies v0.2746 MAPK8IP3 Zornitza Stark Marked gene: MAPK8IP3 as ready
Fetal anomalies v0.2745 MAP1B Zornitza Stark Marked gene: MAP1B as ready
Fetal anomalies v0.2745 MAP1B Zornitza Stark Phenotypes for gene: MAP1B were changed from polymicrogyria; PVNH; Periventricular nodular heterotopia 9, MIM# 618918 to Polymicrogyria; Periventricular nodular heterotopia 9, MIM# 618918
Fetal anomalies v0.2743 ASTN1 Zornitza Stark Marked gene: ASTN1 as ready
Fetal anomalies v0.2741 PDE3A Zornitza Stark Marked gene: PDE3A as ready
Fetal anomalies v0.2740 HYAL1 Zornitza Stark Marked gene: HYAL1 as ready
Fetal anomalies v0.2740 HYAL1 Zornitza Stark Phenotypes for gene: HYAL1 were changed from MUCOPOLYSACCHARIDOSIS TYPE 9 to Mucopolysaccharidosis type IX, MIM# 601492; MONDO:0011093
Fetal anomalies v0.2738 FMN1 Zornitza Stark Marked gene: FMN1 as ready
Fetal anomalies v0.2737 HSD17B10 Zornitza Stark Marked gene: HSD17B10 as ready
Fetal anomalies v0.2737 HSD17B10 Zornitza Stark Phenotypes for gene: HSD17B10 were changed from 2-METHYL-3-HYDROXYBUTYRYL-COA DEHYDROGENASE DEFICIENCY; MENTAL RETARDATION SYNDROMIC X-LINKED TYPE 10 to HSD10 mitochondrial disease, MIM# 300438
Fetal anomalies v0.2735 HPGD Zornitza Stark Marked gene: HPGD as ready
Fetal anomalies v0.2735 HPGD Zornitza Stark Phenotypes for gene: HPGD were changed from CRANIOOSTEOARTHROPATHY to Hypertrophic osteoarthropathy, primary, autosomal recessive 1 MIM#259100; Cranioosteoarthropathy MIM#259100
Fetal anomalies v0.2733 FAT1 Zornitza Stark Marked gene: FAT1 as ready
Fetal anomalies v0.2732 GLMN Zornitza Stark Marked gene: GLMN as ready
Fetal anomalies v0.2730 GK Zornitza Stark Marked gene: GK as ready
Fetal anomalies v0.2729 MED25 Krithika Murali gene: MED25 was added
gene: MED25 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MED25 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED25 were set to 25792360; 32816121; 32816121; 32324310
Phenotypes for gene: MED25 were set to multiple congenital anomalies; congenital heart defects; hypospadias, thin corpus callosum, cerebral ventricular dilatation; Basel-Vanagait-Smirin-Yosef syndrome - #616449; Congenital cataract-microcephaly-naevus flammeus syndrome MONDO:0014643
Review for gene: MED25 was set to GREEN
Added comment: Multiple individuals reported - biallelic variants associated with severe syndromic neurodevelopmental disorder diagnosed from infancy.

PMID 32324310 - report one patient with antenatal ultrasound demonstrating cleft lip and clenched hands.

Additional features associated wtih this condition that may be diagnosed antenatally include cleft palate, cardiac septal defects, hypospadias, polymicrogyria, thin corpus callosum, microcephaly and cerebral ventricular dilatation.
Sources: Literature
Fetal anomalies v0.2729 GDI1 Zornitza Stark Marked gene: GDI1 as ready
Fetal anomalies v0.2729 GDI1 Zornitza Stark Phenotypes for gene: GDI1 were changed from MENTAL RETARDATION X-LINKED TYPE 41; MENTAL RETARDATION X-LINKED TYPE 48 to Intellectual developmental disorder, X-linked 41 MIM#300849
Fetal anomalies v0.2728 SHMT2 Krithika Murali gene: SHMT2 was added
gene: SHMT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Polymicrogyria; corpus callosum anomalies; Microcephaly; Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities - #619121
Review for gene: SHMT2 was set to GREEN
Added comment: Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities particularly thin corpus callosum and polymicrogyria (NEDCASB) associated with biallelic SHMT2 variants. Antenatal detection of microcephaly reported.

--
Detailed PanelApp review Oct 2020 - no new evidence to add

García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 with OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs.

Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones.

SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes.

While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.

Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect.

The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity).
Sources: Literature
Fetal anomalies v0.2728 MAST1 Krithika Murali gene: MAST1 was added
gene: MAST1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MAST1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST1 were set to 32818970; 32198973; 31721002; 30449657
Phenotypes for gene: MAST1 were set to Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations - #61827; corpus callosum anomalies; cortical malformations; cerebellar hypoplasia
Review for gene: MAST1 was set to GREEN
Added comment: Neurodevelopmental disorder with muscular hypotonia and varying brain anomalies which may be diagnosed antenatally.

Reported cases include x1 individual reported to have hydrocephalus antenatally (PMID 32818970). MRI-B at 17 months demonstrated polymicrogyria, hyperplastic corpus callosum, progressive pontine hypoplasia and enlarged ventricles.

Another female patient reported with antenatal findings of increased nuchal translucency in a pregnancy complicated by oligohydramnios, IUGR, pre-eclampsia and pre-term delivery at 32 weeks (PMID 32198973). Postnatally diagnosed with cortical malformations without cerebellar hypoplasia.

6 unrelated patients with mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCHCM) with de novo heterozygous mutations in MAST1 gene (30449657). In vitro functional studies showed that 1 of the variants (lys276del) increased MAST1 binding to microtubules compared to controls. Mutant mice heterozygous for a Mast1 leu278del allele showed a thicker corpus callosum compared to wildtype, and an overall reduction in cortical volume and thickness and decreased cerebellar volume and number of granule and Purkinje cells due to increased apoptosis compared to controls.

1 Emirati patient with ID, microcephaly, and dysmorphic features, with missense variant in MAST1 (30449657)
Sources: Literature
Fetal anomalies v0.2728 MAPK8IP3 Krithika Murali gene: MAPK8IP3 was added
gene: MAPK8IP3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK8IP3 were set to 30945334; 30612693
Phenotypes for gene: MAPK8IP3 were set to Neurodevelopmental disorder with or without variable brain abnormalities - #618443; cerebral atrophy; corpus callosum anomalies; polymicrogyria
Review for gene: MAPK8IP3 was set to GREEN
Added comment: 13 unrelated individuals and 5 individuals from 4 families identified with de novo heterozygous MAPK8IP3 variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy and hypoplasia of the corpus callosum consistently reported in affected individuals
Sources: Literature
Fetal anomalies v0.2728 MAP1B Krithika Murali gene: MAP1B was added
gene: MAP1B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP1B were set to 31317654; 33772511; 30150678; 30214071
Phenotypes for gene: MAP1B were set to polymicrogyria; PVNH; Periventricular nodular heterotopia 9, MIM# 618918
Review for gene: MAP1B was set to GREEN
Added comment: At least 5 families described with phenotypic features that include variable brain malformations potentially detectable antenatally.
Sources: Literature
Fetal anomalies v0.2728 GAMT Zornitza Stark Marked gene: GAMT as ready
Fetal anomalies v0.2727 NMNAT2 Zornitza Stark Marked gene: NMNAT2 as ready
Fetal anomalies v0.2725 NKX6-2 Zornitza Stark Marked gene: NKX6-2 as ready
Fetal anomalies v0.2722 ASTN1 Krithika Murali gene: ASTN1 was added
gene: ASTN1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ASTN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASTN1 were set to 29706646; 11861479
Phenotypes for gene: ASTN1 were set to Polymicrogyria; hypoplastic corpus callosum
Review for gene: ASTN1 was set to AMBER
Added comment: No OMIM gene disease association. No updated evidence since previous PanelApp review April 2020.

PMID 29706646 - Wiszniewski et al 2018 - genomic analysis of individuals with disorders of cortical development. Identified one individual with compound het ASTN1 variants with diffuse polymicrogyria, spastic tetraplegia, epilepsy and developmental delay. Second consanguineous family with two sisters with homozygous missense variant in ASTN1 had hypoplastic corpus callosum.

Animal model demonstrates abnormal neuronal migration in Astn1-/- deficient mice (PMID 11861479).
Sources: Literature
Fetal anomalies v0.2722 NECTIN1 Zornitza Stark Marked gene: NECTIN1 as ready
Fetal anomalies v0.2719 NDUFB11 Zornitza Stark Phenotypes for gene: NDUFB11 were changed from Mitochondrial complex I deficiency, nuclear type 30 MIM#301021 to Mitochondrial complex I deficiency, nuclear type 30 MIM#301021; Linear skin defects with multiple congenital anomalies 3, XLD (MIM#300952)
Fetal anomalies v0.2718 NDUFB11 Zornitza Stark Marked gene: NDUFB11 as ready
Fetal anomalies v0.2718 NDUFB11 Zornitza Stark Phenotypes for gene: NDUFB11 were changed from MICROPHTHALMIA WITH LINEAR SKIN DEFECTS SYNDROME to Mitochondrial complex I deficiency, nuclear type 30 MIM#301021
Fetal anomalies v0.2715 NAGLU Zornitza Stark Marked gene: NAGLU as ready
Fetal anomalies v0.2715 NAGLU Zornitza Stark Phenotypes for gene: NAGLU were changed from MUCOPOLYSACCHARIDOSIS TYPE 3B to Mucopolysaccharidosis type IIIB (Sanfilippo B), MIM# 252920
Fetal anomalies v0.2712 NAGLU Zornitza Stark reviewed gene: NAGLU: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucopolysaccharidosis type IIIB (Sanfilippo B), MIM# 252920; Mode of inheritance: None
Fetal anomalies v0.2712 HYAL1 Ain Roesley reviewed gene: HYAL1: Rating: RED; Mode of pathogenicity: None; Publications: Mucopolysaccharidosis type IX, MIM# 601492, MONDO:0011093; Phenotypes: 10339581, 18344557, 21559944; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2712 FMN1 Krithika Murali gene: FMN1 was added
gene: FMN1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FMN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FMN1 were set to 20610440; 19383632; 15202026
Phenotypes for gene: FMN1 were set to oligosyndactyly; radioulnar synostosis; hearing loss; renal defects
Review for gene: FMN1 was set to AMBER
Added comment: No OMIM gene-disease association. No additional evidence since last review of this gene in Sep 2021.

PMID 20610440 - a 263 Kb homozygous deletion of FMN1 reported in an individual with oligosyndactyly, radioulnar synostosis, hearing loss and renal defects. Supporting null mouse model with oligosyndactyly. A large duplication including FMN1 and GREM1 reported in another individual with Cenani–Lenz syndrome.
Sources: Literature
Fetal anomalies v0.2712 HPGD Ain Roesley reviewed gene: HPGD: Rating: RED; Mode of pathogenicity: None; Publications: 20406614, 32282352, 31878983, 29282707; Phenotypes: Hypertrophic osteoarthropathy, primary, autosomal recessive 1 MIM#259100, Cranioosteoarthropathy MIM#259100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2712 FAT1 Krithika Murali gene: FAT1 was added
gene: FAT1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAT1 were set to 30862798; 26905694; 34202629; 34013115; 33418956; 32902815
Phenotypes for gene: FAT1 were set to multiple congenital anomalies; nephropathy; ocular anomalies; hand and foot anomalies
Review for gene: FAT1 was set to GREEN
Added comment: No OMIM gene-disease association, but multiple affected individuals from unrelated families reported with biallelic FAT1 variants and syndromic features consisting of ocular anomalies, hand/foot malformations and nephropathy. Although diagnosis antenatally not yet reported, some phenotypic features are detectable antenatally.

PMID: 30862798 Larouchi et al 2019 - homozygous frameshift FAT1 variants identified in 10 affected individuals from 5 unrelated consanguineous families. The patients presented with syndromic features including ocular anomalies (ptosis, microphthalmia, coloboma, amblyopia), nephropathy (FSGS, proteinuria, haematuria), toe syndactyly and facial dysmorphism. Animal models showing that deletion of Fat1 leads to coloboma in mouse and zebrafish.

PMID 26905694 Gee et al 2016 – report recessive mutations in FAT1 in four unrelated consanguineous families with a combination of steroid-resistant nephrotic syndrome, tubular ectasia, haematuria and variable neurodevelopmental findings such ID, polymicrogyria and hydrocephalus. X1 child with pulmonary stenosis.

PMID: 34202629 Peluso et al 2021 – Homozygous FAT1 frameshift variant NM_005245.4:c.9729del identified in a child of consanguineous parents with bilateral anophthalmia and hand/foot malformations including - right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. Patient also had congenital heart defects including VSD, ASD and bicuspid aortic valve. Proband also had a microarray which detected a maternally inherited 350 kb 15q26.3 duplication including OMIM morbid gene CERS3 (AR condition) and part of the OMIM morbid gene ADAMTS17 (AR condition). Mother healthy, CNV unrelated to patient’s phenotype.

PMID: 34013115 Fabretti et al 2021 – report 4 patients with biallelic FAT1 variants from 3 unrelated families with syndactyly, ophthalmologic and renal phenotype consistent with previously reported cases.

PMID: 33418956 Haug et al 2021 - Genetic analysis showed that proband with phenotypic features consistent with other reported cases was compound heterozygous for a frameshift FAT1 variant and 1.8Mb 4q35.2 del including FAT1.

PMID: 32902815 Rossanti et al 2021 – Biallelic FAT1 variants reported in a child with isolated mild proteinuria and no syndromic features
Sources: Literature
Fetal anomalies v0.2712 ANGPT2 Zornitza Stark Marked gene: ANGPT2 as ready
Fetal anomalies v0.2711 ANGPT2 Zornitza Stark gene: ANGPT2 was added
gene: ANGPT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ANGPT2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: ANGPT2 were set to 34876502; 32908006
Phenotypes for gene: ANGPT2 were set to Hydrops; Lymphatic malformation-10, MIM#619369
Review for gene: ANGPT2 was set to GREEN
Added comment: Mono-allelic disease: association with lymphoedema in 5 unrelated individuals PMID 32908006

Bi-allelic disease PMID 34876502: single family reported with four fetuses with hydrops fetalis homozygous for ANGPT2 NM_001147.2:c.557A>G. The consanguineous parents and surviving sibblings (a girl and a boy), were heterozygous for this variant. This variant is predicted to create a cryptic exonic splice site, resulting in a r.557_566del and nonsense-mediated mRNA decay. This prediction was supported by the lack of a transcript from this allele in the parents.
Sources: Literature
Fetal anomalies v0.2710 IGF2 Zornitza Stark Marked gene: IGF2 as ready
Fetal anomalies v0.2708 IGF1R Zornitza Stark Marked gene: IGF1R as ready
Fetal anomalies v0.2706 IGF1 Zornitza Stark Marked gene: IGF1 as ready
Fetal anomalies v0.2706 IGF1 Zornitza Stark Phenotypes for gene: IGF1 were changed from INSULIN-LIKE GROWTH FACTOR I DEFICIENCY to Growth retardation with deafness and mental retardation due to IGF1 deficiency, MIM # 608747
Fetal anomalies v0.2703 IFT80 Zornitza Stark Marked gene: IFT80 as ready
Fetal anomalies v0.2701 IFT43 Zornitza Stark Marked gene: IFT43 as ready
Fetal anomalies v0.2699 IFT172 Zornitza Stark Marked gene: IFT172 as ready
Fetal anomalies v0.2699 IFT172 Zornitza Stark Phenotypes for gene: IFT172 were changed from JEUNE SYNDROME; MAINZER-SALDINO SYNDROME to Short-rib thoracic dysplasia 10 with or without polydactyly, MIM# 615630; Bardet-Biedl syndrome
Fetal anomalies v0.2697 IFT122 Zornitza Stark Marked gene: IFT122 as ready
Fetal anomalies v0.2695 IFITM5 Zornitza Stark Marked gene: IFITM5 as ready
Fetal anomalies v0.2692 IER3IP1 Zornitza Stark Marked gene: IER3IP1 as ready
Fetal anomalies v0.2692 IER3IP1 Zornitza Stark Phenotypes for gene: IER3IP1 were changed from Microcephaly, epilepsy, and diabetes syndrome 614231 to Microcephaly, epilepsy, and diabetes syndrome, MIM# 614231; Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome, MONDO:0013647
Fetal anomalies v0.2687 PAX8 Zornitza Stark changed review comment from: Typically presents post-natally.; to: Isolated congenital hypothyroidism typically presents post-natally.

However note PMID 33434492 reports 5 individuals identified in large cohorts with MRKHS and likely deleterious variants in PAX8. At least one of the individuals had congenital hypothyroidism together with features of MRKHS.
Fetal anomalies v0.2687 PAX8 Zornitza Stark Marked gene: PAX8 as ready
Fetal anomalies v0.2684 PAX6 Zornitza Stark Marked gene: PAX6 as ready
Fetal anomalies v0.2684 PAX6 Zornitza Stark Phenotypes for gene: PAX6 were changed from COLOBOMA OF OPTIC NERVE; FOVEAL HYPOPLASIA; ANIRIDIA CEREBELLAR ATAXIA AND MENTAL DEFICIENCY; PETERS ANOMALY; KERATITIS HEREDITARY; ANIRIDIA; BILATERAL OPTIC NERVE HYPOPLASIA to Microphthalmia; Coloboma, ocular, MIM# 120200
Fetal anomalies v0.2681 PAX3 Zornitza Stark Marked gene: PAX3 as ready
Fetal anomalies v0.2681 PAX3 Zornitza Stark Phenotypes for gene: PAX3 were changed from CRANIOFACIAL-DEAFNESS-HAND SYNDROME; WAARDENBURG SYNDROME, TYPE 1 to Craniofacial-deafness-hand syndrome, MIM#122880; Waardenburg syndrome, type 1, MIM#193500; Waardenburg syndrome, type 3, MIM#148820
Fetal anomalies v0.2679 PAX3 Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: Skeletal abnormalities are part of the phenotype.
Fetal anomalies v0.2679 PAPSS2 Zornitza Stark Marked gene: PAPSS2 as ready
Fetal anomalies v0.2677 PALB2 Zornitza Stark Marked gene: PALB2 as ready
Fetal anomalies v0.2676 PAK3 Zornitza Stark Marked gene: PAK3 as ready
Fetal anomalies v0.2676 PAK3 Zornitza Stark changed review comment from: Well established gene-disease association, over 20 families reported.

PMID: 31943058 (2020) - Animal mouse model with a hemizygous variant (p.R67C) in the Pak3 gene, recapitulated some features of the human ID phenotype. Mutant male mice exhibited impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. Analysing critical periods of hippocampal neurogenesis revealed dysfunctional maturation and learning-associated recruitment, as well as accelerated death of selective populations of adult-born hippocampal neurons - offering a possible mechanism to the observed cognitive impairments.; to: Well established gene-disease association, over 20 families reported. Prenatal presentation with agenesis of corpus callosum reported, PMID 31843706.

PMID: 31943058 (2020) - Animal mouse model with a hemizygous variant (p.R67C) in the Pak3 gene, recapitulated some features of the human ID phenotype. Mutant male mice exhibited impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. Analysing critical periods of hippocampal neurogenesis revealed dysfunctional maturation and learning-associated recruitment, as well as accelerated death of selective populations of adult-born hippocampal neurons - offering a possible mechanism to the observed cognitive impairments.
Fetal anomalies v0.2676 PAK3 Zornitza Stark Phenotypes for gene: PAK3 were changed from AGENESIS OF THE CORPUS CALLOSUM; MENTAL RETARDATION X-LINKED TYPE 30 to Mental retardation, X-linked 30/47, MIM# 300558; Agenesis of the corpus callosum
Fetal anomalies v0.2674 PAFAH1B1 Zornitza Stark Marked gene: PAFAH1B1 as ready
Fetal anomalies v0.2674 PAFAH1B1 Zornitza Stark Phenotypes for gene: PAFAH1B1 were changed from SUBCORTICAL BAND HETEROTOPIA; LISSENCEPHALY TYPE 1 to Lissencephaly 1, MIM# 607432; Subcortical laminar heterotopia, MIM# 607432; MONDO:0011830
Fetal anomalies v0.2671 OTX2 Zornitza Stark Marked gene: OTX2 as ready
Fetal anomalies v0.2668 ORC6 Zornitza Stark Marked gene: ORC6 as ready
Fetal anomalies v0.2667 ORC4 Zornitza Stark Marked gene: ORC4 as ready
Fetal anomalies v0.2666 ORC1 Zornitza Stark Marked gene: ORC1 as ready
Fetal anomalies v0.2665 NDUFB11 Ain Roesley reviewed gene: NDUFB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 30423443, 25772934, 28050600); Phenotypes: Mitochondrial complex I deficiency, nuclear type 30 MIM#301021; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Fetal anomalies v0.2665 NAGLU Ain Roesley reviewed gene: NAGLU: Rating: AMBER; Mode of pathogenicity: None; Publications: 8650226; Phenotypes: Mucopolysaccharidosis type IIIB (Sanfilippo B), MIM# 252920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2665 WNT5A Zornitza Stark changed review comment from: LD/ID reported in ~20% according to this cohort/literature review.; to: Robinow syndrome is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies.
Fetal anomalies v0.2665 WNT7A Zornitza Stark changed review comment from: Although WNT7A-related conditions cause ulnar abnormalities, include in this panel due to phenotypic overlap (single forearm bone may be difficult to distinguish, particularly in non-specialist setting).
Sources: Expert list; to: Limb anomalies.


Sources: Expert list
Fetal anomalies v0.2665 ZNF462 Zornitza Stark changed review comment from: 1 family (4 affected members), Weiss et al. (2017) identified a heterozygous nonsense ZNF462 mutation.
3 additional unrelated patients with a similar phenotype with heterozygous ZNF462 mutations.
14 unrelated patients with WSKA, Kruszka et al. (2019) identified heterozygous loss-of-function ZNF462 mutations.; to: 1 family (4 affected members), Weiss et al. (2017) identified a heterozygous nonsense ZNF462 mutation.
3 additional unrelated patients with a similar phenotype with heterozygous ZNF462 mutations.
14 unrelated patients with WSKA, Kruszka et al. (2019) identified heterozygous loss-of-function ZNF462 mutations.

Multiple congenital anomalies syndrome.
Fetal anomalies v0.2665 FOXL2 Zornitza Stark Marked gene: FOXL2 as ready
Fetal anomalies v0.2665 FOXL2 Zornitza Stark Phenotypes for gene: FOXL2 were changed from BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS SYNDROME to Blepharophimosis, epicanthus inversus, and ptosis, type 1 with premature ovarian insufficiency (POI) and type II without POI (MIM# 110100)
Fetal anomalies v0.2661 FN1 Zornitza Stark Marked gene: FN1 as ready
Fetal anomalies v0.2658 FMN2 Zornitza Stark Marked gene: FMN2 as ready
Fetal anomalies v0.2655 HAND1 Zornitza Stark Marked gene: HAND1 as ready
Fetal anomalies v0.2655 HAND1 Zornitza Stark Phenotypes for gene: HAND1 were changed from Congenital heart defects to Congenital heart disease, MONDO:0005453
Fetal anomalies v0.2650 FKBP8 Zornitza Stark Marked gene: FKBP8 as ready
Fetal anomalies v0.2648 FKBP10 Zornitza Stark Marked gene: FKBP10 as ready
Fetal anomalies v0.2646 FGF9 Zornitza Stark Marked gene: FGF9 as ready
Fetal anomalies v0.2642 FAM46A Zornitza Stark Marked gene: FAM46A as ready
Fetal anomalies v0.2640 DYNC1I1 Zornitza Stark Marked gene: DYNC1I1 as ready
Fetal anomalies v0.2639 GATA5 Zornitza Stark Marked gene: GATA5 as ready
Fetal anomalies v0.2639 GATA5 Zornitza Stark Phenotypes for gene: GATA5 were changed from Congenital heart defects, multiple types, 5 - #617912 to Congenital heart defects, multiple types, 5 - MIM#617912
Fetal anomalies v0.2636 MYPN Zornitza Stark Marked gene: MYPN as ready
Fetal anomalies v0.2633 MYOD1 Zornitza Stark Marked gene: MYOD1 as ready
Fetal anomalies v0.2632 MYO18B Zornitza Stark Marked gene: MYO18B as ready
Fetal anomalies v0.2630 MYLK Zornitza Stark Marked gene: MYLK as ready
Fetal anomalies v0.2629 MYL9 Zornitza Stark Marked gene: MYL9 as ready
Fetal anomalies v0.2626 MSTO1 Zornitza Stark Marked gene: MSTO1 as ready
Fetal anomalies v0.2623 MED13L Zornitza Stark Marked gene: MED13L as ready
Fetal anomalies v0.2623 MED13L Zornitza Stark Phenotypes for gene: MED13L were changed from INTELLECTUAL DISABILITY to Impaired intellectual development and distinctive facial features with or without cardiac defects MIM#616789
Fetal anomalies v0.2619 MED13L Zornitza Stark reviewed gene: MED13L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Impaired intellectual development and distinctive facial features with or without cardiac defects MIM#616789; Mode of inheritance: None
Fetal anomalies v0.2619 MECR Zornitza Stark Marked gene: MECR as ready
Fetal anomalies v0.2616 MECOM Zornitza Stark Marked gene: MECOM as ready
Fetal anomalies v0.2616 MECOM Zornitza Stark Phenotypes for gene: MECOM were changed from Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia to Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 MIM#616738
Fetal anomalies v0.2612 MDH2 Zornitza Stark Marked gene: MDH2 as ready
Fetal anomalies v0.2612 MDH2 Zornitza Stark Phenotypes for gene: MDH2 were changed from Early-Onset Severe Encephalopathy to Developmental and epileptic encephalopathy 51 MIM#617339
Fetal anomalies v0.2609 FOXH1 Zornitza Stark Marked gene: FOXH1 as ready
Fetal anomalies v0.2607 MBOAT7 Zornitza Stark Marked gene: MBOAT7 as ready
Fetal anomalies v0.2605 MAT1A Zornitza Stark Marked gene: MAT1A as ready
Fetal anomalies v0.2601 MAP3K7 Zornitza Stark Marked gene: MAP3K7 as ready
Fetal anomalies v0.2598 MAP3K20 Zornitza Stark Marked gene: MAP3K20 as ready
Fetal anomalies v0.2597 MAP3K20 Zornitza Stark reviewed gene: MAP3K20: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Centronuclear myopathy 6 with fiber-type disproportion MIM#617760, Split-foot malformation with mesoaxial polydactyly MIM#616890; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2597 SCUBE3 Zornitza Stark Marked gene: SCUBE3 as ready
Fetal anomalies v0.2597 HAND2 Krithika Murali edited their review of gene: HAND2: Added comment: No OMIM gene disease association. Borderline red-amber gene.

PMID: 26676105 Lu et al 2016 - 145 unrelated patients with CHD, Han Chinese descent versus 200 unrelated controls had HAND2 gene sequencing. In x1 patient with ToF hetrozygous HAND2 c.140T>C p.L47P variant identified, parents unaffected, variant reported to be de novo but paternity not confirmed. Absent from gnomad, x1 het synonymous variant in this position only. Functional analysis showed reduced transcriptional activity

PMID: 32134193 Cohen et al 2020 - 31-month-old male with unicommissural unicuspid aortic valve, moderate aortic stenosis, and mild pulmonic stenosis. CMA identified 546kb deletion on chr 4q34.1 (174364195-174910239[GRCh37/hg19]). Deletion encompasses exons 1 and 2 of SCRG1, HAND2, and HAND2-AS1. Deletion paternally inherited - proband's father had history of ToF. Novel deletion - no similar deletions in Decipher or DGV. Proband also had CHD7 VUS (c.2830C>T, p.Arg944Cys) – but no features of CHARGE syndrome and CHD7 variant present in 7 hets in gnomad

PMID: 30217752 Liu et al 2019 - screened 206 unrelated Han Chinese patients with adult-onset idiopathic DCM and 300 unrelated controls. Identified HAND2 variant c.199G>T; p.(Glu67*). Authors report segregation of the variant with other affected individuals in the family including x2 with VSD/PDA

PMID: 26865696 Sun et al 2016 - HAND2 sequenced in 192 unrelated Han Chinese patient. Het p.S65I variant identified in a patient with VSD and present in all 7 family members with CHD and absent from 13 unaffected members.
Variant present in gnomad – 3 hets (x1 East Asian, x1 South Asian, x1 Latin American)

PMID 20819618 - Shen et al 2010 131 unrelated Han Chinese patients with ToF had HAND2 gene sequencing. Het c.32C>G p.Pro11Arg identified in x2 unrelated patients – no seg, not in gnomad but in area of low coverage.
c.42C>T – present in x1 patient with ToF + VSD – no segregation data, not in gnomad but in area of low coverage; Changed rating: AMBER; Changed publications: 26865696, 32134193, 26676105, 30217752, 20819618
Fetal anomalies v0.2597 SCYL1 Zornitza Stark Marked gene: SCYL1 as ready
Fetal anomalies v0.2597 SCYL1 Zornitza Stark Phenotypes for gene: SCYL1 were changed from Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia to Spinocerebellar ataxia, autosomal recessive 21, MIM# 616719
Fetal anomalies v0.2596 SHANK2 Zornitza Stark Marked gene: SHANK2 as ready
Fetal anomalies v0.2594 SHROOM3 Zornitza Stark Marked gene: SHROOM3 as ready
Fetal anomalies v0.2590 SIN3A Zornitza Stark Marked gene: SIN3A as ready
Fetal anomalies v0.2587 SLC20A1 Zornitza Stark Marked gene: SLC20A1 as ready
Fetal anomalies v0.2587 SLC25A19 Zornitza Stark Marked gene: SLC25A19 as ready
Fetal anomalies v0.2584 SMS Zornitza Stark Marked gene: SMS as ready
Fetal anomalies v0.2584 SRP54 Zornitza Stark Marked gene: SRP54 as ready
Fetal anomalies v0.2583 STX1B Zornitza Stark Marked gene: STX1B as ready
Fetal anomalies v0.2582 SYN1 Zornitza Stark Marked gene: SYN1 as ready
Fetal anomalies v0.2582 SYN1 Zornitza Stark Phenotypes for gene: SYN1 were changed from EPILEPSY, X-LINKED, WITH VARIABLE LEARNING DISABILITIES AND BEHAVIOR DISORDERS to Epilepsy, X-linked, with variable learning disabilities and behaviour disorders, MIM# 300491; Intellectual developmental disorder, X-linked 50, MIM# 300115
Fetal anomalies v0.2581 SZT2 Zornitza Stark Marked gene: SZT2 as ready
Fetal anomalies v0.2579 SPTAN1 Zornitza Stark Marked gene: SPTAN1 as ready
Fetal anomalies v0.2579 SPTAN1 Zornitza Stark Phenotypes for gene: SPTAN1 were changed from EPILEPTIC ENCEPHALOPATHY EARLY INFANTILE TYPE 5 to Developmental and epileptic encephalopathy 5, MIM# 613477
Fetal anomalies v0.2576 EXOC3L2 Zornitza Stark Marked gene: EXOC3L2 as ready
Fetal anomalies v0.2574 EXPH5 Zornitza Stark Marked gene: EXPH5 as ready
Fetal anomalies v0.2571 ELMO2 Zornitza Stark Marked gene: ELMO2 as ready
Fetal anomalies v0.2571 ELMO2 Zornitza Stark Phenotypes for gene: ELMO2 were changed from Intraosseous Vascular Malformation to Vascular malformation, primary intraosseous, MIM# 606893
Fetal anomalies v0.2570 DCC Zornitza Stark Marked gene: DCC as ready
Fetal anomalies v0.2567 TAC3 Zornitza Stark Marked gene: TAC3 as ready
Fetal anomalies v0.2566 TNFRSF13B Zornitza Stark Marked gene: TNFRSF13B as ready
Fetal anomalies v0.2565 TNFRSF13B Zornitza Stark Phenotypes for gene: TNFRSF13B were changed from IMMUNODEFICIENCY, COMMON VARIABLE, 2 to Immunodeficiency, common variable, 2, MIM# 240500
Fetal anomalies v0.2564 NXN Zornitza Stark Marked gene: NXN as ready
Fetal anomalies v0.2563 SNX10 Zornitza Stark Marked gene: SNX10 as ready
Fetal anomalies v0.2563 SOX11 Zornitza Stark Marked gene: SOX11 as ready
Fetal anomalies v0.2563 SOX11 Zornitza Stark Phenotypes for gene: SOX11 were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 to Coffin-Siris syndrome 9, OMIM # 615866
Fetal anomalies v0.2560 MEOX1 Zornitza Stark Marked gene: MEOX1 as ready
Fetal anomalies v0.2559 OTUD6B Zornitza Stark Marked gene: OTUD6B as ready
Fetal anomalies v0.2557 SGCG Zornitza Stark Marked gene: SGCG as ready
Fetal anomalies v0.2557 SLC6A17 Zornitza Stark Marked gene: SLC6A17 as ready
Fetal anomalies v0.2557 SLC6A17 Zornitza Stark Phenotypes for gene: SLC6A17 were changed from MENTAL RETARDATION, AUTOSOMAL RECESSIVE 48 to Mental retardation, autosomal recessive 48, MIM# 616269
Fetal anomalies v0.2556 RAB33B Zornitza Stark Marked gene: RAB33B as ready
Fetal anomalies v0.2556 SERPINH1 Zornitza Stark Marked gene: SERPINH1 as ready
Fetal anomalies v0.2554 SERPINF1 Zornitza Stark Marked gene: SERPINF1 as ready
Fetal anomalies v0.2554 POLR3A Zornitza Stark Marked gene: POLR3A as ready
Fetal anomalies v0.2551 POLR3B Zornitza Stark Marked gene: POLR3B as ready
Fetal anomalies v0.2551 PYCR2 Zornitza Stark Marked gene: PYCR2 as ready
Fetal anomalies v0.2550 PITX1 Zornitza Stark Marked gene: PITX1 as ready
Fetal anomalies v0.2548 FEZF1 Zornitza Stark Marked gene: FEZF1 as ready
Fetal anomalies v0.2547 FEZF1 Zornitza Stark Marked gene: FEZF1 as ready
Fetal anomalies v0.2546 NAXE Zornitza Stark Marked gene: NAXE as ready
Fetal anomalies v0.2546 NAXE Zornitza Stark Phenotypes for gene: NAXE were changed from Lethal Neurometabolic Disorder of Early Childhood to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy , MIM#617186
Fetal anomalies v0.2545 TRMT10C Zornitza Stark Marked gene: TRMT10C as ready
Fetal anomalies v0.2542 PBX1 Zornitza Stark Marked gene: PBX1 as ready
Fetal anomalies v0.2540 PFKM Zornitza Stark Marked gene: PFKM as ready
Fetal anomalies v0.2539 TRPM7 Zornitza Stark changed review comment from: 4 variants identified in a stillbirth cohort. Some supportive evidence that these variants alter channel function.; to: 4 variants identified in a stillbirth cohort.

Ion channel expressed in the nervous and cardiac systems. The variant associated with ALS/dementia in the Guam population, p.Thr1482Ile is present in >23,000 hets in gnomad, which is out of keeping for a rare Mendelian disorder. Note recent publication associating missense variants with cardiac arrhythmia and stillbirth, with some functional data provided to substantiate effect of variant on protein function but not necessarily establish gene-disease association.
Fetal anomalies v0.2539 TRPM7 Zornitza Stark Marked gene: TRPM7 as ready
Fetal anomalies v0.2539 TRPM7 Zornitza Stark reviewed gene: TRPM7: Rating: RED; Mode of pathogenicity: None; Publications: 31423533; Phenotypes: Arrhythmia, stillbirth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.2539 PTH Zornitza Stark Marked gene: PTH as ready
Fetal anomalies v0.2539 PTH Zornitza Stark Phenotypes for gene: PTH were changed from FAMILIAL ISOLATED HYPOPARATHYROIDISM to Hypoparathyroidism, familial isolated 1, MIM# 146200
Fetal anomalies v0.2538 SET Zornitza Stark Marked gene: SET as ready
Fetal anomalies v0.2538 SET Zornitza Stark Phenotypes for gene: SET were changed from SET syndrome to Mental retardation, autosomal dominant 58, MIM# 618106
Fetal anomalies v0.2537 SPARC Zornitza Stark Marked gene: SPARC as ready
Fetal anomalies v0.2537 SPARC Zornitza Stark Gene: sparc has been classified as Red List (Low Evidence).
Fetal anomalies v0.2537 MESD Zornitza Stark Marked gene: MESD as ready
Fetal anomalies v0.2537 NUAK2 Zornitza Stark Marked gene: NUAK2 as ready
Fetal anomalies v0.2535 FZD2 Zornitza Stark Marked gene: FZD2 as ready
Fetal anomalies v0.2533 TRPV3 Zornitza Stark Marked gene: TRPV3 as ready
Fetal anomalies v0.2532 TSFM Zornitza Stark Marked gene: TSFM as ready
Fetal anomalies v0.2531 TUBB3 Zornitza Stark Marked gene: TUBB3 as ready
Fetal anomalies v0.2531 TUBB3 Zornitza Stark Phenotypes for gene: TUBB3 were changed from CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 1; CONGENITAL FIBROSIS OF THE EXTRAOCULAR MUSCLES to Cortical dysplasia, complex, with other brain malformations 1, OMIM # 614039
Fetal anomalies v0.2528 TUBG1 Zornitza Stark Marked gene: TUBG1 as ready
Fetal anomalies v0.2526 VDR Zornitza Stark Marked gene: VDR as ready
Fetal anomalies v0.2522 VEGFC Zornitza Stark Marked gene: VEGFC as ready
Fetal anomalies v0.2522 WNT3 Zornitza Stark Marked gene: WNT3 as ready
Fetal anomalies v0.2521 WNT1 Seb Lunke Marked gene: WNT1 as ready
Fetal anomalies v0.2520 WNT5A Seb Lunke Marked gene: WNT5A as ready
Fetal anomalies v0.2517 WNT7A Seb Lunke Marked gene: WNT7A as ready
Fetal anomalies v0.2515 WT1 Seb Lunke Marked gene: WT1 as ready
Fetal anomalies v0.2513 XRCC4 Seb Lunke Marked gene: XRCC4 as ready
Fetal anomalies v0.2513 XRCC4 Seb Lunke Phenotypes for gene: XRCC4 were changed from PRIMORDIAL DWARFISM to Short stature, microcephaly, and endocrine dysfunction, MIM#616541
Fetal anomalies v0.2511 XYLT1 Seb Lunke Marked gene: XYLT1 as ready
Fetal anomalies v0.2511 XYLT1 Seb Lunke Phenotypes for gene: XYLT1 were changed from DESBUQUOIS DYSPLASIA 2 to Desbuquois dysplasia 2, MIM# 615777; Baratela-Scott syndrome
Fetal anomalies v0.2509 ZC4H2 Seb Lunke Marked gene: ZC4H2 as ready
Fetal anomalies v0.2507 ZEB2 Seb Lunke Marked gene: ZEB2 as ready
Fetal anomalies v0.2504 ZIC1 Seb Lunke Marked gene: ZIC1 as ready
Fetal anomalies v0.2501 ZIC3 Seb Lunke Marked gene: ZIC3 as ready
Fetal anomalies v0.2501 ZIC3 Seb Lunke Phenotypes for gene: ZIC3 were changed from HETEROTAXY SYNDROME; VACTERL ASSOCIATION, X-LINKED, WITH OR WITHOUT HYDROCEPHALUS to Congenital heart defects, nonsyndromic, 1, X-linked, MIM#306955; Heterotaxy, visceral, 1, X-linked, MIM#306955; VACTERL association, X-linked, MIM#314390
Fetal anomalies v0.2499 ZNF462 Seb Lunke Marked gene: ZNF462 as ready
Fetal anomalies v0.2496 STIL Zornitza Stark Marked gene: STIL as ready
Fetal anomalies v0.2494 STRADA Zornitza Stark Marked gene: STRADA as ready
Fetal anomalies v0.2492 SUFU Zornitza Stark Marked gene: SUFU as ready
Fetal anomalies v0.2489 SUFU Zornitza Stark edited their review of gene: SUFU: Added comment: Rib anomalies and cleft palate are a feature of the mono-allelic disorder.

The signs of the bi-alellic disorder are relatively subtle and unlikely to be detectable antenatally.; Changed rating: GREEN; Changed phenotypes: Basal cell nevus syndrome, MIM# 109400; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.2489 SYNE1 Zornitza Stark Marked gene: SYNE1 as ready
Fetal anomalies v0.2488 ZSWIM6 Zornitza Stark Marked gene: ZSWIM6 as ready
Fetal anomalies v0.2484 ZSWIM6 Zornitza Stark edited their review of gene: ZSWIM6: Added comment: Cleft palate and polydactyly are a feature of the skeletal disorder.

Congenital anomalies are not a prominent feature of the neurodevelopmental disorder associated with this gene.; Changed rating: GREEN; Changed phenotypes: Acromelic frontonasal dysostosis (MIM#603671); Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.2484 ZNF423 Zornitza Stark Marked gene: ZNF423 as ready
Fetal anomalies v0.2483 ZMYND11 Zornitza Stark Marked gene: ZMYND11 as ready
Fetal anomalies v0.2483 ZMYND11 Zornitza Stark Phenotypes for gene: ZMYND11 were changed from INTELLECTUAL DISABILITY to Mental retardation, autosomal dominant 30, MIM# 616083
Fetal anomalies v0.2479 ZMYND11 Zornitza Stark changed review comment from: New case series of additional 16 individuals reported, including four individuals from the same family. Common phenotypic features: developmental delay, particularly affecting speech, mild‐moderate intellectual disability, significant behavioral abnormalities, seizures, and hypotonia. There are subtle shared dysmorphic features, including prominent eyelashes and eyebrows, a depressed nasal bridge with bulbous nasal tip, anteverted nares, thin vermilion of the upper lip, and wide mouth. Novel features include brachydactyly and tooth enamel hypoplasia. Most identified variants are likely to result in premature truncation and/or nonsense‐mediated decay. Two ZMYND11 variants located in the final exon reported —p.(Gln586*) (likely escaping nonsense‐mediated decay) and p.(Cys574Arg)—are predicted to disrupt the MYND‐type zinc‐finger motif and likely interfere with binding to its interaction partners.; to: New case series of additional 16 individuals reported, including four individuals from the same family. Common phenotypic features: developmental delay, particularly affecting speech, mild‐moderate intellectual disability, significant behavioral abnormalities, seizures, and hypotonia. There are subtle shared dysmorphic features, including prominent eyelashes and eyebrows, a depressed nasal bridge with bulbous nasal tip, anteverted nares, thin vermilion of the upper lip, and wide mouth. Novel features include brachydactyly and tooth enamel hypoplasia. Most identified variants are likely to result in premature truncation and/or nonsense‐mediated decay. Two ZMYND11 variants located in the final exon reported —p.(Gln586*) (likely escaping nonsense‐mediated decay) and p.(Cys574Arg)—are predicted to disrupt the MYND‐type zinc‐finger motif and likely interfere with binding to its interaction partners.

Presentation is post-natal.
Fetal anomalies v0.2479 ZMYND10 Zornitza Stark Marked gene: ZMYND10 as ready
Fetal anomalies v0.2479 ZMYND10 Zornitza Stark Phenotypes for gene: ZMYND10 were changed from PRIMARY CILIARY DYSKINESIA-22 to Ciliary dyskinesia, primary, 22, MIM#615444
Fetal anomalies v0.2476 YWHAG Zornitza Stark Marked gene: YWHAG as ready
Fetal anomalies v0.2476 YWHAG Zornitza Stark Phenotypes for gene: YWHAG were changed from Early-Onset Epilepsy to Developmental and epileptic encephalopathy 56, (MIMI#617665)
Fetal anomalies v0.2472 YWHAG Zornitza Stark changed review comment from: Developmental and epileptic encephalopathy-56 (DEE56) is a neurodevelopmental disorder characterized by early-onset seizures in most patients, followed by impaired intellectual development, variable behavioral abnormalities, and sometimes additional neurologic features, such as ataxia.

PMID: 33393734 8x patients all de novo missense. Patient cohort shared with PMID: 31926053 7/8 have mild-mod ID 6/8 have seizures
PMID: 33767733 1x de novo missense and 1x nonsense familial with 6 affecteds. All patients from this study have febrile seizures but normal intelligence and motor development.
PMID: 33590706 1x de novo. mild ID and generalized tonic–clonic seizures; to: Developmental and epileptic encephalopathy-56 (DEE56) is a neurodevelopmental disorder characterized by early-onset seizures in most patients, followed by impaired intellectual development, variable behavioral abnormalities, and sometimes additional neurologic features, such as ataxia.

PMID: 33393734 8x patients all de novo missense. Patient cohort shared with PMID: 31926053 7/8 have mild-mod ID 6/8 have seizures
PMID: 33767733 1x de novo missense and 1x nonsense familial with 6 affecteds. All patients from this study have febrile seizures but normal intelligence and motor development.
PMID: 33590706 1x de novo. mild ID and generalized tonic–clonic seizures

Onset in first year of life.
Fetal anomalies v0.2472 YAP1 Zornitza Stark Marked gene: YAP1 as ready
Fetal anomalies v0.2472 YAP1 Zornitza Stark Phenotypes for gene: YAP1 were changed from COLOBOMA, OCULAR, WITH OR WITHOUT HEARING IMPAIRMENT, CLEFT LIP/PALATE, AND/OR MENTAL RETARDATION to Coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or mental retardation, MIM#120433
Fetal anomalies v0.2468 XYLT2 Zornitza Stark Marked gene: XYLT2 as ready
Fetal anomalies v0.2468 XYLT2 Zornitza Stark Phenotypes for gene: XYLT2 were changed from SPONDYLOOCULAR SYNDROME to Spondyloocular syndrome MIM# 605822
Fetal anomalies v0.2465 XYLT2 Zornitza Stark changed review comment from: Cataracts are a key feature of this condition.
Sources: Expert list; to: Congenital heart defects.
Sources: Expert list
Fetal anomalies v0.2465 WDR81 Zornitza Stark Marked gene: WDR81 as ready
Fetal anomalies v0.2465 WDR73 Zornitza Stark Marked gene: WDR73 as ready
Fetal anomalies v0.2462 WBP11 Zornitza Stark Marked gene: WBP11 as ready
Fetal anomalies v0.2462 WBP11 Zornitza Stark Phenotypes for gene: WBP11 were changed from Vertebral, cardiac, tracheoesophageal, renal, and limb defects, OMIM:619227 to Vertebral, cardiac, tracheoesophageal, renal, and limb defects, #MIM:619227
Fetal anomalies v0.2459 VRK1 Zornitza Stark Marked gene: VRK1 as ready
Fetal anomalies v0.2459 VRK1 Zornitza Stark Phenotypes for gene: VRK1 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 1 to Pontocerebellar hypoplasia type 1A MIM#607596
Fetal anomalies v0.2456 VAMP1 Zornitza Stark Marked gene: VAMP1 as ready
Fetal anomalies v0.2454 USP9X Zornitza Stark Marked gene: USP9X as ready
Fetal anomalies v0.2454 USP9X Zornitza Stark Phenotypes for gene: USP9X were changed from MENTAL RETARDATION, X-LINKED 99 to Mental retardation, X-linked 99, XLR (MIM#300919) and XLD (MIM#300968)
Fetal anomalies v0.2451 USP27X Zornitza Stark Marked gene: USP27X as ready
Fetal anomalies v0.2451 USP27X Zornitza Stark Phenotypes for gene: USP27X were changed from INTELLECTUAL DISABILITY to Mental retardation, X-linked 105, MIM#300984
Fetal anomalies v0.2448 USP18 Zornitza Stark Marked gene: USP18 as ready
Fetal anomalies v0.2446 UQCRQ Zornitza Stark Marked gene: UQCRQ as ready
Fetal anomalies v0.2446 UQCRQ Zornitza Stark Phenotypes for gene: UQCRQ were changed from MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX III DEFICIENCY, UQCRQ RELATED to Mitochondrial complex III deficiency, nuclear type 4, MIM #615159
Fetal anomalies v0.2443 UQCRQ Zornitza Stark reviewed gene: UQCRQ: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex III deficiency, nuclear type 4, MIM #615159; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2443 UQCRB Zornitza Stark Marked gene: UQCRB as ready
Fetal anomalies v0.2443 UQCRB Zornitza Stark Phenotypes for gene: UQCRB were changed from MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX III DEFICIENCY, UQCRB-RELATED to Mitochondrial complex III deficiency, nuclear type 3, MIM #615158
Fetal anomalies v0.2440 UQCRB Zornitza Stark reviewed gene: UQCRB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex III deficiency, nuclear type 3, MIM #615158; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2440 UBTF Zornitza Stark Marked gene: UBTF as ready
Fetal anomalies v0.2436 UBE2T Zornitza Stark Marked gene: UBE2T as ready
Fetal anomalies v0.2433 TXNDC15 Zornitza Stark Marked gene: TXNDC15 as ready
Fetal anomalies v0.2430 TUFM Zornitza Stark Marked gene: TUFM as ready
Fetal anomalies v0.2427 TUBGCP4 Zornitza Stark Marked gene: TUBGCP4 as ready
Fetal anomalies v0.2425 TTI2 Zornitza Stark Marked gene: TTI2 as ready
Fetal anomalies v0.2425 TTI2 Zornitza Stark Phenotypes for gene: TTI2 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Mental retardation, autosomal recessive 39 (MIM#615541); Microcephaly
Fetal anomalies v0.2422 TTC25 Zornitza Stark changed review comment from: 2 families reported with PCD. Mouse model showed immotile nodal cilia.
Gene ncodes a component of the outer dynein arm required to develop the main mechanical force to generate ciliary beats. (Gene is non coding in gnomad v2 and coding in v3); to: 2 families reported with PCD. Some individuals had situs inversus. Mouse model showed immotile nodal cilia.
Gene ncodes a component of the outer dynein arm required to develop the main mechanical force to generate ciliary beats. (Gene is non coding in gnomad v2 and coding in v3)
Fetal anomalies v0.2422 TTC25 Zornitza Stark Marked gene: TTC25 as ready
Fetal anomalies v0.2422 TTC25 Zornitza Stark Phenotypes for gene: TTC25 were changed from Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization to Ciliary dyskinesia, primary, 35 (MIM#617092)
Fetal anomalies v0.2420 TSEN34 Zornitza Stark Marked gene: TSEN34 as ready
Fetal anomalies v0.2420 TSEN34 Zornitza Stark Phenotypes for gene: TSEN34 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4 to Pontocerebellar hypoplasia type 2C, MIM# 612390
Fetal anomalies v0.2417 TSEN2 Zornitza Stark Marked gene: TSEN2 as ready
Fetal anomalies v0.2417 TSEN2 Zornitza Stark Phenotypes for gene: TSEN2 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4 to Pontocerebellar hypoplasia type 2B (MIM#612389)
Fetal anomalies v0.2414 TSEN2 Zornitza Stark reviewed gene: TSEN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hypoplasia type 2B (MIM#612389); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2414 TSEN15 Zornitza Stark Marked gene: TSEN15 as ready
Fetal anomalies v0.2414 TSEN15 Zornitza Stark Phenotypes for gene: TSEN15 were changed from Pontocerebellar Hypoplasia and Progressive Microcephaly to Pontocerebellar hypoplasia, type 2F MIM#617026
Fetal anomalies v0.2411 TRMT10A Zornitza Stark Marked gene: TRMT10A as ready
Fetal anomalies v0.2408 TRIO Zornitza Stark Marked gene: TRIO as ready
Fetal anomalies v0.2408 TRIO Zornitza Stark Phenotypes for gene: TRIO were changed from INTELLECTUAL DISABILITY to Mental retardation, autosomal dominant 44, MIM# 617061
Fetal anomalies v0.2404 TRIM32 Zornitza Stark Phenotypes for gene: TRIM32 were changed from Bardet-Biedl syndrome 11, MIM# 615988 to Bardet-Biedl syndrome 11, MIM# 615988; Muscular dystrophy, limb-girdle, autosomal recessive 8, MIM# 254110
Fetal anomalies v0.2403 TRIM32 Zornitza Stark changed review comment from: Single family reported in 2006.; to: BBS: Single family reported in 2006.

Muscular dystrophy: onset is typically in childhood.
Fetal anomalies v0.2403 TRIM32 Zornitza Stark edited their review of gene: TRIM32: Changed phenotypes: Bardet-Biedl syndrome 11, MIM# 615988, Muscular dystrophy, limb-girdle, autosomal recessive 8, MIM# 254110
Fetal anomalies v0.2403 TRIM32 Zornitza Stark Marked gene: TRIM32 as ready
Fetal anomalies v0.2403 TRIM32 Zornitza Stark Phenotypes for gene: TRIM32 were changed from BARDET-BIEDL SYNDROME TYPE 11; LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 2H to Bardet-Biedl syndrome 11, MIM# 615988
Fetal anomalies v0.2401 TRAPPC12 Zornitza Stark Marked gene: TRAPPC12 as ready
Fetal anomalies v0.2400 TRAPPC11 Zornitza Stark Marked gene: TRAPPC11 as ready
Fetal anomalies v0.2400 TRAPPC11 Zornitza Stark Phenotypes for gene: TRAPPC11 were changed from MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2S to Muscular dystrophy, limb-girdle, autosomal recessive 18 MIM# 615356
Fetal anomalies v0.2397 TRAPPC11 Zornitza Stark reviewed gene: TRAPPC11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 18 MIM# 615356; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2397 TRAIP Zornitza Stark Marked gene: TRAIP as ready
Fetal anomalies v0.2395 TRAF3IP1 Zornitza Stark Marked gene: TRAF3IP1 as ready
Fetal anomalies v0.2392 TOR1A Zornitza Stark Marked gene: TOR1A as ready
Fetal anomalies v0.2391 TOE1 Zornitza Stark Marked gene: TOE1 as ready
Fetal anomalies v0.2389 TNNT3 Zornitza Stark Marked gene: TNNT3 as ready
Fetal anomalies v0.2386 TMX2 Zornitza Stark Marked gene: TMX2 as ready
Fetal anomalies v0.2385 TMTC3 Zornitza Stark Marked gene: TMTC3 as ready
Fetal anomalies v0.2382 TMEM98 Zornitza Stark Marked gene: TMEM98 as ready
Fetal anomalies v0.2380 TMEM38B Zornitza Stark Marked gene: TMEM38B as ready
Fetal anomalies v0.2378 TMEM216 Zornitza Stark Marked gene: TMEM216 as ready
Fetal anomalies v0.2376 TMEM107 Zornitza Stark Marked gene: TMEM107 as ready
Fetal anomalies v0.2375 TMEM107 Zornitza Stark edited their review of gene: TMEM107: Added comment: Overall enough evidence variants cause a ciliopathy phenotype.; Changed rating: GREEN; Changed phenotypes: Meckel syndrome 13 (MIM#617562), Orofaciodigital syndrome XVI (MIM#617563), Joubert syndrome 29 617562; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2375 FOXL2 Belinda Chong reviewed gene: FOXL2: Rating: RED; Mode of pathogenicity: None; Publications: 31077882, 18642388, 17089161; Phenotypes: Blepharophimosis, epicanthus inversus, and ptosis, type 1 with premature ovarian insufficiency (POI) and type II without POI (MIM# 110100); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v0.2375 TKT Zornitza Stark Marked gene: TKT as ready
Fetal anomalies v0.2375 TKT Zornitza Stark Phenotypes for gene: TKT were changed from Short Stature, Developmental Delay, and Congenital Heart Defects to Short stature, developmental delay, and congenital heart defects; OMIM #617044
Fetal anomalies v0.2373 THOC2 Zornitza Stark Marked gene: THOC2 as ready
Fetal anomalies v0.2373 THOC2 Zornitza Stark Phenotypes for gene: THOC2 were changed from MENTAL RETARDATION, X-LINKED 12 to Mental retardation, X-linked 12/35 MIM#300957
Fetal anomalies v0.2370 THOC2 Zornitza Stark reviewed gene: THOC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29851191; Phenotypes: Mental retardation, X-linked 12/35 MIM#300957; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v0.2370 TENM3 Zornitza Stark Marked gene: TENM3 as ready
Fetal anomalies v0.2368 TELO2 Zornitza Stark Marked gene: TELO2 as ready
Fetal anomalies v0.2366 TELO2 Zornitza Stark changed review comment from: Five unrelated families reported.
Sources: Expert list; to: Five unrelated families reported.

Microcephaly, congenital heart disease, renal malformations reported.
Sources: Expert list
Fetal anomalies v0.2366 HAND1 Krithika Murali edited their review of gene: HAND1: Added comment: No OMIM gene disease association

PMID: 28112363 Li et al 2017 - HAND1 gene sequenced in 158 unrelated patients with CHDs and 600 controls. A de novo heterozygous truncating variant was identified (c.394A>T p.K132X) in a 5 month old body with double outlet right ventricle and VSD. Absent from gnomad, not present in unaffected parents or in controls. Functional analysis supported loss of HAND1 transcriptional activity.

PMID: 29317578 Wang et al 2017 – article in Chinese, abstract in English. A total of 125 patients with congenital VSD and 210 controls. HAND1 truncating variant identified in an individual with VSD( c.355G>T E119X ). Absent from population database, x1 missense variant at same position 28 hets and x1 synonymous variant with 1 het present in gnomad. No segregation data

PMID: 29179274 Zhi et al 2017 - A novel heterozygous mutation, a substitution of thymine for guanine at nucleotide 346 (c.346G>T), predicting the conversion of a glutamic acid-encoding codon into a stop codon at codon 116 (p.E116X), was detected in a patient with sporadic DCM out of a cohort of 120 Chinese patients with DCM versus 200 healthy controls. Absent from gnomad. No segregation data. Article in Chinese, abstract in English, unlikely to be congenital onset.

PMID: 27942761 Wang et al 2017 - 165 unrelated patients with CHD and 600 unrelated controls. Heterozygous missense HAND1 variant identified in a patient with TOF (c.352C>T p.R118C) . Functional studies supporting significantly reduced transcriptional activity, absent from gnomad, damaging in silicos, no parental testing.

PMID: 26581070 Zhou et al 2016 - heterozygous truncating HAND1 variant, c.313A > T p.R105X identified in a DCM family, absent in controls, reduced transcrptional activities, x1 het inframe deletion at the same position in gnomad and x1 synonymous variant. Segregated with family members with DCM and VSD.

PMID: 31286141 Firulli et al 2020 – mouse models showing that myocardial deletion of Hand1 resulted in morphological defects including interventricular septal defects, abnormal LV papillary muscles and cardiac conduction system defects
PMID: 29016838 Firulli et al 2017 - Hand1A126FS mutation does exhibit embryonic lethal cardiac defects in mouse models; Changed rating: AMBER; Changed publications: 31286141, 29016838, 29317578, 29179274, 28112363, 27942761, 26581070
Fetal anomalies v0.2366 FAM46A Belinda Chong changed review comment from: Comment when marking as ready: HGNC approved name: TENT5A

Osteogenesis imperfecta type XVIII (OI18) is characterized by congenital bowing of the long bones, wormian bones, blue sclerae, vertebral collapse, and multiple fractures in the first years of life.

In 4 children from 3 unrelated consanguineous families with osteogenesis imperfecta, Doyard et al. (2018) identified homozygosity for mutations in the FAM46A gene. The mutations were identified by exome sequencing and confirmed by Sanger sequencing.; to: Comment when marking as ready: HGNC approved name: TENT5A

Osteogenesis imperfecta type XVIII (OI18) is characterized by congenital bowing of the long bones, wormian bones, blue sclerae, vertebral collapse, and multiple fractures in the first years of life.

In 4 children from 3 unrelated consanguineous families with osteogenesis imperfecta, Doyard et al. (2018) identified homozygosity for mutations in the FAM46A gene. The mutations were identified by exome sequencing and confirmed by Sanger sequencing.
Fetal anomalies v0.2366 GATA5 Krithika Murali edited their review of gene: GATA5: Added comment: OMIM gene disease association for multiple congenital heart defects both AR and AD inheritance

--

AR inheritance - x2 patients with congenital heart disease

PMID 28180938 Hempel et al 2017 - x1 DCDA twin female born at 28+6 weeks after PROM. Ascites, non-immune hydrops fetalis and VSD diagnosed prenatally at 20 weeks. Postnatally diagnosed with ASD, PDA, mild HCM and gallstones. Hydrops likely secondary to congenital heart disease. Also diagnosed with clitoromegaly with transient elevation in 17-hydroxyprogrogesterone till 10 weeks of age and normal adrenal androgen levels. 46 XX confirmed on karyotype. Proband compound het for paternally inherited GATA 5 c.56G > C, p.Ser19Trp variant and maternally inherited c.605C > T, p.Arg202Gln. Carrier arents and twin sister with c.605C > T, p.Arg202Gln unaffected. Arg202Gln absent from population database, p.Ser19Trp - 241 hets in gnomad not seen in homozygous form.

Supportive zebrafish models for GATA5 LoF. Previous mouse models suggest that GATA5 plays a role during mammalian embryogenesis, including heart developmen and progesterone receptor expression.

PMID: 27066509 Kassab et al 2015

Lebanese patient cohort with high rates of consangunity. A total of 185 patients with different forms of congenital heart disease (CHD)were screened for GATA4, GATA5, GATA6 variants + 150 healthy individuals. 2 patients with homozygous GATA5 varianst identified. One patient wtih aortic stenosis, coarctation of the aorta, VSD, PDA with homozygous p.T67P variants - in silicos benign, gnomad 4975 hets and 402 homozygotes. Another patient with double outlet right ventricle / ASD / pulmonary stenosis and homozygous p.Y142H – present in gnomad 39 hets, 0 homozygotes, unaffected consanguineous carrier parents.

---
Multiple studies reporting AD inheritance for bicuspid aortic valve, congenital heart disease, DCM, AF - evidence conflicting

PMID 34461831 Ma et al 2021 BMC Cardiovascular Disorders - prospective recruitment of 130 unrelated patients with bicuspid aortic valve with complex congenital heart disease being one of the exclusion criteria. 2 heterozygous GATA5 variants identified present in population database. No segregation data.

PMID: 30229885 Alonso-Montes et al 2018, European Journal of Clinical Investigations - North of Spain cohort. 122 unrelated patients with bicuspid and 154 unaffected patients had GATA4, GATA5 and GATA6 sequencing. Missense p.Arg202Gln in GATA5 identified, absent from gnomad, in-silicos probably damaging, no segregation data.

Zhang et al 2015 PMID 25543888 - DCM cohort heterozygous GATA5 c.719G>A p.G240D identified in a family. Authors report co-segregation with DCM in multiple family members with associated VSD in 2 individuals, functional analyses showed diminished transcriptional activity. In-silicos predict possibily damaging. Variant absent from gnomad but in a region of low exome coverage

Shan et al 2014 PMID 25515806 - analysis of GATA5 gene promoter in 343 patients with VSD and 348 controls. Two novel variants reported in affected individuals but also present in unaffected parents.

PMID 24796370 Bonachea et al 2014 - Cohort of 78 bicuspid aortic patients (50 with isolated BAV and 28 with associated aortic coarctation) had GATA5 sanger sequencing analysis. x2 variants identified. p.Gln3Arg variant present in 447 hets in gnomad – inherited from unaffected mother, p.Leu233Pro – present in 359 hets – apparently de novo

PMID: 23289003 Wei et al 2013 Int Journal Medical Science - cohort of 130 unrelated patients with TOF and 200 unrelated controls. GATA5 c.559C>G p.R187G variant identified in affected individual – although variant absent from gnomad alternative aa change at same position present in gnomad including truncating frameshift variants. GATA5 c.620A>G p.H207R – absent from gnomad. Authors report co-segregation of both variants with TOF in multiple family members, some with additional congenital heart defects.

Wei et al Pediatric Cardiology 2013 PMID 22961344 - GATA5 sequenced in 120 unrelated patients with VSD and 200 controls. Heterozygous GATA5 variant p.L199V identified in a patient with VSD. Author reports co-segregation in multiple affected family members. Variant absent from gnomad with X1 synonymous het variant only at same position; Changed rating: AMBER; Changed publications: 28180938, 27066509, 34461831, 30229885, 28285006, 25543888, 25515806, 24796370, 23295592, 23289003, 22961344
Fetal anomalies v0.2366 TECPR2 Zornitza Stark Marked gene: TECPR2 as ready
Fetal anomalies v0.2366 TECPR2 Zornitza Stark Phenotypes for gene: TECPR2 were changed from HEREDITARY SPASTIC PARAPARESIS to Spastic paraplegia 49, autosomal recessive, 615031; Autonomic-sensory neuropathy; Intellectual disability
Fetal anomalies v0.2364 TECPR2 Zornitza Stark changed review comment from: SPG49 is an autosomal recessive complicated form of spastic paraplegia. PMID 23176824 reported 4 Jewish Bukharian individuals homozygous for same founder variant and delayed psychomotor development, intellectual disability, and onset of spastic paraplegia in the first decade. Affected individuals also had dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, some of which were fatal. Three additional patients from unrelated non-Bukharian families reported in PMID 26542466, harboring two novel variants (c.1319delT, c.C566T) in this gene. In addition to intellectual disability and evolving spasticity, autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events were prominent.

Included due to mild CC abnormalities.; to: SPG49 is an autosomal recessive complicated form of spastic paraplegia. PMID 23176824 reported 4 Jewish Bukharian individuals homozygous for same founder variant and delayed psychomotor development, intellectual disability, and onset of spastic paraplegia in the first decade. Affected individuals also had dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, some of which were fatal. Three additional patients from unrelated non-Bukharian families reported in PMID 26542466, harboring two novel variants (c.1319delT, c.C566T) in this gene. In addition to intellectual disability and evolving spasticity, autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events were prominent.

Included due to mild CC abnormalities, though clinical presentation is predominantly post-natal.
Fetal anomalies v0.2364 TECPR2 Zornitza Stark changed review comment from: SPG49 is an autosomal recessive complicated form of spastic paraplegia. PMID 23176824 reported 4 Jewish Bukharian individuals homozygous for same founder variant and delayed psychomotor development, intellectual disability, and onset of spastic paraplegia in the first decade. Affected individuals also had dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, some of which were fatal. Three additional patients from unrelated non-Bukharian families reported in PMID 26542466, harboring two novel variants (c.1319delT, c.C566T) in this gene. In addition to intellectual disability and evolving spasticity, autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events were prominent; to: SPG49 is an autosomal recessive complicated form of spastic paraplegia. PMID 23176824 reported 4 Jewish Bukharian individuals homozygous for same founder variant and delayed psychomotor development, intellectual disability, and onset of spastic paraplegia in the first decade. Affected individuals also had dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, some of which were fatal. Three additional patients from unrelated non-Bukharian families reported in PMID 26542466, harboring two novel variants (c.1319delT, c.C566T) in this gene. In addition to intellectual disability and evolving spasticity, autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events were prominent.

Included due to mild CC abnormalities.
Fetal anomalies v0.2364 TCTEX1D2 Zornitza Stark Marked gene: TCTEX1D2 as ready
Fetal anomalies v0.2362 TCF20 Zornitza Stark Marked gene: TCF20 as ready
Fetal anomalies v0.2360 TCF20 Zornitza Stark changed review comment from: Many unrelated patients reported, including 24 families reported in Torti 2019 (PMID:30739909). Most variants are protein-truncating.; to: Many unrelated patients reported, including 24 families reported in Torti 2019 (PMID:30739909). Most variants are protein-truncating.

Typically presents post-natally.
Fetal anomalies v0.2360 TBX22 Zornitza Stark Marked gene: TBX22 as ready
Fetal anomalies v0.2357 TBX22 Zornitza Stark edited their review of gene: TBX22: Added comment: More than 10 families reported with cleft palate/ankyloglossia and variants in this gene.

Single family reported with Abruzzo-Erickson syndrome, a syndromic form of cleft palate.; Changed publications: 11559848, 12374769, 14729838, 17868388, 22784330, 22784330
Fetal anomalies v0.2357 TBR1 Zornitza Stark Marked gene: TBR1 as ready
Fetal anomalies v0.2354 TBR1 Zornitza Stark changed review comment from: Heterozygous de novo PTC and missense variants reported in at least 7 unrelated patients with impaired intellectual development with autism and speech delay (PMID: 25232744, 30250039).; to: Heterozygous de novo PTC and missense variants reported in at least 7 unrelated patients with impaired intellectual development with autism and speech delay (PMID: 25232744, 30250039).

Pachygyria in some individuals.
Fetal anomalies v0.2354 TAF13 Zornitza Stark Marked gene: TAF13 as ready
Fetal anomalies v0.2354 TAF13 Zornitza Stark Phenotypes for gene: TAF13 were changed from Autosomal-Recessive Intellectual Disability and Microcephaly to Mental retardation, autosomal recessive 60, MIM# 617432; Microcephaly
Fetal anomalies v0.2352 MYPN Ain Roesley reviewed gene: MYPN: Rating: RED; Mode of pathogenicity: None; Publications: 28017374, 28220527, 31133047; Phenotypes: Nemaline myopathy 11, autosomal recessive MIM#617336 AR, cardiomyopathy MIM#615248 AD; Mode of inheritance: None; Current diagnostic: yes
Fetal anomalies v0.2352 MYLK Ain Roesley changed review comment from: 2 consanguineous families for AR Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 MIM#249210

Well established for AD Aortic aneurysm, familial thoracic 7, MIM#600922; to: 2 consanguineous families for AR Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 MIM#249210
1x hom fs and 1x hom splice

Well established for AD Aortic aneurysm, familial thoracic 7, MIM#600922
Fetal anomalies v0.2352 MED13L Ain Roesley reviewed gene: MED13L: Rating: AMBER; Mode of pathogenicity: None; Publications: 33930262, 29959045, 32646507; Phenotypes: Impaired intellectual development and distinctive facial features with or without cardiac defects MIM#616789; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v0.2352 TACO1 Zornitza Stark Marked gene: TACO1 as ready
Fetal anomalies v0.2349 MECR Ain Roesley reviewed gene: MECR: Rating: RED; Mode of pathogenicity: None; Publications: 27817865, 33401012, 31137067, 31070877; Phenotypes: Childhood-onset dystonia with optic atrophy and basal ganglia abnormalities is an autosomal recessive neurologic disorder characterized by onset of involuntary movements in the first decade of life. Optic atrophy develops around the same time or slightly later. Severity is variable, and some patients lose independent ambulation. Brain imaging shows abnormalities in the basal ganglia. Cognition appears to be unaffected. 7 unrelated families reported.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2349 EMX2 Zornitza Stark Marked gene: EMX2 as ready
Fetal anomalies v0.2346 EML1 Zornitza Stark Marked gene: EML1 as ready
Fetal anomalies v0.2344 EMG1 Zornitza Stark Marked gene: EMG1 as ready
Fetal anomalies v0.2343 MECOM Ain Roesley reviewed gene: MECOM: Rating: GREEN; Mode of pathogenicity: None; Publications: 29146883, 29519864, 26581901; Phenotypes: Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 MIM#616738; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v0.2343 EMC1 Zornitza Stark Marked gene: EMC1 as ready
Fetal anomalies v0.2343 EMC1 Zornitza Stark Phenotypes for gene: EMC1 were changed from Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy. to Cerebellar atrophy, visual impairment, and psychomotor retardation, MIM# 616875
Fetal anomalies v0.2339 EMC1 Zornitza Stark changed review comment from: Four unrelated families with bi-allelic variants in this gene reported. Single individual with heterozygous variant: insufficient evidence at present for mono allelic variants causing disease.
Sources: Expert list; to: Four unrelated families with bi-allelic variants in this gene reported. Microcephaly is acquired; CC abnormalities reported.

Single individual with heterozygous variant: insufficient evidence at present for mono allelic variants causing disease.
Sources: Expert list
Fetal anomalies v0.2339 EIF2S3 Zornitza Stark Marked gene: EIF2S3 as ready
Fetal anomalies v0.2337 EIF2S3 Zornitza Stark changed review comment from: 9 families reported (3 had the same variant) with MEHMO syndrome (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity).; to: 9 families reported (3 had the same variant) with MEHMO syndrome (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity).

Cleft palate also reported.
Fetal anomalies v0.2337 EHBP1L1 Zornitza Stark Marked gene: EHBP1L1 as ready
Fetal anomalies v0.2336 EEF1A2 Zornitza Stark Marked gene: EEF1A2 as ready
Fetal anomalies v0.2336 EEF1A2 Zornitza Stark Phenotypes for gene: EEF1A2 were changed from INFANTILE EPILEPTIC ENCEPHALOPATHY to Mental retardation, autosomal dominant 38, MIM# 616393; MONDO:0014617; Developmental and epileptic encephalopathy 33, MIM# 616409; MONDO:0014625
Fetal anomalies v0.2334 EEF1A2 Zornitza Stark Mode of pathogenicity for gene: EEF1A2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.2331 EEF1A2 Zornitza Stark changed review comment from: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1A2 null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.; to: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1A2 null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.

However, presentation is typically post-natal.
Fetal anomalies v0.2331 EED Zornitza Stark Marked gene: EED as ready
Fetal anomalies v0.2328 DRC1 Zornitza Stark Marked gene: DRC1 as ready
Fetal anomalies v0.2328 DRC1 Zornitza Stark Phenotypes for gene: DRC1 were changed from PRIMARY CILARY DYSKINEASIA to Ciliary dyskinesia, primary, 21, MIM# 615294
Fetal anomalies v0.2325 DPM3 Zornitza Stark Marked gene: DPM3 as ready
Fetal anomalies v0.2325 DPM3 Zornitza Stark Phenotypes for gene: DPM3 were changed from ?Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15, 618992; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, 612937 to Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15, 618992; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, 612937
Fetal anomalies v0.2322 DPM2 Zornitza Stark Marked gene: DPM2 as ready
Fetal anomalies v0.2320 FOXH1 Krithika Murali edited their review of gene: FOXH1: Added comment: No OMIM gene disease association. Overall, evidence for this gene and its association with congenital heart disease is conflicting.

Roessler et al 2008 PMID 18538293
Pilot consortium study of 375 unrelated individuals prospectively ascertained with cardiovascular malformations. Patients not seen at NIH and parents/siblings not consented. Therefore only samples from proband collected. Also screened 300-500 patients with holoprosencephaly and 125 unrelated controls. Over 60 heterozygous FOXH1 variants reported in patients with congenital heart disease or holoprosencephaly. The majority of reported variants were of questionable pathogenicity as they were present in gnomad, had variants present in gnomad with alternative amino acid changes at the same position, had limited evidence of effect on FOXH1 functional activity or were synonymous variants. Furthermore, no variant segregation data available.

De Luca et al 2009 PMID 19933292
FOXH1 (Pro21Ser) missense variant identified. Not present in gnomad but in area of low coverage, alternative aa change reported in the same location in x1 het. Identified in proband with TGA and x2 other unaffected family members. Proband who was also heterozogous for an amino acid substitution (Gly17Cys) in the ZIC3 gene

Wei et al 2020 Clinical Genetics PMID 32003456
Exome sequencing performed in 605 patients with sporadic conotruncal defects and 300 controls in patients of Chinese descent with ages ranging from 6 days to 12 years old, majority <2 years old. 14 gene panel used. Identified 7 FOXH1 missense variants in 10 unrelated patients with congenital heart disease. All reported variants associated with reduced protein expression of FOXH1 protein on Western blot to varying degrees. No segregation data provided.
• FOXH1 c.104C>G p.P35R identified in a 9 month old with double outlet right ventricle. Absent from gnomad but is in an area of low exome coverage. Variant with alternative amino acid change at same position (FOXH1 c.104C>T p.P35L) previously identified in a patient with congenital heart disease (Roessler et al 2008)
• X2 patients - FOXH1 c.205T>C p.Phe69Leu. Also present in gnomad – x1 het non-Finnish European. X1 patient with alternative amino acid change at same position also identified (FOXH1 c.206T>C p.Phe69Ser) – absent from gnomad.
• X2 patients with FOXH1 c.209T>C p.Phe70Ser - absent from gnomad
• X2 patients with FOXH1 c.232A>G p.Lys78Glu – x2 hets gnomad (European non-Finnish, South Asian)
• X1 patient with FOXH1 c.277A>G p.Lys93Glu – x1 het gnomad (European Finnish)
• X1 patients FOXH1 c.277A>G p.Glu165Gln – absent from gnomad, benign in silicos

PMID 12094232, PMID 16304598 - Previous mouse models have demonstrated a role for Foxh1 in heart morphogenesis.; Changed rating: AMBER; Changed publications: 18538293, 19933292, 32003456, 12094232, 16304598; Changed phenotypes: Congenital heart disease
Fetal anomalies v0.2320 DPH1 Zornitza Stark Marked gene: DPH1 as ready
Fetal anomalies v0.2319 DONSON Zornitza Stark Marked gene: DONSON as ready
Fetal anomalies v0.2316 DOCK7 Zornitza Stark Marked gene: DOCK7 as ready
Fetal anomalies v0.2316 MBOAT7 Ain Roesley changed review comment from: 20 families with ID and seizures as main features
microcephaly reported though OFC at birth are largely unknown
low birth weight (>-3SD) reported in 1 family; to: > 20 families with ID and seizures as main features
microcephaly reported though OFC at birth are largely unknown
low birth weight (>-3SD) reported in 1 family
Fetal anomalies v0.2316 DOCK7 Zornitza Stark Phenotypes for gene: DOCK7 were changed from EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 23 to Developmental and epileptic encephalopathy 23 MIM#615859
Fetal anomalies v0.2313 DNM2 Zornitza Stark Marked gene: DNM2 as ready
Fetal anomalies v0.2310 DNM2 Zornitza Stark changed review comment from: Single family reported with lethal congenital contractures, 3 sibs, postulated hypomorphic missense. Monoallelic variants in this gene is associated with neuropathy/myopathy/mitochondrial disease.
Sources: Expert Review; to: Single family reported with lethal congenital contractures, 3 sibs, postulated hypomorphic missense. Monoallelic variants in this gene is associated with neuropathy/myopathy/mitochondrial disease and generally have onset in childhood or later.
Sources: Expert Review
Fetal anomalies v0.2310 DNM1L Zornitza Stark Marked gene: DNM1L as ready
Fetal anomalies v0.2307 DNM1L Zornitza Stark changed review comment from: Dominant and recessive disease described depending on domain affected; dominant negative effect of heterozygous missense variants. LoF/LoF or LoF/missense for AR variants.; to: Dominant and recessive disease described depending on domain affected; dominant negative effect of heterozygous missense variants. LoF/LoF or LoF/missense for AR variants.

Decreased fetal movements reported.
Fetal anomalies v0.2307 MAP3K7 Ain Roesley reviewed gene: MAP3K7: Rating: GREEN; Mode of pathogenicity: None; Publications: 27426734, 27426733; Phenotypes: Cardiospondylocarpofacial syndrome MIM#157800 AD, Frontometaphyseal dysplasia 2 MIM#617137 AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v0.2307 MAP3K20 Ain Roesley reviewed gene: MAP3K20: Rating: GREEN; Mode of pathogenicity: None; Publications: 27816943, 26755636; Phenotypes: Centronuclear myopathy 6 with fiber-type disproportion MIM#617760, Split-foot malformation with mesoaxial polydactyly MIM#616890; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2307 DYNC2LI1 Zornitza Stark Marked gene: DYNC2LI1 as ready
Fetal anomalies v0.2304 DNM1 Zornitza Stark Marked gene: DNM1 as ready
Fetal anomalies v0.2300 DNM1 Zornitza Stark changed review comment from: Well-established link between heterozygous variants in DNM1 and developmental and epileptic encephalopathy. Yigit et al. 2021 (PMID: 34172529) recently reported two unrelated patients with DEE and homozygous truncating variants (c.97C>T; p.(Gln33*) and c.850C>T; p.(Gln284*), respectively) in the DNM1 gene. All parents were heterozygous carriers but did not show any clinical symptoms indicating a recessive inheritance pattern. No function studies were performed.; to: Well-established link between heterozygous variants in DNM1 and developmental and epileptic encephalopathy. Yigit et al. 2021 (PMID: 34172529) recently reported two unrelated patients with DEE and homozygous truncating variants (c.97C>T; p.(Gln33*) and c.850C>T; p.(Gln284*), respectively) in the DNM1 gene. All parents were heterozygous carriers but did not show any clinical symptoms indicating a recessive inheritance pattern. No function studies were performed.

Clinical presentation is typically post-natal.
Fetal anomalies v0.2300 DNAL1 Zornitza Stark Marked gene: DNAL1 as ready
Fetal anomalies v0.2300 DNAL1 Zornitza Stark Phenotypes for gene: DNAL1 were changed from Ciliary dyskinesia, primary, 16, 614017 to Ciliary dyskinesia, primary, 16, MIM# 614017
Fetal anomalies v0.2298 DNAJC12 Zornitza Stark Marked gene: DNAJC12 as ready
Fetal anomalies v0.2296 DNAJC12 Zornitza Stark changed review comment from: Highly variable neurological phenotype, including ID, dystonia, parkinsonism. Treatable.
Sources: Expert list; to: Highly variable neurological phenotype, including ID, dystonia, parkinsonism. Treatable.

Clinical presentation is post-natal.
Sources: Expert list
Fetal anomalies v0.2296 DNAI2 Zornitza Stark Marked gene: DNAI2 as ready
Fetal anomalies v0.2296 DNAI2 Zornitza Stark Phenotypes for gene: DNAI2 were changed from Ciliary dyskinesia, primary, 9, with or without situs inversus,612444 to Ciliary dyskinesia, primary, 9, with or without situs inversus, MIM#612444
Fetal anomalies v0.2293 DNAAF5 Zornitza Stark Marked gene: DNAAF5 as ready
Fetal anomalies v0.2291 DNAAF2 Zornitza Stark Marked gene: DNAAF2 as ready
Fetal anomalies v0.2289 DLX5 Zornitza Stark Marked gene: DLX5 as ready
Fetal anomalies v0.2289 DLX5 Zornitza Stark Phenotypes for gene: DLX5 were changed from ?Split-hand/foot malformation 1 with sensorineural hearing loss, 220600; Split-hand/foot malformation 1, 183600 to Split-hand/foot malformation 1 with sensorineural hearing loss MIM#220600; Split-hand/foot malformation 1 MIM#183600
Fetal anomalies v0.2286 DLG4 Zornitza Stark Marked gene: DLG4 as ready
Fetal anomalies v0.2286 DLG4 Zornitza Stark Added comment: Comment when marking as ready: Clinical presentation is post-natal.
Fetal anomalies v0.2281 DISP1 Zornitza Stark Marked gene: DISP1 as ready
Fetal anomalies v0.2278 DIAPH1 Zornitza Stark Marked gene: DIAPH1 as ready
Fetal anomalies v0.2275 DHX30 Zornitza Stark Marked gene: DHX30 as ready
Fetal anomalies v0.2271 DHX30 Zornitza Stark changed review comment from: Twelve unrelated individuals reported with de novo missense variants, some recurrent. Missense cluster within nucleic acid binding motifs (~p.457-p.787).

Post-natal onset.; to: Twelve unrelated individuals reported with de novo missense variants, some recurrent. Missense cluster within nucleic acid binding motifs (~p.457-p.787).

Post-natal presentation.
Fetal anomalies v0.2271 DHX30 Zornitza Stark changed review comment from: Twelve unrelated individuals reported with de novo missense variants, some recurrent. Missense cluster within nucleic acid binding motifs (~p.457-p.787).; to: Twelve unrelated individuals reported with de novo missense variants, some recurrent. Missense cluster within nucleic acid binding motifs (~p.457-p.787).

Post-natal onset.
Fetal anomalies v0.2271 DHDDS Zornitza Stark Marked gene: DHDDS as ready
Fetal anomalies v0.2267 DHDDS Zornitza Stark changed review comment from: Five unrelated individuals reported with mono-allelic variants and a neurodevelopmental phenotype.
Sources: Expert list; to: Five unrelated individuals reported with mono-allelic variants and a neurodevelopmental phenotype. However, presentation is post-natal.
Sources: Expert list
Fetal anomalies v0.2267 DENND5A Zornitza Stark Marked gene: DENND5A as ready
Fetal anomalies v0.2265 DDX6 Zornitza Stark Marked gene: DDX6 as ready
Fetal anomalies v0.2261 DDX6 Zornitza Stark changed review comment from: Five unrelated individuals reported with 5 different de novo heterozygous missense mutations in exon 11 of the DDX6 gene. All variants occurred at conserved residues in either the QxxR or V motifs within the second RecA-2 domain of the helicase core; this region is involved in RNA and/or ATP binding, suggesting functional consequences.
Sources: Literature; to: Five unrelated individuals reported with 5 different de novo heterozygous missense mutations in exon 11 of the DDX6 gene. All variants occurred at conserved residues in either the QxxR or V motifs within the second RecA-2 domain of the helicase core; this region is involved in RNA and/or ATP binding, suggesting functional consequences.

Multiple congenital anomalies.

Sources: Literature
Fetal anomalies v0.2261 DDX59 Zornitza Stark Marked gene: DDX59 as ready
Fetal anomalies v0.2259 HYLS1 Zornitza Stark Marked gene: HYLS1 as ready
Fetal anomalies v0.2257 HYLS1 Zornitza Stark changed review comment from: A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human and patient cells have shown mislocalisation of the protein to the nucleus (PMID: 15843405, PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774). 2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932). No other variants have been reported as pathogenic in this gene. Amber rating given only single founder variant reported with a hydrocephalus phenotype with supporting functional data from multiple animal models indicative of ciliopathy.; to: A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human and patient cells have shown mislocalisation of the protein to the nucleus (PMID: 15843405, PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774). 2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932). No other variants have been reported as pathogenic in this gene.

Overall, sufficient evidence that variants in this gene cause a ciliopathy.
Fetal anomalies v0.2257 HUWE1 Zornitza Stark Marked gene: HUWE1 as ready
Fetal anomalies v0.2257 HUWE1 Zornitza Stark Phenotypes for gene: HUWE1 were changed from MENTAL RETARDATION SYNDROMIC X-LINKED TURNER TYPE to Mental retardation, X-linked syndromic, Turner type, MIM#309590
Fetal anomalies v0.2255 HUWE1 Zornitza Stark changed review comment from: Females variably affected, ranging from asymptomatic carriers to fully manifesting the condition (particularly with de novo variants).; to: IUGR, joint contractures, microcephaly/macrocephaly are features.
Fetal anomalies v0.2255 HSPG2 Zornitza Stark Marked gene: HSPG2 as ready
Fetal anomalies v0.2255 HSPG2 Zornitza Stark changed review comment from: ID reported in ~25% of affected individuals.; to: Multiple congenital anomalies are a feature of both conditions.
Fetal anomalies v0.2255 HSPG2 Zornitza Stark edited their review of gene: HSPG2: Changed phenotypes: Schwartz-Jampel syndrome, type 1, MIM#255800, Dyssegmental dysplasia, Silverman-Handmaker type, MIM# 224410
Fetal anomalies v0.2255 HSD17B4 Zornitza Stark Marked gene: HSD17B4 as ready
Fetal anomalies v0.2255 HSD17B4 Zornitza Stark Phenotypes for gene: HSD17B4 were changed from PERRAULT SYNDROME; D-BIFUNCTIONAL PROTEIN DEFICIENCY to D-bifunctional protein deficiency, AR (MIM#261515)
Fetal anomalies v0.2253 HSD17B4 Zornitza Stark edited their review of gene: HSD17B4: Changed phenotypes: D-bifunctional protein deficiency, AR (MIM#261515)
Fetal anomalies v0.2253 HSD17B4 Zornitza Stark changed review comment from: DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. Less severe presentations have been termed type IV deficiency or Perrault syndrome.; to: DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. Less severe presentations have been termed type IV deficiency or Perrault syndrome.

Cortical dysplasia, renal cysts are reported features.
Fetal anomalies v0.2253 HRAS Zornitza Stark Marked gene: HRAS as ready
Fetal anomalies v0.2251 HRAS Zornitza Stark Mode of pathogenicity for gene: HRAS was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Fetal anomalies v0.2249 HRAS Zornitza Stark changed review comment from: Well established gene-disease association, over 100 affected individuals reported with a characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and developmental disability. Facial warts, particularly nasolabial, are often present in childhood.; to: Well established gene-disease association, over 100 affected individuals reported with a characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and developmental disability.
Fetal anomalies v0.2249 HOXA13 Zornitza Stark Marked gene: HOXA13 as ready
Fetal anomalies v0.2247 HIVEP2 Zornitza Stark Marked gene: HIVEP2 as ready
Fetal anomalies v0.2247 HIVEP2 Zornitza Stark Phenotypes for gene: HIVEP2 were changed from HIVEP2 associated syndromic developmental delay with intellectual disability to Mental retardation, autosomal dominant 43, MIM# 616977
Fetal anomalies v0.2244 HIVEP2 Zornitza Stark changed review comment from: More than 10 unrelated individuals reported, most variants are LOF, supportive mouse model.; to: More than 10 unrelated individuals reported, most variants are LOF, supportive mouse model.

Microcephaly and CC abnormalities reported in some.
Fetal anomalies v0.2244 HDAC8 Zornitza Stark Marked gene: HDAC8 as ready
Fetal anomalies v0.2242 HDAC8 Zornitza Stark changed review comment from: In a recent series of 246 individuals from diverse populations, congenital diaphragmatic hernia was not a common feature of HDAC8-related CdL.; to: Multiple congenital anomalies are a feature.
Fetal anomalies v0.2242 HCFC1 Zornitza Stark Marked gene: HCFC1 as ready
Fetal anomalies v0.2242 HCFC1 Zornitza Stark Phenotypes for gene: HCFC1 were changed from COBALAMIN DISORDER; MENTAL RETARDATION, X-LINKED 3 to Mental retardation, X-linked 3 (methylmalonic acidaemia and homocysteinaemia, cblX type) MIM# 309541
Fetal anomalies v0.2240 HCFC1 Zornitza Stark changed review comment from: Variants in the HCFC1 gene are associated with cases of syndromic and non-syndromic intellectual disability. Individuals present with severely delayed psychomotor development apparent in infancy, and severe neurological involvement including intractable epilepsy, facial dysmorphism, and intellectual disability.; to: Variants in the HCFC1 gene are associated with cases of syndromic and non-syndromic intellectual disability. Individuals present with severely delayed psychomotor development apparent in infancy, and severe neurological involvement including intractable epilepsy, facial dysmorphism, and intellectual disability.

Microcephaly is a feature.
Fetal anomalies v0.2240 HCCS Zornitza Stark Marked gene: HCCS as ready
Fetal anomalies v0.2240 HCCS Zornitza Stark Phenotypes for gene: HCCS were changed from MICROPHTHALMIA SYNDROMIC TYPE 7 to Linear skin defects with multiple congenital anomalies 1, MIM# 309801
Fetal anomalies v0.2238 SCUBE3 Chirag Patel reviewed gene: SCUBE3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33308444; Phenotypes: Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies, OMIM # 619184; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2236 GUSB Zornitza Stark Marked gene: GUSB as ready
Fetal anomalies v0.2236 GUSB Zornitza Stark Phenotypes for gene: GUSB were changed from MUCOPOLYSACCHARIDOSIS TYPE 7 to Mucopolysaccharidosis VII, MIM# 253220; MONDO:0009662
Fetal anomalies v0.2234 GUCY2C Zornitza Stark Marked gene: GUCY2C as ready
Fetal anomalies v0.2234 GUCY2C Zornitza Stark Phenotypes for gene: GUCY2C were changed from MECONIUM ILEUS; FAMILIAL DIARRHEA DIARRHEA 6 to Meconium ileus, MIM# 614665
Fetal anomalies v0.2230 GTF2H5 Zornitza Stark Marked gene: GTF2H5 as ready
Fetal anomalies v0.2228 GRIN2B Zornitza Stark Marked gene: GRIN2B as ready
Fetal anomalies v0.2228 GRIN2B Zornitza Stark Phenotypes for gene: GRIN2B were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT 6; AUTISM; EPILEPTIC ENCEPHALOPATHY to Mental retardation, autosomal dominant 6, MIM# 613970; Epileptic encephalopathy, early infantile, 27, MIM# 616139
Fetal anomalies v0.2224 GRIN1 Zornitza Stark Marked gene: GRIN1 as ready
Fetal anomalies v0.2221 GPSM2 Zornitza Stark Marked gene: GPSM2 as ready
Fetal anomalies v0.2219 GPI Zornitza Stark Marked gene: GPI as ready
Fetal anomalies v0.2215 SMS Chirag Patel changed review comment from: Snyder-Robinson X-linked syndromic intellectual developmental disorder (MRXSSR) is an X-linked intellectual disability syndrome with characteristic features including facial asymmetry, marfanoid habitus, unsteady gait, thickened lower lip, nasal dysarthric speech, narrow or cleft palate, diminished muscle mass, osteoporosis, kyphoscoliosis, long great toes, short stature, pectus carinatum, and myopia. Does not present antenatally/perinatally. Not suitable for fetal anomalies panel.; to: X-linked syndromic intellectual developmental disorder with characteristic features including dysmorphism, marfanoid habitus, unsteady gait, nasal dysarthric speech, diminished muscle mass, osteoporosis, kyphoscoliosis, long great toes, short stature, pectus carinatum, and myopia. Does not present antenatally. Not suitable for fetal anomalies panel.
Fetal anomalies v0.2210 GPC3 Zornitza Stark Marked gene: GPC3 as ready
Fetal anomalies v0.2208 GORAB Zornitza Stark Marked gene: GORAB as ready
Fetal anomalies v0.2205 GNPTG Zornitza Stark Marked gene: GNPTG as ready
Fetal anomalies v0.2201 GNPTG Zornitza Stark changed review comment from: Mucolipidosis type III gamma is characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates. More than 20 unrelated families reported, mouse model.; to: Mucolipidosis type III gamma is characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates. More than 20 unrelated families reported, mouse model.

Progressive metabolic disorder with childhood onset.
Fetal anomalies v0.2195 SOX11 Chirag Patel edited their review of gene: SOX11: Added comment: Coffin-Siris syndrome is characterized by mild intellectual disability, dysmorphic facial features, hypertrichosis, microcephaly, growth deficiency, and hypoplastic fifth toenails. sox11a/b knockdown in zebrafish causes brain abnormalities, potentially explaining the brain phenotype of CSS. Numerous cases reported with heterozygous mutations. Can present with IUGR antenatally. Suitable for fetal anomalies panel.; Changed publications: PubMed: 24886874, 33785884, 33430815, 33086258, 31530938
Fetal anomalies v0.2179 PBX1 Chirag Patel reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 28566479, 29036646; Phenotypes: Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, OMIM #617641; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.2073 PDE4D Zornitza Stark Marked gene: PDE4D as ready
Fetal anomalies v0.2071 PDCD10 Zornitza Stark Marked gene: PDCD10 as ready
Fetal anomalies v0.2069 PCYT1A Zornitza Stark Marked gene: PCYT1A as ready
Fetal anomalies v0.2067 LHX3 Zornitza Stark Marked gene: LHX3 as ready
Fetal anomalies v0.2067 LHX3 Zornitza Stark Phenotypes for gene: LHX3 were changed from PITUITARY HORMONE DEFICIENCY COMBINED TYPE 3 to Pituitary hormone deficiency, combined, 3 (MIM#221750)
Fetal anomalies v0.2064 LHX3 Zornitza Stark reviewed gene: LHX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 3 (MIM#221750); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2063 LGI4 Zornitza Stark Marked gene: LGI4 as ready
Fetal anomalies v0.2063 LGI4 Zornitza Stark Phenotypes for gene: LGI4 were changed from ARTHROGRYPOSIS MULTIPLEX CONGENITA to Arthrogryposis multiplex congenita, neurogenic, with myelin defect, MIM#617468
Fetal anomalies v0.2062 LGI4 Zornitza Stark changed review comment from: Severe AMC, most affected individuals die in utero or in newborn period; unclear if ID is truly part of the phenotype.; to: Severe AMC, most affected individuals die in utero or in newborn period.
Fetal anomalies v0.2062 LFNG Zornitza Stark Marked gene: LFNG as ready
Fetal anomalies v0.2060 LBR Zornitza Stark Marked gene: LBR as ready
Fetal anomalies v0.2058 LARP7 Zornitza Stark Marked gene: LARP7 as ready
Fetal anomalies v0.2058 LARP7 Zornitza Stark Gene: larp7 has been classified as Green List (High Evidence).
Fetal anomalies v0.2058 LARP7 Zornitza Stark Phenotypes for gene: LARP7 were changed from ALAZAMI SYNDROME to Alazami syndrome, MIM# 615071; Microcephalic primordial dwarfism, Alazami type MONDO:0014031
Fetal anomalies v0.2057 LARP7 Zornitza Stark Publications for gene: LARP7 were set to
Fetal anomalies v0.2056 LARGE1 Zornitza Stark Marked gene: LARGE1 as ready
Fetal anomalies v0.2056 LARGE1 Zornitza Stark Gene: large1 has been classified as Green List (High Evidence).
Fetal anomalies v0.2056 LARGE1 Zornitza Stark Phenotypes for gene: LARGE1 were changed from MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY CONGENITAL WITH BRAIN AND EYE ANOMALIES TYPE A6; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY CONGENITAL WITH MENTAL RETARDATION TYPE B6 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 6, MIM# 613154
Fetal anomalies v0.2055 LARGE1 Zornitza Stark Publications for gene: LARGE1 were set to
Fetal anomalies v0.2054 LAMA2 Zornitza Stark Marked gene: LAMA2 as ready
Fetal anomalies v0.2054 LAMA2 Zornitza Stark Phenotypes for gene: LAMA2 were changed from CONGENITAL MUSCULAR DYSTROPHY to Muscular dystrophy, congenital, merosin deficient or partially deficient, MIM# 607855
Fetal anomalies v0.2052 LAMA1 Zornitza Stark Marked gene: LAMA1 as ready
Fetal anomalies v0.2052 LAMA1 Zornitza Stark Phenotypes for gene: LAMA1 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; CEREBELLAR DYSPLASIA WITH CYSTS WITH OR WITHOUT RETINAL DYSTROPHY to Poretti-Boltshauser syndrome, MIM# 615960
Fetal anomalies v0.2050 LAMA1 Zornitza Stark changed review comment from: Four families with Poretti-Bolthauser syndrome identified in a cohort of 'unsolved' Joubert syndrome patients -- included due to phenotypic overlap.
Sources: Literature; to: Cerebellar abnormalities.

Four families with Poretti-Bolthauser syndrome identified in a cohort of 'unsolved' Joubert syndrome patients.

Sources: Literature
Fetal anomalies v0.2050 L1CAM Zornitza Stark Marked gene: L1CAM as ready
Fetal anomalies v0.2050 L1CAM Zornitza Stark Phenotypes for gene: L1CAM were changed from MENTAL RETARDATION-APHASIA-SHUFFLING GAIT-ADDUCTED THUMBS SYNDROME; PARTIAL AGENESIS OF THE CORPUS CALLOSUM; HYDROCEPHALUS DUE TO STENOSIS OF THE AQUEDUCT OF SYLVIUS; SPASTIC PARAPLEGIA X-LINKED TYPE 1 to Hydrocephalus due to aqueductal stenosis, MIM# 307000
Fetal anomalies v0.2048 L1CAM Zornitza Stark changed review comment from: L1CAM conditions are typically associated with adducted thumb/lower limb spasticity. Single report identified of arthrogryposis.; to: Well established gene-disease association.
Fetal anomalies v0.2048 KYNU Zornitza Stark Marked gene: KYNU as ready
Fetal anomalies v0.2048 KYNU Zornitza Stark Phenotypes for gene: KYNU were changed from Vertebral, cardiac, renal, and limb defects syndrome 2 617661 to Vertebral, cardiac, renal, and limb defects syndrome 2 , MIM#617661
Fetal anomalies v0.2047 KYNU Zornitza Stark changed review comment from: Not convinced ID is part of the phenotype.; to: Multiple congenital anomalies.
Fetal anomalies v0.2047 KYNU Zornitza Stark edited their review of gene: KYNU: Changed rating: GREEN; Changed phenotypes: Vertebral, cardiac, renal, and limb defects syndrome 2, MIM#617661; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.2047 KRAS Zornitza Stark Marked gene: KRAS as ready
Fetal anomalies v0.2047 KRAS Zornitza Stark Phenotypes for gene: KRAS were changed from NOONAN SYNDROME TYPE 3; CARDIOFACIOCUTANEOUS SYNDROME to Noonan syndrome 3, MIM# 609942; Cardiofaciocutaneous syndrome 2, MIM# 615278
Fetal anomalies v0.2044 KRAS Zornitza Stark changed review comment from: Well established gene-disease association in individuals with Noonan syndrome, CFC and overlapping Noonan-CFC.; to: Well established gene-disease association in individuals with Noonan syndrome, CFC and overlapping Noonan-CFC.

Multiple congenital anomalies, esp cardiac; hydrops.
Fetal anomalies v0.2044 KMT2D Zornitza Stark Marked gene: KMT2D as ready
Fetal anomalies v0.2041 KMT2D Zornitza Stark changed review comment from: Rare reports of CDH in Kabuki syndrome, not a characteristic or common feature; however, 4 identified in this CDH cohort.; to: Multiple congenital anomalies syndrome.
Fetal anomalies v0.2041 KMT2C Zornitza Stark Marked gene: KMT2C as ready
Fetal anomalies v0.2039 KMT2C Zornitza Stark changed review comment from: Mostly PTCs, 2 missense reported in ClinVar but in silicos evidence only; to: Mostly PTCs, 2 missense reported in ClinVar but in silicos evidence only.

Multiple congenital anomalies syndrome.
Fetal anomalies v0.2039 KMT2A Zornitza Stark Marked gene: KMT2A as ready
Fetal anomalies v0.2037 SPARC Chirag Patel Classified gene: SPARC as Red List (low evidence)
Fetal anomalies v0.2037 SPARC Chirag Patel Gene: sparc has been classified as Red List (Low Evidence).
Fetal anomalies v0.2036 SPARC Chirag Patel reviewed gene: SPARC: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v0.2036 KLHL41 Zornitza Stark Marked gene: KLHL41 as ready
Fetal anomalies v0.2034 KLHL40 Zornitza Stark Marked gene: KLHL40 as ready
Fetal anomalies v0.2032 KIF7 Zornitza Stark Marked gene: KIF7 as ready
Fetal anomalies v0.2032 KIF7 Zornitza Stark Phenotypes for gene: KIF7 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; ACROCALLOSAL SYNDROME to Hydrolethalus syndrome 2, MIM# 614120; Acrocallosal syndrome
Fetal anomalies v0.2030 KIF1BP Zornitza Stark Marked gene: KIF1BP as ready
Fetal anomalies v0.2028 KIF1BP Zornitza Stark changed review comment from: Comment when marking as ready: HGNC approved name KIFBP.; to: Comment when marking as ready: HGNC approved name KIFBP.

Multiple congenital anomalies syndrome.
Fetal anomalies v0.2028 KIF1A Zornitza Stark Marked gene: KIF1A as ready
Fetal anomalies v0.2028 KIF1A Zornitza Stark Phenotypes for gene: KIF1A were changed from NESCAV SYNDROME, 614255; NEUROPATHY, HEREDITARY SENSORY, TYPE IIC, 614213 to NESCAV syndrome, MIM# 614255
Fetal anomalies v0.2024 KIF11 Zornitza Stark Marked gene: KIF11 as ready
Fetal anomalies v0.2024 KIF11 Zornitza Stark Phenotypes for gene: KIF11 were changed from AUTOSOMAL-DOMINANT MICROCEPHALY ASSOCIATED WITH LYMPHEDEMA AND/OR CHORIORETINOPATHY to Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation, MIM# 152950; MONDO:0007918
Fetal anomalies v0.2020 KIAA0586 Zornitza Stark Marked gene: KIAA0586 as ready
Fetal anomalies v0.2006 TSFM Chirag Patel changed review comment from: Combined oxidative phosphorylation deficiency-3 not presenting antenatally. Not suitable for fetal anomalies panel.; to: Combined oxidative phosphorylation deficiency-3 can present with paucity of fetal movements, IUGR, and hypertrophic cardiomyopathy postnatally. Suitable for fetal anomalies panel.
Fetal anomalies v0.2004 TUBB3 Chirag Patel reviewed gene: TUBB3: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 20829227, 25059107, 32169460, 30272120; Phenotypes: Cortical dysplasia, complex, with other brain malformations 1, OMIM # 614039, Fibrosis of extraocular muscles, congenital, 3A, OMIM # 600638; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.2002 VEGFC Chirag Patel changed review comment from: Primary lymphoedema not presenting antenatally. Not suitable for fetal anomalies panel.; to: Primary lymphoedema not presenting antenatally. Not suitable for fetal anomalies panel.
Fetal anomalies v0.2000 ZNF462 Chirag Patel changed review comment from: Dysgenesis of corpus callosum and structural heart defects reported as part of syndrome.; to: Dysgenesis of corpus callosum and structural heart defects reported as part of syndrome.
Suitable for fetal anomalies panel.
Fetal anomalies v0.1999 ZNF462 Chirag Patel commented on gene: ZNF462: Dysgenesis of corpus callosum and structural heart defects reported as part of syndrome.
Fetal anomalies v0.1999 KDM6A Zornitza Stark Marked gene: KDM6A as ready
Fetal anomalies v0.1998 KDM6A Zornitza Stark changed review comment from: Cannot find specific reports of CDH in association with variants in this gene.; to: Multiple congenital anomalies syndrome.
Fetal anomalies v0.1998 KDM5C Zornitza Stark Marked gene: KDM5C as ready
Fetal anomalies v0.1998 KDM5C Zornitza Stark Phenotypes for gene: KDM5C were changed from MENTAL RETARDATION SYNDROMIC X-LINKED JARID1C-RELATED to Mental retardation, X-linked, syndromic, Claes-Jensen type, MIM# 300534; MONDO:0010355
Fetal anomalies v0.1995 KDM5C Zornitza Stark changed review comment from: Intellectual disability, progressive lower limb spasticity, epilepsy and a number of other more variable features. Affected females reported PMID 32279304.; to: Intellectual disability, progressive lower limb spasticity, epilepsy and a number of other more variable features. Affected females reported PMID 32279304.

Micro and macrocephaly reported.
Fetal anomalies v0.1995 KCNJ1 Zornitza Stark Marked gene: KCNJ1 as ready
Fetal anomalies v0.1995 KCNJ1 Zornitza Stark Phenotypes for gene: KCNJ1 were changed from Bartter syndrome 241200 to Bartter syndrome, type 2, MIM#241200
Fetal anomalies v0.1994 KCNJ1 Zornitza Stark changed review comment from: I am not convinced ID is an intrinsic part of the phenotype.; to: Can present with polyhydramnios.
Fetal anomalies v0.1994 KANSL1 Zornitza Stark Marked gene: KANSL1 as ready
Fetal anomalies v0.1991 KANSL1 Zornitza Stark changed review comment from: Well established gene-disease association, CNVs common.; to: Well established gene-disease association, CNVs common. Cardiac and GU abnormalities reported.
Fetal anomalies v0.1991 JAG1 Zornitza Stark Marked gene: JAG1 as ready
Fetal anomalies v0.1989 JAG1 Zornitza Stark changed review comment from: ID is not typically part of the phenotype.; to: Congenital heart disease is part of the phenotype.
Fetal anomalies v0.1989 SLC33A1 Zornitza Stark Phenotypes for gene: SLC33A1 were changed from CONGENITAL CATARACTS, HEARING LOSS, AND NEURODEGENERATION, OMIM#614482 to Congenital cataracts, hearing loss, and neurodegeneration, MIM# 614482
Fetal anomalies v0.1988 MAMLD1 Zornitza Stark Marked gene: MAMLD1 as ready
Fetal anomalies v0.1985 ITGA8 Zornitza Stark Marked gene: ITGA8 as ready
Fetal anomalies v0.1983 INPP5K Zornitza Stark Marked gene: INPP5K as ready
Fetal anomalies v0.1983 INPP5K Zornitza Stark Phenotypes for gene: INPP5K were changed from Muscular dystrophy, congenital, with cataracts and intellectual disability to Muscular dystrophy, congenital, with cataracts and intellectual disability MIM#617404
Fetal anomalies v0.1981 LAMP2 Zornitza Stark Marked gene: LAMP2 as ready
Fetal anomalies v0.1979 LAMB3 Zornitza Stark Marked gene: LAMB3 as ready
Fetal anomalies v0.1978 IGFBP7 Zornitza Stark Marked gene: IGFBP7 as ready
Fetal anomalies v0.1978 IGFBP7 Zornitza Stark Phenotypes for gene: IGFBP7 were changed from RETINAL ARTERIAL MACROANEURYSM WITH SUPRAVALVULAR PULMONIC STENOSIS to Retinal arterial macroaneurysm with supravalvular pulmonic stenosis MIM#614224
Fetal anomalies v0.1975 LAMA3 Zornitza Stark Marked gene: LAMA3 as ready
Fetal anomalies v0.1972 NSD2 Zornitza Stark Marked gene: NSD2 as ready
Fetal anomalies v0.1971 NSD2 Zornitza Stark gene: NSD2 was added
gene: NSD2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NSD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NSD2 were set to 30345613; 31171569
Phenotypes for gene: NSD2 were set to Rauch-Steindl syndrome, MIM# 619695
Review for gene: NSD2 was set to GREEN
Added comment: 7 unrelated individuals reported with LOF variants. Gene thought to be responsible for many of the features of Wolf-Hirschorn syndrome.

Prenatal growth retardation is a feature.
Sources: Literature
Fetal anomalies v0.1970 SMAD4 Seb Lunke Marked gene: SMAD4 as ready
Fetal anomalies v0.1970 SMAD4 Seb Lunke Phenotypes for gene: SMAD4 were changed from JUVENILE POLYPOSIS SYNDROME; MYHRE SYNDROME; JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME to Myhre syndrome, OMIM#139210, MONDO:0007688
Fetal anomalies v0.1969 SMAD3 Seb Lunke Marked gene: SMAD3 as ready
Fetal anomalies v0.1968 SLC33A1 Seb Lunke Marked gene: SLC33A1 as ready
Fetal anomalies v0.1968 SLC33A1 Seb Lunke Phenotypes for gene: SLC33A1 were changed from AUTOSOMAL-RECESSIVE DISORDER WITH CONGENITAL CATARACTS, HEARING LOSS, AND LOW SERUM COPPER AND CERULOPLASMIN to CONGENITAL CATARACTS, HEARING LOSS, AND NEURODEGENERATION, OMIM#614482
Fetal anomalies v0.1966 SLC33A1 Seb Lunke reviewed gene: SLC33A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31194315; Phenotypes: CONGENITAL CATARACTS, HEARING LOSS, AND NEURODEGENERATION, OMIM#614482; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1966 KISS1R Zornitza Stark Marked gene: KISS1R as ready
Fetal anomalies v0.1965 KCTD7 Zornitza Stark Marked gene: KCTD7 as ready
Fetal anomalies v0.1965 KCTD7 Zornitza Stark Phenotypes for gene: KCTD7 were changed from PROGRESSIVE MYOCLONIC EPILEPSY TYPE 3; NEURONAL CEROID LIPOFUSCINOSIS to Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM#611726)
Fetal anomalies v0.1963 IDH1 Zornitza Stark Marked gene: IDH1 as ready
Fetal anomalies v0.1963 IDH1 Zornitza Stark Phenotypes for gene: IDH1 were changed from Maffucci syndrome 614569; Ollier disease/ Dyschondroplasia 166000; Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria 614875 to Ollier disease MONDO:0008145; Maffucci syndrome MONDO:0013808
Fetal anomalies v0.1959 HPD Zornitza Stark Marked gene: HPD as ready
Fetal anomalies v0.1959 HPD Zornitza Stark Phenotypes for gene: HPD were changed from TYROSINEMIA TYPE 3; HAWKINSINURIA to Hawkinsinuria (MIM#140350), AD; Tyrosinemia type III (MIM#276710), AR
Fetal anomalies v0.1955 HNRNPH2 Zornitza Stark Marked gene: HNRNPH2 as ready
Fetal anomalies v0.1952 KCNT1 Zornitza Stark Marked gene: KCNT1 as ready
Fetal anomalies v0.1952 KCNT1 Zornitza Stark Phenotypes for gene: KCNT1 were changed from SEVERE AUTOSOMAL DOMINANT NOCTURNAL FRONTAL LOBE EPILEPSY; MALIGNANT MIGRATING PARTIAL SEIZURES OF INFANCY to Epilepsy, nocturnal frontal lobe, 5 (MIM#615005); Epileptic encephalopathy, early infantile, 14 (MIM#614959)
Fetal anomalies v0.1949 KCNQ2 Zornitza Stark Marked gene: KCNQ2 as ready
Fetal anomalies v0.1949 KCNQ2 Zornitza Stark Phenotypes for gene: KCNQ2 were changed from EPILEPTIC ENCEPHALOPATHY EARLY INFANTILE TYPE 7; BENIGN NEONATAL EPILEPSY TYPE 1 to Developmental and epileptic encephalopathy 7 (MIM#613720); Myokymia (MIM#121200); Seizures, benign neonatal, 1 (MIM#121200)
Fetal anomalies v0.1946 HMGA2 Zornitza Stark Marked gene: HMGA2 as ready
Fetal anomalies v0.1943 KCNJ11 Zornitza Stark Marked gene: KCNJ11 as ready
Fetal anomalies v0.1940 NAA10 Zornitza Stark Marked gene: NAA10 as ready
Fetal anomalies v0.1938 NAA10 Zornitza Stark edited their review of gene: NAA10: Added comment: For Ogden association, PMID 34075687:
lethal X-linked. 9 males from 3 families with recurrent Ser37Pro
All presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias

For non-lethal syndromic ID:
reported in 10 males and (mostly de novo) in 37 females
variants causing this are missense located along the protein and 1 truncating; Changed publications: 30842225, 24431331, 34075687; Changed phenotypes: Microphthalmia, syndromic 1, MIM# 309800 Ogden syndrome MIM#300855
Fetal anomalies v0.1938 SF3B4 Seb Lunke Marked gene: SF3B4 as ready
Fetal anomalies v0.1933 INPP5K Ain Roesley reviewed gene: INPP5K: Rating: AMBER; Mode of pathogenicity: None; Publications: 28190456, 28190459, 28940338, 31630891, 33193651, 33792664; Phenotypes: Muscular dystrophy, congenital, with cataracts and intellectual disability MIM#617404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1933 LAMA3 Daniel Flanagan changed review comment from: Biallelic LAMA3 variants cause junctional epidermolysis bullosa, blistering is present at birth or shortly after.

LAMA3 also associated with Laryngoonychocutaneous syndrome, which seems to have ulceration in the first few months of life.; to: Biallelic LAMA3 variants cause epidermolysis bullosa, blistering is present at birth or shortly after.

LAMA3 also associated with Laryngoonychocutaneous syndrome, which appears to have ulceration and other features onset in the first few months of life.
Fetal anomalies v0.1933 IGFBP7 Ain Roesley reviewed gene: IGFBP7: Rating: RED; Mode of pathogenicity: None; Publications: Retinal arterial macroaneurysm with supravalvular pulmonic stenosis 614224; Phenotypes: Retinal arterial macroaneurysm with supravalvular pulmonic stenosis MIM#614224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1933 LAMA3 Daniel Flanagan reviewed gene: LAMA3: Rating: RED; Mode of pathogenicity: None; Publications: 7633458, 8530087, 11810295, 10366601; Phenotypes: Epidermolysis bullosa, generalized atrophic benign (MIM#226650), Epidermolysis bullosa, junctional, Herlitz type (MIM#226700), Laryngoonychocutaneous syndrome (MIM#245660); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1933 KCTD7 Daniel Flanagan changed review comment from: Biallelic KCTD7 variants reported in multile families with myoclonic epilepsy. No antenatally relevant features.; to: Biallelic KCTD7 variants reported in multile families with myoclonic epilepsy.

Two affected siblings had microcephaly by the age of 12 years and 10 years, but were normal at infancy.
Fetal anomalies v0.1933 KCTD7 Daniel Flanagan reviewed gene: KCTD7: Rating: RED; Mode of pathogenicity: None; Publications: 33767931, 33970744, 22693283, 22748208; Phenotypes: Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM#611726); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1933 HPD Ain Roesley reviewed gene: HPD: Rating: RED; Mode of pathogenicity: None; Publications: 10942115, 17560158, 27604308; Phenotypes: Hawkinsinuria (MIM#140350), AD, Tyrosinemia type III (MIM#276710), AR; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1933 KCNT1 Daniel Flanagan reviewed gene: KCNT1: Rating: RED; Mode of pathogenicity: None; Publications: 23086397, 23086396, 31872048, 31532509; Phenotypes: Epilepsy, nocturnal frontal lobe, 5 (MIM#615005), Epileptic encephalopathy, early infantile, 14 (MIM#614959); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.1933 IFT140 Zornitza Stark Marked gene: IFT140 as ready
Fetal anomalies v0.1931 IFT140 Zornitza Stark edited their review of gene: IFT140: Added comment: Note mono-allelic variants have been associated with renal cysts, but age of onset uncertain.; Changed publications: 22503633, 23418020, 28288023, 28724397, 26216056, 26968735, 34890546
Fetal anomalies v0.1931 PI4KA Zornitza Stark Marked gene: PI4KA as ready
Fetal anomalies v0.1930 PI4KA Zornitza Stark gene: PI4KA was added
gene: PI4KA was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis MIM#616531; Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis MONDO:0014679
Review for gene: PI4KA was set to GREEN
Added comment: 8 families reported with CNS abnormalities.
Sources: Expert Review
Fetal anomalies v0.1929 GNAS Zornitza Stark Marked gene: GNAS as ready
Fetal anomalies v0.1929 GNAS Zornitza Stark Phenotypes for gene: GNAS were changed from ALBRIGHT HEREDITARY OSTEODYSTROPHY; GNAS HYPERFUNCTION; PSEUDOHYPOPARATHYROIDISM TYPE 1B; ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA to Pseudohypoparathyroidism Ia, MIM# 103580
Fetal anomalies v0.1926 GNAS Zornitza Stark reviewed gene: GNAS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pseudohypoparathyroidism Ia, MIM# 103580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Fetal anomalies v0.1926 GNAO1 Zornitza Stark Marked gene: GNAO1 as ready
Fetal anomalies v0.1926 GNAO1 Zornitza Stark Phenotypes for gene: GNAO1 were changed from EPILEPTIC ENCEPHALOPATHY to Epileptic encephalopathy, early infantile, 17, MIM#615473; Neurodevelopmental disorder with involuntary movements, MIM# 617493
Fetal anomalies v0.1923 GNAO1 Zornitza Stark changed review comment from: Loss of function mutations (PTCs and missense) cause EEIE, and gain of function mutations (missense, inframe deletion) cause NDIM. Almost all reports are de novo, rare parental mosaicism also reported (PMID: 30682224); to: Loss of function mutations (PTCs and missense) cause EEIE, and gain of function mutations (missense, inframe deletion) cause NDIM. Almost all reports are de novo, rare parental mosaicism also reported (PMID: 30682224)

Microcephaly reported in some individuals.
Fetal anomalies v0.1923 GNAO1 Zornitza Stark edited their review of gene: GNAO1: Changed phenotypes: Epileptic encephalopathy, early infantile, 17, MIM#615473, Neurodevelopmental disorder with involuntary movements, MIM# 617493
Fetal anomalies v0.1923 GMPPB Zornitza Stark Marked gene: GMPPB as ready
Fetal anomalies v0.1923 GMPPB Zornitza Stark Phenotypes for gene: GMPPB were changed from MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 14 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350
Fetal anomalies v0.1922 GMPPB Zornitza Stark edited their review of gene: GMPPB: Changed phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350
Fetal anomalies v0.1922 GLIS3 Zornitza Stark Marked gene: GLIS3 as ready
Fetal anomalies v0.1920 GLI3 Zornitza Stark Marked gene: GLI3 as ready
Fetal anomalies v0.1918 GLE1 Zornitza Stark Marked gene: GLE1 as ready
Fetal anomalies v0.1918 GLE1 Zornitza Stark Phenotypes for gene: GLE1 were changed from ARTHROGRYPOSIS, LETHAL, WITH ANTERIOR HORN CELL DISEASE to Lethal congenital contracture syndrome 1, MIM# 253310
Fetal anomalies v0.1916 GLDN Zornitza Stark Marked gene: GLDN as ready
Fetal anomalies v0.1916 GLDN Zornitza Stark Phenotypes for gene: GLDN were changed from Lethal arthroogryposis to Lethal congenital contracture syndrome 11, MIM# 617194; MONDO:0014965
Fetal anomalies v0.1914 GJA8 Zornitza Stark Marked gene: GJA8 as ready
Fetal anomalies v0.1914 GJA8 Zornitza Stark Phenotypes for gene: GJA8 were changed from CATARACT ZONULAR PULVERULENT TYPE 1; CATARACT-MICROCORNEA SYNDROME to Cataract 1, multiple types, MIM# 116200; Microphthalmia
Fetal anomalies v0.1911 GJA1 Zornitza Stark changed review comment from: Gene is associated with a large number of phenotypes, but ID is not a typical feature of any of these conditions.; to: Gene is associated with a large number of fatally-relevant phenotypes.
Fetal anomalies v0.1911 GJA1 Zornitza Stark Marked gene: GJA1 as ready
Fetal anomalies v0.1911 GJA1 Zornitza Stark Phenotypes for gene: GJA1 were changed from AUTOSOMAL RECESSIVE OCULODENTODIGITAL DYSPLASIA; HALLERMANN-STREIFF SYNDROME; HYPOPLASTIC LEFT HEART SYNDROME; AUTOSOMAL DOMINANT OCULODENTODIGITAL DYSPLASIA to Atrioventricular septal defect 3, MIM#600309; Craniometaphyseal dysplasia, autosomal recessive, MIM#218400; Hypoplastic left heart syndrome 1, MIM#241550; Oculodentodigital dysplasia, MIM#164200; Oculodentodigital dysplasia, autosomal recessive, MIM#257850; Syndactyly, type III, MIM# 186100
Fetal anomalies v0.1910 GJA1 Zornitza Stark edited their review of gene: GJA1: Changed phenotypes: Atrioventricular septal defect 3, MIM#600309, Craniometaphyseal dysplasia, autosomal recessive, MIM#218400, Hypoplastic left heart syndrome 1, MIM#241550, Oculodentodigital dysplasia, MIM#164200, Oculodentodigital dysplasia, autosomal recessive, MIM#257850, Syndactyly, type III, MIM# 186100
Fetal anomalies v0.1910 GJA1 Zornitza Stark edited their review of gene: GJA1: Changed phenotypes: Atrioventricular septal defect 3, MIM#600309, Craniometaphyseal dysplasia, autosomal recessive, MIM#218400, Hypoplastic left heart syndrome 1, MIM#241550, Oculodentodigital dysplasia, MIM#164200, Oculodentodigital dysplasia, autosomal recessive, MIM#257850, Palmoplantar keratoderma with congenital alopecia, MIM#104100, Syndactyly, type III, MIM# 186100
Fetal anomalies v0.1910 GDF5 Zornitza Stark Marked gene: GDF5 as ready
Fetal anomalies v0.1907 EDN1 Zornitza Stark Marked gene: EDN1 as ready
Fetal anomalies v0.1907 EDN1 Zornitza Stark Phenotypes for gene: EDN1 were changed from AURICULOCONDYLAR SYNDROME to Auriculocondylar syndrome 3, MIM# 615706
Fetal anomalies v0.1903 SLC25A20 Zornitza Stark Marked gene: SLC25A20 as ready
Fetal anomalies v0.1903 SLC25A20 Zornitza Stark Phenotypes for gene: SLC25A20 were changed from CARNITINE-ACYLCARNITINE TRANSLOCASE DEFICIENCY to Carnitine-acylcarnitine translocase deficiency, MIM#212138
Fetal anomalies v0.1900 SLC25A20 Zornitza Stark changed review comment from: Clinical features include neurologic abnormalities, cardiomyopathy and arrhythmias, skeletal muscle damage, and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate.; to: Clinical features include neurologic abnormalities, cardiomyopathy and arrhythmias, skeletal muscle damage, and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate.

Unclear if can present antenatally.
Fetal anomalies v0.1900 SLC25A20 Zornitza Stark edited their review of gene: SLC25A20: Added comment: Clinical features include neurologic abnormalities, cardiomyopathy and arrhythmias, skeletal muscle damage, and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate.; Changed rating: GREEN
Fetal anomalies v0.1900 SLC27A4 Seb Lunke Marked gene: SLC27A4 as ready
Fetal anomalies v0.1898 TRPV4 Zornitza Stark Phenotypes for gene: TRPV4 were changed from METATROPIC DYSPLASIA; SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE to Brachyolmia type 3, MIM# 113500; Metatropic dysplasia, MIM# 156530; SED, Maroteaux type, MIM# 184095; Spondylometaphyseal dysplasia, Kozlowski type, MIM# 184252
Fetal anomalies v0.1896 TRPV6 Zornitza Stark Phenotypes for gene: TRPV6 were changed from Hyperparathyroidism, transient neonatal, 618188; Transient Neonatal Hyperparathyroidism to Hyperparathyroidism, transient neonatal, MIM#618188
Fetal anomalies v0.1893 TRPV6 Zornitza Stark reviewed gene: TRPV6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperparathyroidism, transient neonatal, MIM# 618188; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1889 EDN1 Belinda Chong reviewed gene: EDN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23315542 23913798 24268655; Phenotypes: Auriculocondylar syndrome 3, MIM# 615706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1889 SLC26A3 Seb Lunke Marked gene: SLC26A3 as ready
Fetal anomalies v0.1889 SLC26A3 Seb Lunke Phenotypes for gene: SLC26A3 were changed from Chloride diarrhea, congenital, Finnish type 214700 to Diarrhea 1, secretory chloride, congenital, MIM#214700
Fetal anomalies v0.1885 SLC26A3 Seb Lunke reviewed gene: SLC26A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31325522, 31477378, 21394828; Phenotypes: Diarrhea 1, secretory chloride, congenital, MIM#214700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1883 SLC26A2 Seb Lunke Marked gene: SLC26A2 as ready
Fetal anomalies v0.1874 SLC25A24 Seb Lunke Marked gene: SLC25A24 as ready
Fetal anomalies v0.1874 SLC25A24 Seb Lunke Phenotypes for gene: SLC25A24 were changed from Gorlin-Chaudhry-Moss syndrome (GCMS); Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction to Fontaine progeroid syndrome, MIM#612289
Fetal anomalies v0.1869 SLC25A20 Seb Lunke reviewed gene: SLC25A20: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Carnitine-acylcarnitine translocase deficiency, MIM#212138; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1869 TRPV4 Alison Yeung Marked gene: TRPV4 as ready
Fetal anomalies v0.1869 TRPV4 Alison Yeung reviewed gene: TRPV4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Brachyolmia type 3, MIM# 113500, Metatropic dysplasia, MIM# 156530, SED, Maroteaux type, MIM# 184095, Spondylometaphyseal dysplasia, Kozlowski type, MIM# 184252; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v0.1869 TRPV6 Alison Yeung Marked gene: TRPV6 as ready
Fetal anomalies v0.1868 TRPV6 Alison Yeung reviewed gene: TRPV6: Rating: GREEN; Mode of pathogenicity: None; Publications: 32383311, 31930989, 29861107; Phenotypes: Hyperparathyroidism, transient neonatal, MIM# 618188, Early onset chronic pancreatitis susceptibility; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1868 TSC1 Alison Yeung Marked gene: TSC1 as ready
Fetal anomalies v0.1868 TSC2 Alison Yeung Marked gene: TSC2 as ready
Fetal anomalies v0.1868 TTC37 Alison Yeung Marked gene: TTC37 as ready
Fetal anomalies v0.1867 TTC7A Alison Yeung Marked gene: TTC7A as ready
Fetal anomalies v0.1867 TUBA1A Alison Yeung Marked gene: TUBA1A as ready
Fetal anomalies v0.1866 TUBA8 Alison Yeung Marked gene: TUBA8 as ready
Fetal anomalies v0.1866 TUBB4A Alison Yeung Marked gene: TUBB4A as ready
Fetal anomalies v0.1866 TWIST1 Alison Yeung Marked gene: TWIST1 as ready
Fetal anomalies v0.1866 UROS Alison Yeung Marked gene: UROS as ready
Fetal anomalies v0.1865 DZIP1L Zornitza Stark Marked gene: DZIP1L as ready
Fetal anomalies v0.1864 REN Zornitza Stark Marked gene: REN as ready
Fetal anomalies v0.1864 REN Zornitza Stark Phenotypes for gene: REN were changed from Renal tubular dysgenesis 267430 to Renal tubular dysgenesis, MIM#267430
Fetal anomalies v0.1862 REN Zornitza Stark reviewed gene: REN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Renal tubular dysgenesis, MIM#267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1862 RELN Zornitza Stark Marked gene: RELN as ready
Fetal anomalies v0.1860 RAB23 Zornitza Stark Marked gene: RAB23 as ready
Fetal anomalies v0.1860 RAB23 Zornitza Stark Phenotypes for gene: RAB23 were changed from ACROCEPHALOPOLYSYNDACTYLY TYPE 2 to Carpenter syndrome (MIM#201000)
Fetal anomalies v0.1858 KCNJ10 Zornitza Stark Marked gene: KCNJ10 as ready
Fetal anomalies v0.1858 KCNJ10 Zornitza Stark Phenotypes for gene: KCNJ10 were changed from SEIZURES-SENSORINEURAL DEAFNESS-ATAXIA-MENTAL RETARDATION-ELECTROLYTE IMBALANCE to SESAME syndrome (MIM#612780); Enlarged vestibular aqueduct, digenic (MIM#600791)
Fetal anomalies v0.1856 DSG1 Zornitza Stark Marked gene: DSG1 as ready
Fetal anomalies v0.1856 DSG1 Zornitza Stark Phenotypes for gene: DSG1 were changed from SEVERE DERMATITIS, MULTIPLE ALLERGIES AND METABOLIC WASTING to Erythroderma, congenital, with palmoplantar keratoderma, hypotrichosis, and hyper IgE, AR (MIM#615508)
Fetal anomalies v0.1854 DSG1 Zornitza Stark reviewed gene: DSG1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26288349; Phenotypes: Erythroderma, congenital, with palmoplantar keratoderma, hypotrichosis, and hyper IgE, AR (MIM#615508); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1854 DPF2 Zornitza Stark Marked gene: DPF2 as ready
Fetal anomalies v0.1851 DNAJC19 Zornitza Stark Marked gene: DNAJC19 as ready
Fetal anomalies v0.1849 REN Naomi Baker reviewed gene: REN: Rating: GREEN; Mode of pathogenicity: None; Publications: 16116425, 22095942; Phenotypes: Renal tubular dysgenesis, MIM#267430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1849 RAB23 Naomi Baker reviewed gene: RAB23: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:17503333, 21412941, 23599695, 25168863; Phenotypes: Carpenter syndrome (MIM#201000); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1849 KCNJ10 Daniel Flanagan reviewed gene: KCNJ10: Rating: RED; Mode of pathogenicity: None; Publications: 19289823, 19420365, 21849804, 19426954; Phenotypes: SESAME syndrome (MIM#612780), Enlarged vestibular aqueduct, digenic (MIM#600791); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1849 JAGN1 Zornitza Stark Marked gene: JAGN1 as ready
Fetal anomalies v0.1844 DSG1 Belinda Chong reviewed gene: DSG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19558595, 29315490, 31192455, 23974871, 29229434, 33666035; Phenotypes: Erythroderma, congenital, with palmoplantar keratoderma, hypotrichosis, and hyper IgE, AR (MIM#615508), Keratosis palmoplantaris striata I, AD (MIM# 148700); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1844 KBTBD13 Zornitza Stark Marked gene: KBTBD13 as ready
Fetal anomalies v0.1840 GDF1 Zornitza Stark Marked gene: GDF1 as ready
Fetal anomalies v0.1840 GDF1 Zornitza Stark Phenotypes for gene: GDF1 were changed from Right atrial isomerism (Ivemark); Congenital heart defects, multiple types to Congenital heart defects, multiple types, 6 613854; Right atrial isomerism (Ivemark) 208530
Fetal anomalies v0.1838 GBE1 Zornitza Stark Marked gene: GBE1 as ready
Fetal anomalies v0.1837 GBA2 Zornitza Stark Marked gene: GBA2 as ready
Fetal anomalies v0.1837 GBA2 Zornitza Stark Phenotypes for gene: GBA2 were changed from AUTOSOMAL-RECESSIVE CEREBELLAR ATAXIA WITH SPASTICITY. to Spastic paraplegia 46, autosomal recessive, MIM#614409
Fetal anomalies v0.1835 GBA Zornitza Stark Marked gene: GBA as ready
Fetal anomalies v0.1833 GATA6 Zornitza Stark Marked gene: GATA6 as ready
Fetal anomalies v0.1833 GATA6 Zornitza Stark Phenotypes for gene: GATA6 were changed from ATRIOVENTRICULAR SEPTAL DEFECT 5; PANCREATIC AGENESIS, DIAPHRAGMATIC HERNIA AND CONGENITAL HEART DEFECTS; ATRIAL SEPTAL DEFECT 9 to Pancreatic agenesis and congenital heart defects, MIM# 600001
Fetal anomalies v0.1830 GATA2 Zornitza Stark Marked gene: GATA2 as ready
Fetal anomalies v0.1826 GALC Zornitza Stark Marked gene: GALC as ready
Fetal anomalies v0.1825 G6PC3 Zornitza Stark Marked gene: G6PC3 as ready
Fetal anomalies v0.1823 G6PC3 Zornitza Stark edited their review of gene: G6PC3: Added comment: Congenital heart defects are a feature.; Changed rating: GREEN
Fetal anomalies v0.1823 FYCO1 Zornitza Stark Marked gene: FYCO1 as ready
Fetal anomalies v0.1823 FYCO1 Zornitza Stark Phenotypes for gene: FYCO1 were changed from Cataract 18 (MIN#610019) AR to Cataract 18 (MIM#610019) AR
Fetal anomalies v0.1822 FYCO1 Zornitza Stark Phenotypes for gene: FYCO1 were changed from CATARACT, AUTOSOMAL RECESSIVE CONGENITAL 2 to Cataract 18 (MIN#610019) AR
Fetal anomalies v0.1820 FTL Zornitza Stark Marked gene: FTL as ready
Fetal anomalies v0.1820 FTL Zornitza Stark Phenotypes for gene: FTL were changed from HEREDITARY HYPERFERRITINEMIA-CATARACT SYNDROME to Hyperferritinemia-cataract syndrome, MIM# 600886
Fetal anomalies v0.1818 FTL Zornitza Stark edited their review of gene: FTL: Added comment: Cataracts are congenital in some and may be detectable antenatally.; Changed rating: GREEN; Changed phenotypes: Hyperferritinemia-cataract syndrome, MIM# 600886; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.1818 FRMD4A Zornitza Stark Marked gene: FRMD4A as ready
Fetal anomalies v0.1818 FRMD4A Zornitza Stark Phenotypes for gene: FRMD4A were changed from ?Corpus callosum, agenesis of, with facial anomalies and cerebellar ataxia, 616819 to Intellectual disability; microcephaly; Corpus callosum, agenesis of, with facial anomalies and cerebellar ataxia, MIM# 616819
Fetal anomalies v0.1815 FREM1 Zornitza Stark Marked gene: FREM1 as ready
Fetal anomalies v0.1813 FREM1 Zornitza Stark changed review comment from: Single individual reported with compound het variants in this gene, supportive mouse model. Individual did not have features of BNAR/MOTA syndromes.
Sources: Literature; to: Single individual reported with compound het variants in this gene and CDH, supportive mouse model. Individual did not have features of BNAR/MOTA syndromes.
Sources: Literature
Fetal anomalies v0.1813 FREM1 Zornitza Stark edited their review of gene: FREM1: Added comment: Bi-allelic variants are associated with multiple congenital anomaly syndromes (MOTA and BNAR), which likely represent a spectrum.

Three families reported with trigonocephaly and single missense variants.; Changed rating: GREEN; Changed publications: 32016392, 21931569, 21507892, 19732862, 20301721, 28111185; Changed phenotypes: Manitoba oculotrichoanal syndrome 248450, Bifid nose with or without anorectal and renal anomalies, MIM# 608980, Trigonocephaly 2, MIM# 614485
Fetal anomalies v0.1813 FRAS1 Zornitza Stark Marked gene: FRAS1 as ready
Fetal anomalies v0.1812 FRAS1 Zornitza Stark changed review comment from: ID is part of the phenotype; to: Multiple congenital anomalies syndrome.
Fetal anomalies v0.1812 SGPL1 Seb Lunke Marked gene: SGPL1 as ready
Fetal anomalies v0.1811 FOXRED1 Zornitza Stark Marked gene: FOXRED1 as ready
Fetal anomalies v0.1810 FOXRED1 Zornitza Stark Phenotypes for gene: FOXRED1 were changed from MITOCHONDRIAL COMPLEX I DEFICIENCY to Mitochondrial complex I deficiency, nuclear type 19 MIM#618241
Fetal anomalies v0.1808 DNAJB11 Zornitza Stark Marked gene: DNAJB11 as ready
Fetal anomalies v0.1805 LRIG2 Zornitza Stark Marked gene: LRIG2 as ready
Fetal anomalies v0.1802 DNAJB11 Belinda Chong reviewed gene: DNAJB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 29706351, 29777155, 33129895, 34177435; Phenotypes: Polycystic kidney disease 6 with or without polycystic liver disease, MIM#618061, Ivermark II syndrome.; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1802 FOXP3 Zornitza Stark Marked gene: FOXP3 as ready
Fetal anomalies v0.1798 FOXE3 Zornitza Stark Marked gene: FOXE3 as ready
Fetal anomalies v0.1798 FOXE3 Zornitza Stark Phenotypes for gene: FOXE3 were changed from ANTERIOR SEGMENT MESENCHYMAL DYSGENESIS; Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256; Cataract 34, multiple types, OMIM:612968; {Aortic aneurysm, familial thoracic 11, susceptibility to}, OMIM:617349 CONGENITAL PRIMARY APHAKIA to Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256; Cataract 34, multiple types, OMIM:612968
Fetal anomalies v0.1793 GZF1 Zornitza Stark Marked gene: GZF1 as ready
Fetal anomalies v0.1791 GSC Zornitza Stark Marked gene: GSC as ready
Fetal anomalies v0.1789 GRM1 Zornitza Stark Marked gene: GRM1 as ready
Fetal anomalies v0.1789 GRM1 Zornitza Stark Phenotypes for gene: GRM1 were changed from CONGENITAL CEREBELLAR ATAXIA to Spinocerebellar ataxia, autosomal recessive 13 MIM#614831
Fetal anomalies v0.1786 GRM1 Zornitza Stark reviewed gene: GRM1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia, autosomal recessive 13 MIM#614831; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1784 LRAT Daniel Flanagan reviewed gene: LRAT: Rating: RED; Mode of pathogenicity: None; Publications: 11381255, 18055821, 22570351, 17011878, 29973277, 24625443, 22559933, 31448181; Phenotypes: Leber congenital amaurosis 14 MIM#613341, Retinal dystrophy, early-onset severe MIM#613341, Retinitis pigmentosa, juvenile MIM#613341; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1783 GREB1L Zornitza Stark Marked gene: GREB1L as ready
Fetal anomalies v0.1779 GPX4 Zornitza Stark Marked gene: GPX4 as ready
Fetal anomalies v0.1776 GPKOW Zornitza Stark Marked gene: GPKOW as ready
Fetal anomalies v0.1775 GPC6 Zornitza Stark Marked gene: GPC6 as ready
Fetal anomalies v0.1773 GNA11 Zornitza Stark Marked gene: GNA11 as ready
Fetal anomalies v0.1771 GNA11 Zornitza Stark changed review comment from: Post-natal presentation.; to: Post-natal presentation for calcium disorders.

Somatic variants present in cutaneous haemangiomas, which can be of perinatal onset.
Fetal anomalies v0.1767 FOXC2 Zornitza Stark Marked gene: FOXC2 as ready
Fetal anomalies v0.1767 FOXC2 Zornitza Stark Phenotypes for gene: FOXC2 were changed from LYMPHEDEMA-DISTICHIASIS SYNDROME; HEREDITARY LYMPHEDEMA II to Lymphoedema-distichiasis syndrome, MIM# 153400
Fetal anomalies v0.1765 FOXC2 Zornitza Stark changed review comment from: Single individual reported with CDH, some supportive functional data.
Sources: Literature; to: Lymphoedema-distichiasis is an autosomal dominant disorder that classically presents as lymphoedema of the limbs and double rows of eyelashes (distichiasis). Other features that may present antenatally include cardiac defects, cleft palate, spinal extradural cysts, and CDH. Well established gene-disease association, multiple families reported.
Sources: Literature
Fetal anomalies v0.1765 GZF1 Ain Roesley reviewed gene: GZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33009817, 28475863; Phenotypes: Joint laxity, short stature, and myopia, MIM# 617662, Larsen-like syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1765 GSC Ain Roesley reviewed gene: GSC: Rating: GREEN; Mode of pathogenicity: None; Publications: 24290375; Phenotypes: Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, MIM# 602471; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1765 GRM1 Ain Roesley reviewed gene: GRM1: Rating: RED; Mode of pathogenicity: None; Publications: 22901947, 26308914; Phenotypes: Spinocerebellar ataxia, autosomal recessive 13 MIM#614831; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1765 FOXC1 Zornitza Stark Marked gene: FOXC1 as ready
Fetal anomalies v0.1762 FOXC1 Zornitza Stark edited their review of gene: FOXC1: Added comment: ARS can present antenatally with congenital heart disease and umbilical defects.; Changed rating: GREEN; Changed publications: 30255586; Changed phenotypes: Axenfeld-Rieger syndrome, type 3, MIM# 602482; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.1762 FOLR1 Zornitza Stark Marked gene: FOLR1 as ready
Fetal anomalies v0.1759 FOLR1 Zornitza Stark changed review comment from: Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy, and leukodystrophy. Recognition and diagnosis of this disorder is critical because folinic acid therapy can reverse the clinical symptoms and improve brain abnormalities and function.; to: Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy, and leukodystrophy. Not pertinent to fetal panel.
Fetal anomalies v0.1759 SLC25A38 Seb Lunke Marked gene: SLC25A38 as ready
Fetal anomalies v0.1756 SLC17A5 Seb Lunke Marked gene: SLC17A5 as ready
Fetal anomalies v0.1754 SLC12A6 Seb Lunke Marked gene: SLC12A6 as ready
Fetal anomalies v0.1738 DHTKD1 Zornitza Stark Marked gene: DHTKD1 as ready
Fetal anomalies v0.1731 Zornitza Stark removed gene:EDAR from the panel
Fetal anomalies v0.1725 DLX5 Belinda Chong reviewed gene: DLX5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22121204, 24496061, 25196357, 20534536, 12112878; Phenotypes: Split-hand/foot malformation 1 with sensorineural hearing loss MIM#220600, Split-hand/foot malformation 1 MIM#183600; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1725 SKI Seb Lunke Marked gene: SKI as ready
Fetal anomalies v0.1724 SKI Seb Lunke Added comment: Comment on mode of pathogenicity: LoF not fully established on only missense described so far. Some functional work suggest potential GoF for TGF beta signalling, but not conclusive. Not enough evidence so far to go against LoF.
Fetal anomalies v0.1723 DHTKD1 Belinda Chong reviewed gene: DHTKD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23141294, 29661920, 28902413, 27604308, 23141293, 25860818; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2Q, MIM#615025, Alpha-aminoadipic and alpha-ketoadipic aciduria MIM#204750; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1720 SIX5 Seb Lunke Marked gene: SIX5 as ready
Fetal anomalies v0.1719 COX15 Zornitza Stark Marked gene: COX15 as ready
Fetal anomalies v0.1719 COX15 Zornitza Stark Phenotypes for gene: COX15 were changed from LEIGH SYNDROME; MITOCHONDRIAL COMPLEX IV DEFICIENCY to Mitochondrial complex IV deficiency, nuclear type 6, MIM# 615119
Fetal anomalies v0.1716 COX15 Zornitza Stark reviewed gene: COX15: Rating: AMBER; Mode of pathogenicity: None; Publications: 21412973, 33746038, 32232962; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 6, MIM# 615119; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1716 COX10 Zornitza Stark Marked gene: COX10 as ready
Fetal anomalies v0.1716 COX10 Zornitza Stark Phenotypes for gene: COX10 were changed from LEIGH SYNDROME; MITOCHONDRIAL COMPLEX IV DEFICIENCY to Mitochondrial complex IV deficiency, nuclear type 3, MIM# 619046
Fetal anomalies v0.1713 COX10 Zornitza Stark changed review comment from: More than 5 unrelated families reported, mitochondrial encephalopathy including developmental delay in some, though early severe multi-system disease or regression are the typical patterns of neurological involvement.; to: More than 5 unrelated families reported, mitochondrial encephalopathy including developmental delay in some, though early severe multi-system disease or regression are the typical patterns of neurological involvement.

At least one individual reported with severe HCM in neonatal period.
Fetal anomalies v0.1703 CLTC Zornitza Stark Marked gene: CLTC as ready
Fetal anomalies v0.1703 CLTC Zornitza Stark Phenotypes for gene: CLTC were changed from Fetal growth restriction; Mental retardation, autosomal dominant 56, OMIM:617854; Fetal akinesia to Mental retardation, autosomal dominant 56, MIM# 617854
Fetal anomalies v0.1693 CISD2 Zornitza Stark changed review comment from: Neurodegenerative disorder with hearing and visual impairment, but intellectual disability is not a feature.; to: Neurodegenerative disorder with hearing and visual impairment.
Fetal anomalies v0.1692 CHRNA4 Zornitza Stark Marked gene: CHRNA4 as ready
Fetal anomalies v0.1689 CHRDL1 Zornitza Stark Marked gene: CHRDL1 as ready
Fetal anomalies v0.1688 CHD2 Zornitza Stark changed review comment from: Post-natal onset.; to: Post-natal onset for DDE.

Association with ARVC rated LIMITED by ClinGen.
Fetal anomalies v0.1688 CHD2 Zornitza Stark Marked gene: CHD2 as ready
Fetal anomalies v0.1686 CCNO Zornitza Stark Marked gene: CCNO as ready
Fetal anomalies v0.1686 CCNO Zornitza Stark Phenotypes for gene: CCNO were changed from CILIARY DYSKINESIA, PRIMARY, 29 to Ciliary dyskinesia, primary, 29 615872
Fetal anomalies v0.1684 CCDC65 Zornitza Stark Marked gene: CCDC65 as ready
Fetal anomalies v0.1684 CCDC65 Zornitza Stark Phenotypes for gene: CCDC65 were changed from PRIMARY CILIARY DYSKINESIA to Ciliary dyskinesia, primary, 27, MIM# 615504
Fetal anomalies v0.1682 CCDC65 Zornitza Stark changed review comment from: Same homozygous PTC (p.I293Pfs*2) reported in 3 Ashkenzi Jewish families. PMID: 24094744 performs functional assay on null zebrafish model - replicates human phenotype supporting LOF. Three different LoF reported in context of primary ciliary dyskinesia by diagnostic laboratories in ClinVar.; to: Same homozygous PTC (p.I293Pfs*2) reported in 3 Ashkenzi Jewish families. PMID: 24094744 performs functional assay on null zebrafish model - replicates human phenotype supporting LOF. Three different LoF reported in context of primary ciliary dyskinesia by diagnostic laboratories in ClinVar.

Situs inversus not reported.
Fetal anomalies v0.1682 CCDC115 Zornitza Stark Marked gene: CCDC115 as ready
Fetal anomalies v0.1680 CC2D1A Zornitza Stark Marked gene: CC2D1A as ready
Fetal anomalies v0.1680 CC2D1A Zornitza Stark Phenotypes for gene: CC2D1A were changed from MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 3 to Mental retardation, autosomal recessive 3, MIM# 608443
Fetal anomalies v0.1678 CC2D1A Zornitza Stark reviewed gene: CC2D1A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, autosomal recessive 3, MIM# 608443; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1678 CBS Zornitza Stark Marked gene: CBS as ready
Fetal anomalies v0.1677 CAVIN1 Zornitza Stark Marked gene: CAVIN1 as ready
Fetal anomalies v0.1676 CALCRL Zornitza Stark Marked gene: CALCRL as ready
Fetal anomalies v0.1676 CAD Zornitza Stark Marked gene: CAD as ready
Fetal anomalies v0.1676 CAD Zornitza Stark Phenotypes for gene: CAD were changed from Uridine-responsive epileptic encephalopathy to Epileptic encephalopathy, early infantile, 50, MIM# MIM 616457
Fetal anomalies v0.1674 CAD Zornitza Stark changed review comment from: Four unrelated families (two with same variant and Roma background, likely founder).
Sources: Expert list; to: Four unrelated families (two with same variant and Roma background, likely founder). Onset in infancy.
Sources: Expert list
Fetal anomalies v0.1672 C2orf71 Zornitza Stark Marked gene: C2orf71 as ready
Fetal anomalies v0.1671 SETBP1 Zornitza Stark commented on gene: SETBP1: GoF variants cause Schinzel-Giedion syndrome, a severe multi-system disorder characterized by recognizable facial characteristics, severe-profound intellectual disability, intractable epilepsy, cortical visual impairment, deafness, and congenital anomalies such as cardiac defects, urogenital defects, and bone abnormalities. Causative pathogenic variants are clustered within a 12-base pair hot spot region in exon 4.

LoF variants cause SETBP1-haploinsufficiency syndrome, characterized by hypotonia and mild motor developmental delay; intellectual abilities ranging from normal to severe disability; speech and language disorder; behavioral problems (most commonly attention/concentration deficits and hyperactivity, impulsivity), and refractive errors and strabismus. Over 40 individuals reviewed in PMID 34807554. This disorder typically presents post-natally.
Fetal anomalies v0.1669 SCO2 Zornitza Stark Phenotypes for gene: SCO2 were changed from Mitochondrial complex IV deficiency, nuclear type 2, MIM#604377; FATAL INFANTILE CARDIOENCEPHALOMYOPATHY DUE TO CYTOCHROME C OXIDASE DEFICIENCY to Mitochondrial complex IV deficiency, nuclear type 2, MIM# 604377
Fetal anomalies v0.1666 SCO2 Zornitza Stark changed review comment from: Typically manifests post-natally though rare fetal presentations reported, PMID 15210538.; to: Severe neonatal presentations, and at least two reports of fetal presentations.
Fetal anomalies v0.1666 SCO2 Zornitza Stark reviewed gene: SCO2: Rating: AMBER; Mode of pathogenicity: None; Publications: 15210538; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 2, MIM# 604377; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1666 TRAP1 Zornitza Stark Marked gene: TRAP1 as ready
Fetal anomalies v0.1665 SH3PXD2B Seb Lunke Marked gene: SH3PXD2B as ready
Fetal anomalies v0.1665 SH3PXD2B Seb Lunke Phenotypes for gene: SH3PXD2B were changed from FRANK-TER HAAR SYNDROME to Frank-ter Haar syndrome, MIM#249420
Fetal anomalies v0.1663 SH3PXD2B Seb Lunke reviewed gene: SH3PXD2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 15523657, 24105366; Phenotypes: Frank-ter Haar syndrome, MIM#249420; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1663 SETBP1 Seb Lunke Marked gene: SETBP1 as ready
Fetal anomalies v0.1663 SETBP1 Seb Lunke Added comment: Comment when marking as ready: Well established gene disease association with facial and skeletal abnormalities detectable in utero.
Fetal anomalies v0.1661 SCO2 Seb Lunke Marked gene: SCO2 as ready
Fetal anomalies v0.1661 SCO2 Seb Lunke Phenotypes for gene: SCO2 were changed from FATAL INFANTILE CARDIOENCEPHALOMYOPATHY DUE TO CYTOCHROME C OXIDASE DEFICIENCY to Mitochondrial complex IV deficiency, nuclear type 2, MIM#604377; FATAL INFANTILE CARDIOENCEPHALOMYOPATHY DUE TO CYTOCHROME C OXIDASE DEFICIENCY
Fetal anomalies v0.1660 SCO2 Seb Lunke Added comment: Comment on list classification: Generally severe, rapidly progressive hypertrophic cardiomyopathy that presents in the neonatal period, early spontaneous abortions and fetal wastage described in one family.
Fetal anomalies v0.1658 SCN4A Seb Lunke Marked gene: SCN4A as ready
Fetal anomalies v0.1658 SCN4A Seb Lunke Phenotypes for gene: SCN4A were changed from HYPERKALEMIC PERIODIC PARALYSIS TYPE 1; PARAMYOTONIA CONGENITA OF VON EULENBURG; HYPOKALEMIC PERIODIC PARALYSIS to Congenital myopathy; Myasthenic syndrome, congenital, 16 MIM#614198
Fetal anomalies v0.1652 BRWD3 Zornitza Stark Marked gene: BRWD3 as ready
Fetal anomalies v0.1652 BRWD3 Zornitza Stark Phenotypes for gene: BRWD3 were changed from MENTAL RETARDATION X-LINKED TYPE 93 to tellectual developmental disorder, X-linked 93, MIM# 300659
Fetal anomalies v0.1650 BRCA1 Zornitza Stark Marked gene: BRCA1 as ready
Fetal anomalies v0.1648 BCKDHB Zornitza Stark Marked gene: BCKDHB as ready
Fetal anomalies v0.1647 BCKDHA Zornitza Stark Marked gene: BCKDHA as ready
Fetal anomalies v0.1646 AUTS2 Zornitza Stark Marked gene: AUTS2 as ready
Fetal anomalies v0.1646 AUTS2 Zornitza Stark Added comment: Comment when marking as ready: Note CNVs common.
Fetal anomalies v0.1642 AUTS2 Zornitza Stark changed review comment from: Mental retardation, autosomal dominant 26, MIM#615834; to: Low birth weight and microcephaly reported.
Fetal anomalies v0.1642 AUH Zornitza Stark Marked gene: AUH as ready
Fetal anomalies v0.1641 ATP8B1 Zornitza Stark Marked gene: ATP8B1 as ready
Fetal anomalies v0.1640 ATP6V1B1 Zornitza Stark Marked gene: ATP6V1B1 as ready
Fetal anomalies v0.1640 ATP6V1B1 Zornitza Stark Phenotypes for gene: ATP6V1B1 were changed from DISTAL RENAL TUBULAR ACIDOSIS WITH DEAFNESS to Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300
Fetal anomalies v0.1639 ATP6V1B1 Zornitza Stark reviewed gene: ATP6V1B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Distal renal tubular acidosis 2 with progressive sensorineural hearing loss, MIM# 267300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1639 ATP1A3 Zornitza Stark Marked gene: ATP1A3 as ready
Fetal anomalies v0.1639 ATP1A3 Zornitza Stark Phenotypes for gene: ATP1A3 were changed from RAPID-ONSET DYSTONIA-PARKINSONISM; ALTERNATING HEMIPLEGIA OF CHILDHOOD to Developmental and epileptic encephalopathy 99, MIM# 619606; Polymicrogyria
Fetal anomalies v0.1635 ATP13A2 Zornitza Stark Marked gene: ATP13A2 as ready
Fetal anomalies v0.1635 ATP13A2 Zornitza Stark Phenotypes for gene: ATP13A2 were changed from PARKINSON DISEASE 9 to Kufor-Rakeb syndrome, MIM# 606693; Spastic paraplegia 78, autosomal recessive, MIM# 617225
Fetal anomalies v0.1634 ATP13A2 Zornitza Stark reviewed gene: ATP13A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Kufor-Rakeb syndrome, MIM# 606693, Spastic paraplegia 78, autosomal recessive, MIM# 617225; Mode of inheritance: None
Fetal anomalies v0.1634 ATM Zornitza Stark Marked gene: ATM as ready
Fetal anomalies v0.1633 ACAT1 Zornitza Stark Marked gene: ACAT1 as ready
Fetal anomalies v0.1632 ACADS Zornitza Stark Marked gene: ACADS as ready
Fetal anomalies v0.1631 ACADM Zornitza Stark Marked gene: ACADM as ready
Fetal anomalies v0.1630 ASL Zornitza Stark Marked gene: ASL as ready
Fetal anomalies v0.1630 ASL Zornitza Stark Phenotypes for gene: ASL were changed from ARGININOSUCCINATE LYASE DEFICIENCY to Argininosuccinic aciduria, MIM#207900
Fetal anomalies v0.1629 ARG1 Zornitza Stark Marked gene: ARG1 as ready
Fetal anomalies v0.1629 ARG1 Zornitza Stark Gene: arg1 has been classified as Red List (Low Evidence).
Fetal anomalies v0.1629 ARG1 Zornitza Stark Phenotypes for gene: ARG1 were changed from ARGININEMIA to Argininaemia, MIM# 207800
Fetal anomalies v0.1628 ARG1 Zornitza Stark reviewed gene: ARG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Argininaemia, MIM# 207800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1626 APTX Zornitza Stark Marked gene: APTX as ready
Fetal anomalies v0.1626 APTX Zornitza Stark Phenotypes for gene: APTX were changed from ATAXIA WITH OCULOMOTOR APRAXIA 1 to Ataxia, early-onset, with oculomotor apraxia and hypoalbuminaemia, MIM#208920
Fetal anomalies v0.1625 APTX Zornitza Stark edited their review of gene: APTX: Changed phenotypes: Ataxia, early-onset, with oculomotor apraxia and hypoalbuminaemia, MIM#208920
Fetal anomalies v0.1625 APOPT1 Zornitza Stark Marked gene: APOPT1 as ready
Fetal anomalies v0.1625 APOPT1 Zornitza Stark Phenotypes for gene: APOPT1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY to Mitochondrial complex IV deficiency, nuclear type 17, MIM#619061
Fetal anomalies v0.1623 APOPT1 Zornitza Stark changed review comment from: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time.

Clinical presentation is typically in childhood.; to: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time.

Clinical presentation is typically in early childhood.
Fetal anomalies v0.1623 APOPT1 Zornitza Stark changed review comment from: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time.; to: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time.

Clinical presentation is typically in childhood.
Fetal anomalies v0.1623 AP3B1 Zornitza Stark Marked gene: AP3B1 as ready
Fetal anomalies v0.1621 ANO5 Zornitza Stark Marked gene: ANO5 as ready
Fetal anomalies v0.1621 ANO5 Zornitza Stark Phenotypes for gene: ANO5 were changed from GNATHODIAPHYSEAL DYSPLASIA; MIYOSHI MUSCULAR DYSTROPHY TYPE 3 to Gnathodiaphyseal dysplasia, MIM# 166260; Miyoshi muscular dystrophy 3, MIM# 613319; Muscular dystrophy, limb-girdle, autosomal recessive 12, MIM# 611307
Fetal anomalies v0.1620 ANO5 Zornitza Stark reviewed gene: ANO5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Gnathodiaphyseal dysplasia, MIM# 166260, Miyoshi muscular dystrophy 3, MIM# 613319, Muscular dystrophy, limb-girdle, autosomal recessive 12, MIM# 611307; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.1620 ALS2 Zornitza Stark Marked gene: ALS2 as ready
Fetal anomalies v0.1620 ALS2 Zornitza Stark Phenotypes for gene: ALS2 were changed from ALS2-RELATED DISORDERS to Spastic paralysis, infantile onset ascending, MIM#607225
Fetal anomalies v0.1619 ALDOB Zornitza Stark Marked gene: ALDOB as ready
Fetal anomalies v0.1619 ALDOB Zornitza Stark Phenotypes for gene: ALDOB were changed from HEREDITARY FRUCTOSE INTOLERANCE to Fructose intolerance, hereditary, MIM#229600
Fetal anomalies v0.1618 ALDH5A1 Zornitza Stark Marked gene: ALDH5A1 as ready
Fetal anomalies v0.1616 ALDH5A1 Zornitza Stark changed review comment from: Over 50 unrelated families reported. Intellectual disability is part of the phenotype, which also includes developmental delay, hypotonia, ataxia, seizures, hyperkinetic behaviour, aggression, and sleep disturbances.; to: Over 50 unrelated families reported. Typically presents post-natally with intellectual disability, hypotonia, ataxia, seizures, hyperkinetic behaviour, aggression, and sleep disturbances.
Fetal anomalies v0.1616 TWIST2 Alison Yeung Marked gene: TWIST2 as ready
Fetal anomalies v0.1616 TWIST2 Alison Yeung Added comment: Comment when marking as ready: Congenital conditions associated with multiple fetal anomalies including ambiguous genitalia, microtia, macrostomia
Fetal anomalies v0.1616 ALDH4A1 Zornitza Stark Marked gene: ALDH4A1 as ready
Fetal anomalies v0.1615 TWIST2 Alison Yeung reviewed gene: TWIST2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26119818, 20691403; Phenotypes: Ablepharon-macrostomia syndrome, MIM# 200110, Barber-Say syndrome, MIM# 209885, Focal facial dermal dysplasia 3, Setleis type, MIM# 227260; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1613 VLDLR Zornitza Stark Phenotypes for gene: VLDLR were changed from CEREBELLAR ATAXIA MENTAL RETARDATION AND DYSEQUILIBRIUM SYNDROME TYPE 1 to Cerebellar hypoplasia and mental retardation with or without quadrupedal locomotion 1, MIM# 224050
Fetal anomalies v0.1611 TXNL4A Alison Yeung Marked gene: TXNL4A as ready
Fetal anomalies v0.1611 VLDLR Alison Yeung Marked gene: VLDLR as ready
Fetal anomalies v0.1611 VLDLR Alison Yeung reviewed gene: VLDLR: Rating: GREEN; Mode of pathogenicity: None; Publications: 16080122, 18326629, 10380922; Phenotypes: Cerebellar hypoplasia and mental retardation with or without quadrupedal locomotion 1, MIM# 224050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1611 ALAD Zornitza Stark Marked gene: ALAD as ready
Fetal anomalies v0.1610 FLVCR2 Zornitza Stark Marked gene: FLVCR2 as ready
Fetal anomalies v0.1608 FLVCR2 Zornitza Stark edited their review of gene: FLVCR2: Added comment: The proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome is a (usually) prenatally lethal disorder characterized by hydranencephaly, a distinctive glomerular vasculopathy in the central nervous system and retina, and diffuse ischemic lesions of the brain stem, basal ganglia, and spinal cord with calcifications. It is usually diagnosed by ultrasound between 26 and 33 weeks' gestation.

At least 5 unrelated families reported.; Changed rating: GREEN; Changed publications: 30712878, 20206334, 20518025, 20690116, 25677735; Changed phenotypes: Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome, MIM# 225790
Fetal anomalies v0.1608 FLT4 Zornitza Stark Marked gene: FLT4 as ready
Fetal anomalies v0.1608 FLT4 Zornitza Stark Phenotypes for gene: FLT4 were changed from MILROY DISEASE to Congenital heart defects, multiple types, 7, MIM# 618780; Lymphatic malformation 1, MIM# 153100
Fetal anomalies v0.1605 FLNB Zornitza Stark Marked gene: FLNB as ready
Fetal anomalies v0.1605 FLNB Zornitza Stark Phenotypes for gene: FLNB were changed from BOOMERANG DYSPLASIA; SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME; ATELOSTEOGENESIS TYPE 3; AUTOSOMAL DOMINANT LARSEN SYNDROME; ATELOSTEOGENESIS TYPE 1 to Larsen syndrome, MIM#150250; Atelosteogenesis, type I, MIM# 108720; Atelosteogenesis, type III, MIM# 108721; Boomerang dysplasia, MIM# 112310; Spondylocarpotarsal synostosis syndrome, MIM# 272460
Fetal anomalies v0.1604 FLNB Zornitza Stark changed review comment from: Gene associated with a number of skeletal dysplasias, ID not typically a feature.; to: Gene associated with a number of skeletal dysplasias, which are relevant to the pre-natal setting.
Fetal anomalies v0.1604 FLNB Zornitza Stark edited their review of gene: FLNB: Changed rating: GREEN; Changed phenotypes: Larsen syndrome, MIM#150250, Atelosteogenesis, type I, MIM# 108720, Atelosteogenesis, type III, MIM# 108721, Boomerang dysplasia, MIM# 112310, Spondylocarpotarsal synostosis syndrome, MIM# 272460; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.1604 FLNA Zornitza Stark Marked gene: FLNA as ready
Fetal anomalies v0.1604 FLNA Zornitza Stark Phenotypes for gene: FLNA were changed from PERIVENTRICULAR NODULAR HETEROTOPIA TYPE 1; EPILEPTIC ENCEPHALOPATHY; FG SYNDROME TYPE 2; X-LINKED CONGENITAL IDIOPATHIC INTESTINAL PSEUDOOBSTRUCTION; MELNICK-NEEDLES SYNDROME; FRONTOMETAPHYSEAL DYSPLASIA; OTOPALATODIGITAL SYNDROME TYPE 2; TERMINAL OSSEOUS DYSPLASIA; OTOPALATODIGITAL SYNDROME TYPE 1 to Melnick-Needles syndrome, 309350; Otopalatodigital syndrome, type I 311300; Otopalatodigital syndrome, type II 304120; Terminal osseous dysplasia 300244; Heterotopia, periventricular, 1 MIM# 300049 Cardiac valvular dysplasia, X-linked MIM# 314400
Fetal anomalies v0.1602 FLNA Zornitza Stark changed review comment from: Melnick-Needles associated with radial shortening in affected women. Male fetuses reported with absent thumbs
Sources: Expert list; to: Multiple FLNA-related disorders are relevant to this panel.

Melnick-Needles associated with radial shortening in affected women. Male fetuses reported with absent thumbs
Sources: Expert list
Fetal anomalies v0.1602 FLNA Zornitza Stark edited their review of gene: FLNA: Changed phenotypes: Melnick-Needles syndrome, 309350, Otopalatodigital syndrome, type I 311300, Otopalatodigital syndrome, type II 304120, Terminal osseous dysplasia 300244, Heterotopia, periventricular, 1 MIM# 300049 Cardiac valvular dysplasia, X-linked MIM# 314400
Fetal anomalies v0.1602 FKTN Zornitza Stark Marked gene: FKTN as ready
Fetal anomalies v0.1602 FKTN Zornitza Stark Phenotypes for gene: FKTN were changed from MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY LIMB-GIRDLE TYPE C4; CARDIOMYOPATHY DILATED TYPE 1X; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY CONGENITAL WITHOUT MENTAL RETARDATION TYPE B4; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY CONGENITAL WITH BRAIN AND EYE ANOMALIES TYPE A4 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 253800
Fetal anomalies v0.1600 FKTN Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association. Brain abnormalities are part of the more severe end of the spectrum.
Fetal anomalies v0.1600 FKTN Zornitza Stark edited their review of gene: FKTN: Changed phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 253800
Fetal anomalies v0.1600 FKRP Zornitza Stark Marked gene: FKRP as ready
Fetal anomalies v0.1600 FKRP Zornitza Stark Phenotypes for gene: FKRP were changed from MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY CONGENITAL WITH BRAIN AND EYE ANOMALIES TYPE A5; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY CONGENITAL WITH OR WITHOUT MENTAL RETARDATION TYPE B5; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY LIMB-GIRDLE TYPE C5 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5 613153
Fetal anomalies v0.1598 FKRP Zornitza Stark edited their review of gene: FKRP: Changed phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5 613153
Fetal anomalies v0.1598 FH Zornitza Stark Marked gene: FH as ready
Fetal anomalies v0.1598 FH Zornitza Stark Phenotypes for gene: FH were changed from FUMARASE DEFICIENCY to Fumarase deficiency, MIM# 606812
Fetal anomalies v0.1596 FH Zornitza Stark edited their review of gene: FH: Changed rating: GREEN; Changed phenotypes: Fumarase deficiency, MIM# 606812
Fetal anomalies v0.1596 FGFR3 Zornitza Stark Marked gene: FGFR3 as ready
Fetal anomalies v0.1596 FGFR3 Zornitza Stark Phenotypes for gene: FGFR3 were changed from CAMPTODACTYLY TALL STATURE AND HEARING LOSS SYNDROME; LACRIMO-AURICULO-DENTO-DIGITAL SYNDROME; ACHONDROPLASIA; THANATOPHORIC DYSPLASIA TYPE 2; HYPOCHONDROPLASIA; MUENKE SYNDROME; THANATOPHORIC DYSPLASIA TYPE 1; CROUZON SYNDROME WITH ACANTHOSIS NIGRICANS to LADD syndrome, MIM#149730; Achondroplasia, MIM# 100800; Thanatophoric dysplasia, type I, MIM# 187600; Thanatophoric dysplasia, type II, MIM# 187601
Fetal anomalies v0.1594 FGFR3 Zornitza Stark changed review comment from: Well established gene-disease association. Variable radial ray defects (at the most severe, bilateral radial aplasia) are a feature of LADD syndrome.
Sources: Expert list; to: Well established gene-disease association with skeletal dysplasias of variable severity, including perinatal lethal. Variable radial ray defects (at the most severe, bilateral radial aplasia) are a feature of LADD syndrome.
Sources: Expert list
Fetal anomalies v0.1594 FGFR2 Zornitza Stark Marked gene: FGFR2 as ready
Fetal anomalies v0.1594 FGFR2 Zornitza Stark Phenotypes for gene: FGFR2 were changed from JACKSON-WEISS SYNDROME; FAMILIAL SCAPHOCEPHALY SYNDROME; CROUZON SYNDROME; LACRIMO-AURICULO-DENTO-DIGITAL SYNDROME; BEARE-STEVENSON CUTIS GYRATA SYNDROME; ACROCEPHALOSYNDACTYLY TYPE V; APERT SYNDROME; ANTLEY-BIXLER SYNDROME to LADD syndrome, MIM#149730; Apert syndrome, MIM# 101200; Crouzon syndrome, MIM# 123500; Jackson-Weiss syndrome, MIM# 123150; Pfeiffer syndrome, MIM# 101600; Saethre-Chotzen syndrome, MIM# 101400
Fetal anomalies v0.1592 FGFR2 Zornitza Stark changed review comment from: Well established gene-disease association. Radial ray abnormalities are a feature of LADD syndrome.
Sources: Expert list; to: Well established gene-disease association with multiple craniosynostosis syndromes. Radial ray abnormalities are a feature of LADD syndrome.
Sources: Expert list
Fetal anomalies v0.1592 FGFR1 Zornitza Stark Marked gene: FGFR1 as ready
Fetal anomalies v0.1592 FGFR1 Zornitza Stark Phenotypes for gene: FGFR1 were changed from Hartsfield syndrome; Encephalocraniocutaneous lipomatosis; OSTEOGLOPHONIC DYSPLASIA; KALLMANN SYNDROME TYPE 2; PFEIFFER SYNDROME; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM to Pfeiffer syndrome, MIM# 101600
Fetal anomalies v0.1589 FGF3 Zornitza Stark Marked gene: FGF3 as ready
Fetal anomalies v0.1589 FGF3 Zornitza Stark Phenotypes for gene: FGF3 were changed from DEAFNESS WITH LABYRINTHINE APLASIA, MICROTIA AND MICRODONTIA to Deafness, congenital with inner ear agenesis, microtia, and microdontia, MIM#610706
Fetal anomalies v0.1587 FGF10 Zornitza Stark Marked gene: FGF10 as ready
Fetal anomalies v0.1584 FGD1 Zornitza Stark Marked gene: FGD1 as ready
Fetal anomalies v0.1584 FGD1 Zornitza Stark Phenotypes for gene: FGD1 were changed from AARSKOG-SCOTT SYNDROME to Aarskog-Scott syndrome, MIM # 305400; Mental retardation, X-linked syndromic 16, MIM# 305400
Fetal anomalies v0.1582 FGD1 Zornitza Stark changed review comment from: Aarskog-Scott syndrome is characterised by short stature, hypertelorism, shawl scrotum, brachydactyly, joint hyperextensibility, short nose, widow's peak, and inguinal hernia. Most patients do not have intellectual disability, but some may have neurobehavioral features. Carrier females may present with subtle features, such as widow's peak or short stature.

Numerous cases reported with variants in FGD1 gene with replication over time.; to: Aarskog-Scott syndrome is characterised by short stature, hypertelorism, shawl scrotum, brachydactyly, joint hyperextensibility, short nose, widow's peak, and inguinal hernia. Most patients do not have intellectual disability, but some may have neurobehavioral features. Carrier females may present with subtle features, such as widow's peak or short stature.

Cleft lip/palate reported.

Numerous cases reported with variants in FGD1 gene with replication over time.
Fetal anomalies v0.1582 FBXL4 Zornitza Stark Marked gene: FBXL4 as ready
Fetal anomalies v0.1580 FBN2 Zornitza Stark Marked gene: FBN2 as ready
Fetal anomalies v0.1579 FBN1 Zornitza Stark Marked gene: FBN1 as ready
Fetal anomalies v0.1579 FBN1 Zornitza Stark Phenotypes for gene: FBN1 were changed from MASS SYNDROME/OVERLAP CONNECTIVE TISSUE DISEASE; MARFAN SYNDROME; SHPRINTZEN-GOLDBERG CRANIOSYNOSTOSIS SYNDROME to Marfan syndrome, MIM# 154700
Fetal anomalies v0.1577 FBLN5 Zornitza Stark Marked gene: FBLN5 as ready
Fetal anomalies v0.1576 FAR1 Zornitza Stark Marked gene: FAR1 as ready
Fetal anomalies v0.1576 FAR1 Zornitza Stark Gene: far1 has been classified as Green List (High Evidence).
Fetal anomalies v0.1576 FAR1 Zornitza Stark Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154 to Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154; Cataracts, spastic paraparesis, and speech delay, MIM#619338
Fetal anomalies v0.1575 FAR1 Zornitza Stark Publications for gene: FAR1 were set to
Fetal anomalies v0.1574 FAR1 Zornitza Stark Mode of inheritance for gene: FAR1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.1573 FANCI Zornitza Stark Marked gene: FANCI as ready
Fetal anomalies v0.1571 FANCG Zornitza Stark Marked gene: FANCG as ready
Fetal anomalies v0.1569 FANCF Zornitza Stark Marked gene: FANCF as ready
Fetal anomalies v0.1567 FANCE Zornitza Stark Marked gene: FANCE as ready
Fetal anomalies v0.1565 FANCD2 Zornitza Stark Marked gene: FANCD2 as ready
Fetal anomalies v0.1563 FANCC Zornitza Stark Marked gene: FANCC as ready
Fetal anomalies v0.1561 FANCB Zornitza Stark Marked gene: FANCB as ready
Fetal anomalies v0.1559 FANCA Zornitza Stark Marked gene: FANCA as ready
Fetal anomalies v0.1556 VPS53 Zornitza Stark Phenotypes for gene: VPS53 were changed from Progressive cerebella-cerebral atrophy type 2; PONTOCEREBELLAR HYPOPLASIA, TYPE 2E 615851 to Pontocerebellar hypoplasia, type 2E, OMIM #615851
Fetal anomalies v0.1555 VPS53 Zornitza Stark reviewed gene: VPS53: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hypoplasia, type 2E, OMIM #615851; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1549 GM2A Zornitza Stark Marked gene: GM2A as ready
Fetal anomalies v0.1549 GM2A Zornitza Stark Phenotypes for gene: GM2A were changed from GM2-GANGLIOSIDOSIS TYPE AB to GM2-gangliosidosis, AB variant MIM#272750
Fetal anomalies v0.1547 GM2A Zornitza Stark reviewed gene: GM2A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: GM2-gangliosidosis, AB variant MIM#272750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1547 VPS53 Alison Yeung Marked gene: VPS53 as ready
Fetal anomalies v0.1547 VPS53 Alison Yeung reviewed gene: VPS53: Rating: GREEN; Mode of pathogenicity: None; Publications: 24577744, 12920088; Phenotypes: Pontocerebellar hypoplasia, type 2E, OMIM #615851; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1547 GANAB Zornitza Stark Marked gene: GANAB as ready
Fetal anomalies v0.1547 GFRA1 Zornitza Stark Marked gene: GFRA1 as ready
Fetal anomalies v0.1545 GATA3 Zornitza Stark Marked gene: GATA3 as ready
Fetal anomalies v0.1542 NKX2-6 Krithika Murali edited their review of gene: NKX2-6: Added comment: Review updated - 3 unrelated families now reported

PMID 15649947 (Heathcote et al 2005) - first reported biallelic variants NKX2-6 associated with type 1 truncus arteriosis in a large consanguineous family previously described by (Abushaban et al 2003 - 12574981)

PMID 24421281 (Ta-Shma et al 2014) Subsequently reported, another consanguineous family with conotruncal defects (including VSD and TA) and homozygous nonsense NKX2-6 variants. One individual from that family was
also noted to have athymia

PMID 32198970 (Ritter et al 2019) - Reported compound het variants in x2 siblings with truncus arteriosus (2nd sibling diagnosed antenatally) from non-consanguineous family

Additional studies of NKX2-6 identified a
- heterozygous missense variant c.472A > C (p.Lys158Gln) that segregated with VSD (PMID 25380965 Wang et al 2015)
- heterozygous missense variant c.525G > C (p.Gln175His) that segregated in a family with atrial fibrillation (PMID 25319568 Wang et al 2014)

Included in PanelApp as biallelic inheritance but possibility of less severe phenotype with monoallelic inheritance possible - but one reported family only.; Changed publications: 24421281, 15649947, 32198970, 25380965, 25319568
Fetal anomalies v0.1542 GLI1 Zornitza Stark Marked gene: GLI1 as ready
Fetal anomalies v0.1539 WNT10B Alison Yeung Marked gene: WNT10B as ready
Fetal anomalies v0.1538 GABRB2 Zornitza Stark Marked gene: GABRB2 as ready
Fetal anomalies v0.1531 ZNF699 Zornitza Stark Marked gene: ZNF699 as ready
Fetal anomalies v0.1530 ZMYM2 Zornitza Stark Marked gene: ZMYM2 as ready
Fetal anomalies v0.1529 UBR7 Zornitza Stark Marked gene: UBR7 as ready
Fetal anomalies v0.1528 TLL1 Zornitza Stark Marked gene: TLL1 as ready
Fetal anomalies v0.1527 TBX2 Zornitza Stark Marked gene: TBX2 as ready
Fetal anomalies v0.1526 TBX2 Zornitza Stark reviewed gene: TBX2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Vertebral anomalies and variable endocrine and T-cell dysfunction - MIM#618223; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1526 FAM58A Zornitza Stark Marked gene: FAM58A as ready
Fetal anomalies v0.1526 FAM58A Zornitza Stark Phenotypes for gene: FAM58A were changed from STAR SYNDROME to STAR syndrome MIM#300707
Fetal anomalies v0.1524 WRAP53 Alison Yeung Marked gene: WRAP53 as ready
Fetal anomalies v0.1523 STK4 Zornitza Stark Marked gene: STK4 as ready
Fetal anomalies v0.1522 SPRED2 Zornitza Stark Marked gene: SPRED2 as ready
Fetal anomalies v0.1521 SPEN Zornitza Stark Marked gene: SPEN as ready
Fetal anomalies v0.1520 SMAD6 Zornitza Stark Marked gene: SMAD6 as ready
Fetal anomalies v0.1519 FAM20C Zornitza Stark Marked gene: FAM20C as ready
Fetal anomalies v0.1517 ROBO4 Zornitza Stark Marked gene: ROBO4 as ready
Fetal anomalies v0.1516 PRKACB Zornitza Stark Marked gene: PRKACB as ready
Fetal anomalies v0.1515 PRKACA Zornitza Stark Marked gene: PRKACA as ready
Fetal anomalies v0.1514 FAM20A Zornitza Stark Marked gene: FAM20A as ready
Fetal anomalies v0.1511 LINS1 Zornitza Stark Marked gene: LINS1 as ready
Fetal anomalies v0.1511 LINS1 Zornitza Stark Phenotypes for gene: LINS1 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Mental retardation, autosomal recessive 27 (MIM#614340); autosomal recessive intellectual disability (MIM#614340)
Fetal anomalies v0.1509 PRDM6 Zornitza Stark Marked gene: PRDM6 as ready
Fetal anomalies v0.1508 PRDM6 Zornitza Stark reviewed gene: PRDM6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Patent ductus arteriosus 3 - MIM#617039; Mode of inheritance: None
Fetal anomalies v0.1508 FAM126A Zornitza Stark Marked gene: FAM126A as ready
Fetal anomalies v0.1506 NKX2-6 Zornitza Stark Marked gene: NKX2-6 as ready
Fetal anomalies v0.1506 NKX2-6 Zornitza Stark Phenotypes for gene: NKX2-6 were changed from to Conotruncal heart malformations - MIM#217095; Persistent truncus arteriosus - MIM#217095
Fetal anomalies v0.1504 NKX2-6 Zornitza Stark reviewed gene: NKX2-6: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Conotruncal heart malformations - MIM#217095, Persistent truncus arteriosus - MIM#217095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1504 KRT74 Zornitza Stark Marked gene: KRT74 as ready
Fetal anomalies v0.1500 FAH Zornitza Stark Marked gene: FAH as ready
Fetal anomalies v0.1500 YY1 Alison Yeung Marked gene: YY1 as ready
Fetal anomalies v0.1496 MYBPC3 Zornitza Stark Marked gene: MYBPC3 as ready
Fetal anomalies v0.1495 KCNJ8 Zornitza Stark Marked gene: KCNJ8 as ready
Fetal anomalies v0.1493 MMP15 Zornitza Stark Marked gene: MMP15 as ready
Fetal anomalies v0.1492 MIB1 Zornitza Stark Marked gene: MIB1 as ready
Fetal anomalies v0.1491 MESP1 Zornitza Stark Marked gene: MESP1 as ready
Fetal anomalies v0.1490 HSPA9 Zornitza Stark Marked gene: HSPA9 as ready
Fetal anomalies v0.1489 GM2A Ain Roesley reviewed gene: GM2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 28417072, 28192816, 27402091; Phenotypes: GM2-gangliosidosis, AB variant MIM#272750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.1489 FOXH1 Zornitza Stark reviewed gene: FOXH1: Rating: RED; Mode of pathogenicity: None; Publications: 32003456; Phenotypes: Congenital heart disease; Mode of inheritance: None
Fetal anomalies v0.1489 FBRSL1 Zornitza Stark Marked gene: FBRSL1 as ready
Fetal anomalies v0.1488 OSTM1 Zornitza Stark Marked gene: OSTM1 as ready
Fetal anomalies v0.1488 CITED2 Zornitza Stark Marked gene: CITED2 as ready
Fetal anomalies v0.1486 CITED2 Zornitza Stark reviewed gene: CITED2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33706167, 33439552, 31515672, 29536580; Phenotypes: Atrial septal defect 8 - MIM#614433, Ventricular septal defect 2 - MIM#614431; Mode of inheritance: None
Fetal anomalies v0.1486 BMPR2 Zornitza Stark Marked gene: BMPR2 as ready
Fetal anomalies v0.1485 OPHN1 Zornitza Stark Marked gene: OPHN1 as ready
Fetal anomalies v0.1483 OCLN Zornitza Stark Marked gene: OCLN as ready
Fetal anomalies v0.1483 OPHN1 Zornitza Stark Phenotypes for gene: OPHN1 were changed from Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance, 300486 to Intellectual developmental disorder, X-linked syndromic, Billuart type (MIM#300486)
Fetal anomalies v0.1481 OBSL1 Zornitza Stark Marked gene: OBSL1 as ready
Fetal anomalies v0.1477 NR0B1 Zornitza Stark Marked gene: NR0B1 as ready
Fetal anomalies v0.1477 NUBPL Zornitza Stark Marked gene: NUBPL as ready
Fetal anomalies v0.1477 NUBPL Zornitza Stark Phenotypes for gene: NUBPL were changed from MITOCHONDRIAL COMPLEX I DEFICIENCY to Mitochondrial complex I deficiency, nuclear type 21 (MIM#618242)
Fetal anomalies v0.1475 NR5A1 Zornitza Stark Marked gene: NR5A1 as ready
Fetal anomalies v0.1469 GATA3 Ain Roesley reviewed gene: GATA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29663634; Phenotypes: Hypoparathyroidism, sensorineural deafness, and renal dysplasia MIM146255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v0.1469 ZNF699 Krithika Murali gene: ZNF699 was added
gene: ZNF699 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF699 were set to 33875846
Phenotypes for gene: ZNF699 were set to DEGCAGS syndrome - #619488
Review for gene: ZNF699 was set to GREEN
Added comment: DEGCAGS syndrome is an autosomal recessive syndromic neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding from infancy.

Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems.

Additional features may include sensorineural hearing loss, hypotonia, anemia or pancytopenia, and immunodeficiency with recurrent infections.
Sources: Literature, Expert list
Fetal anomalies v0.1469 ZMYM2 Krithika Murali gene: ZMYM2 was added
gene: ZMYM2 was added to Fetal anomalies. Sources: Expert list,Literature
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities - MIM#619522
Review for gene: ZMYM2 was set to GREEN
Added comment: Approximately half of patients have congenital anomalies of the kidney and urinary tract (CAKUT) and/or congenital cardiac defects, including septal defects
Sources: Expert list, Literature
Fetal anomalies v0.1469 UBR7 Krithika Murali gene: UBR7 was added
gene: UBR7 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: UBR7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBR7 were set to 33340455
Phenotypes for gene: UBR7 were set to Li-Campeau syndrome - MIM#619189
Review for gene: UBR7 was set to GREEN
Added comment: Biallalic variants associated with Li-Campeau syndrome - identified in 7 affected individuals from 6 unrelated families. Phenotypic features include cardiac defects (5/7 - VSD, ASD, PDA, PFO)

Other phenotypic features include: short stature (ht <3rd centile), developmental delay, urogenital anomalies (cryptorchidism, small penis); seizures; hypotonia; hypothyroidism; ptosis; dysmorphic features
Sources: Literature, Expert list
Fetal anomalies v0.1469 TLL1 Krithika Murali gene: TLL1 was added
gene: TLL1 was added to Fetal anomalies. Sources: Expert list,Literature
Mode of inheritance for gene: TLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TLL1 were set to 18830233; 30538173; 27418595; 31570783
Phenotypes for gene: TLL1 were set to Atrial septal defect 6 - MIM#613087; congenital heart disease
Review for gene: TLL1 was set to GREEN
Added comment: Biallelic variants embryonically lethal in mouse model from cardiac failure with associated cardiac defects. Heterozygous missense variants detected in patients from an ASD cohort with supportive follow-up functional studies
Sources: Expert list, Literature
Fetal anomalies v0.1469 TBX2 Krithika Murali gene: TBX2 was added
gene: TBX2 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: TBX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBX2 were set to 29726930
Phenotypes for gene: TBX2 were set to Vertebral anomalies and variable endocrine and T-cell dysfunction - MIM#618223; Congenital heart disease; skeletal abnormalities; thymus aplasia
Review for gene: TBX2 was set to GREEN
Added comment: Liu et al. (2018) reported 4 affected individuals from 2 unrelated families with congenital cardiac defects (ASD, PDA, double outlet right ventricle, pulmonary stenosis), skeletal abnormalities (camptodactyly, congenital fusion thoracic spine, hemivertebrae ).Thymus aplasia/hypoplasia, cleft palate also noted.

Other associated features include - facial dysmorphisms, variable developmental delay, and endocrine system disorders (e.g. autoimmune hypothyroidism, hypoparathyroidism).
Sources: Literature, Expert list
Fetal anomalies v0.1469 FAM58A Belinda Chong reviewed gene: FAM58A: Rating: GREEN; Mode of pathogenicity: None; Publications: 18297069, 8818947, 28225384; Phenotypes: STAR syndrome MIM#300707; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Fetal anomalies v0.1469 STK4 Krithika Murali gene: STK4 was added
gene: STK4 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: STK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STK4 were set to 22294732; 26117625; 22174160; 22952854
Phenotypes for gene: STK4 were set to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations - MIM#614868
Review for gene: STK4 was set to GREEN
Added comment: Biallelic variants identified in 12 affected individuals from 5 unrelated families with two mouse model studies. Immunodeficiencyphenotype but cardiac malformations that are potentially detectable antenatally also a typical feature.
Sources: Literature, Expert list
Fetal anomalies v0.1469 SPRED2 Krithika Murali gene: SPRED2 was added
gene: SPRED2 was added to Fetal anomalies. Sources: Expert list,Literature
Mode of inheritance for gene: SPRED2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRED2 were set to 34626534
Phenotypes for gene: SPRED2 were set to cardiac defects; skeletal anomalies
Review for gene: SPRED2 was set to GREEN
Added comment: Homozygous variants identified in four subjects from three families with a clinical phenotype that included developmental delay, ID, cardiac defects, short stature, skeletal anomalies and dysmorphic features. Cardiac defects and skeletal anomalies potentially ascertainable antenatally.
Sources: Expert list, Literature
Fetal anomalies v0.1469 SPEN Krithika Murali gene: SPEN was added
gene: SPEN was added to Fetal anomalies. Sources: Expert list,Literature
Mode of inheritance for gene: SPEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPEN were set to 33596411
Phenotypes for gene: SPEN were set to Radio-Tartaglia syndrome - MIM#619312
Review for gene: SPEN was set to GREEN
Added comment: Radio et al. (2021) reported heterozygous SPEN variants in 34 individuals from 33 unrelated families with had global developmental delay, ID, behavioural issues and dysmorphic features. Other features included hypotonia, gait imbalance, pyramidal signs and seizures.

Findings potentially ascertainable antenatally:
- Brain imaging abnormalities include polymicrogyria, heterotopia, cerebellar atrophy, periventricular white matter defects, agenesis of the corpus callosum, and tethered cord.
- Congenital heart defects also present in a significant proportion.
Sources: Expert list, Literature
Fetal anomalies v0.1469 SMAD6 Krithika Murali gene: SMAD6 was added
gene: SMAD6 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: SMAD6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD6 were set to 22275001; 31138930; 27606499; 32499606
Phenotypes for gene: SMAD6 were set to Aortic valve disease 2 - MIM#614823; {Craniosynostosis 7, susceptibility to} - MIM#617439; {Radioulnar synostosis, nonsyndromic} - #179300
Review for gene: SMAD6 was set to GREEN
Added comment: Heterozygous SMAD6 variants have been reported with:
congenital cardiovascular malformations including valvular disease
radioulnar synostosis
craniosynostosis (penetrance is 57%. A common polymorphism near BMP2 (rs1884302) was initially proposed to influence penetrance, but follow-up study did not corroborate this. In vitro luciferase assays suggest loss of SMAD6 inhibitory function)
Sources: Literature, Expert list
Fetal anomalies v0.1469 ROBO4 Krithika Murali gene: ROBO4 was added
gene: ROBO4 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: ROBO4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ROBO4 were set to 30455415
Phenotypes for gene: ROBO4 were set to Aortic valve disease 3- MIM#618496
Review for gene: ROBO4 was set to GREEN
Added comment: Heterozygous variants identified in individuals from 2 unrelated families with bicuspid aortic valve and aortic dilatation. Supportive functional data. Incomplete penetrance also a feature.
Sources: Literature, Expert list
Fetal anomalies v0.1469 PRKACB Krithika Murali gene: PRKACB was added
gene: PRKACB was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Cardioacrofacial dysplasia 2 - MIM#619143
Review for gene: PRKACB was set to GREEN
Added comment: Heterozygous variants reported in 4 unrelated probands with Cardioacrofacial dysplasia-2 (CAFD2) - characterized by congenital cardiac defects (atrium or atrioventricular septal defect mainly); limb anomalies (including short limbs, brachydactyly, and postaxial polydactyly); and dysmorphic facial features. Developmental delay of variable severity has also been observed
Sources: Literature, Expert list
Fetal anomalies v0.1469 PRKACA Krithika Murali gene: PRKACA was added
gene: PRKACA was added to Fetal anomalies. Sources: Expert list,Literature
Mode of inheritance for gene: PRKACA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRKACA were set to 33058759
Phenotypes for gene: PRKACA were set to Cardioacrofacial dysplasia 1-MIM#619142
Review for gene: PRKACA was set to GREEN
Added comment: Heterozygous variants were identified in affected individuals from 3 unrelated families and associated with cardioacrofacial dysplasia-1 (CAFD1). Phenotype includes congenital cardiac defects (mainly atrium or atrioventricular septal defect), limb anomalies (short limbs, brachydactyly, postaxial polydactyly) and dysmorphic facial features. Fetal phenotype also reported.
Sources: Expert list, Literature
Fetal anomalies v0.1469 LINS1 Daniel Flanagan reviewed gene: LINS1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23773660, 21937992, 32499722, 28181389; Phenotypes: Mental retardation, autosomal recessive 27 (MIM#614340), autosomal recessive intellectual disability (MIM#614340); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1469 PRDM6 Krithika Murali gene: PRDM6 was added
gene: PRDM6 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: PRDM6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRDM6 were set to 27181681
Phenotypes for gene: PRDM6 were set to Patent ductus arteriosus 3 - MIM#617039
Review for gene: PRDM6 was set to GREEN
Added comment: In 3 unrelated families segregating autosomal dominant nonsyndromic patent ductus arteriosus - usually diagnosed in the neonate
Sources: Literature, Expert list
Fetal anomalies v0.1469 NKX2-6 Krithika Murali edited their review of gene: NKX2-6: Added comment: Homozygous variants were identified in multiple affected individuals from two unrelated consanguineous families. Phenotypic features included multiple conotruncal malformations, persistent truncus arteriosus and athymia; Changed phenotypes: Conotruncal heart malformations - MIM#217095, Persistent truncus arteriosus - MIM#217095
Fetal anomalies v0.1469 NKX2-6 Krithika Murali gene: NKX2-6 was added
gene: NKX2-6 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: NKX2-6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NKX2-6 were set to 24421281; 15649947
Review for gene: NKX2-6 was set to GREEN
Added comment: Homozygous variants were identified in multiple affected individuals from two unrelated consanguineous families. Phenotypic features included multiple conotruncal malformations and athymia
Sources: Literature, Expert list
Fetal anomalies v0.1469 MYBPC3 Krithika Murali gene: MYBPC3 was added
gene: MYBPC3 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: MYBPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYBPC3 were set to 16679492; 17937428; 19858127
Phenotypes for gene: MYBPC3 were set to Neonatal hypertrophic cardiomyopathy; Cardiomyopathy, hypertrophic, 4 - MIM#115197
Review for gene: MYBPC3 was set to GREEN
Added comment: 16679492 - two unrelated neonates with severe hypertrophic cardiomyopathy caused by compound heterozygous truncating mutations in the MYBPC3 gene (no antenatal findings reported)

17937428 - 20 Old Order Amish children with severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site mutation in the MYBPC3 gene, diagnosed in the first 3 weeks of life, surviving individuals required cardiac transplant before age 1

19858127 - infant with fatal cardiomyopathy and skeletal myopathy due to a homozygous mutation, p.R943X
Sources: Literature, Expert list
Fetal anomalies v0.1469 MMP15 Krithika Murali gene: MMP15 was added
gene: MMP15 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: MMP15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMP15 were set to 33875846
Phenotypes for gene: MMP15 were set to Congenital heart disease
Review for gene: MMP15 was set to AMBER
Added comment: Gene reviewed Dec 2021 - 3 individuals from two families with bi-allelic variants and very similar phenotype including rare combination of symtoms (Alagille-like) cholestasis with hepatomegaly and congenital heart disease.
Sources: Literature, Expert list
Fetal anomalies v0.1469 MIB1 Krithika Murali gene: MIB1 was added
gene: MIB1 was added to Fetal anomalies. Sources: Expert list,Literature
Mode of inheritance for gene: MIB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIB1 were set to 33057194
Phenotypes for gene: MIB1 were set to Congenital heart disease
Review for gene: MIB1 was set to AMBER
Added comment: Last reviewed March and Dec 2021 - no additional evidence

Li 2018 (PMID: 30322850):
- in 4 CHD patients: p.Q237H (gv2v3 absent), p.W271G (gv2v3 absent), p.S520R (v2 5 hets) and p.T312Kfs*55 (NMD-pred, absent but many comparables in gnomAD).
- HEK293T cells transfection studies showed: T312Kfs*55 and W271G strongly impaired MIB1 function on substrate ubiquitination, while Q237H and S520R had slight or no obvious changes. Interaction between MIB1 and JAG1 is severely interrupted by p.T312Kfs*55 and p.W271G, but not really in the other 2 missense.
- Overexpression of wt or mutant in zebrafish all resulted in dysmorphic pheno, therefore not informative.

PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Expert list, Literature
Fetal anomalies v0.1469 MESP1 Krithika Murali gene: MESP1 was added
gene: MESP1 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: MESP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MESP1 were set to 28677747; 28050627; 27185833; 26694203
Phenotypes for gene: MESP1 were set to Congenital heart disease
Review for gene: MESP1 was set to AMBER
Added comment: Gene last reviewed April 2021 - Rare/novel variants reported in at least 7 unrelated individuals with congenital heart disease, in-silicos conflicting, familial segregation only available for some (one de novo, three inherited, others unresolved). Functional data implicates gene in cardiac development.

No additional published evidence.
Sources: Literature, Expert list
Fetal anomalies v0.1469 HSPA9 Krithika Murali gene: HSPA9 was added
gene: HSPA9 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: HSPA9 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: HSPA9 were set to 26598328; 32869452; 26491070
Phenotypes for gene: HSPA9 were set to Even-plus syndrome - MIM#616854; Anemia, sideroblastic, 4- #182170
Review for gene: HSPA9 was set to GREEN
Added comment: Biallelic variants in 4 individuals from 5 families. Significant skeletal features and marked nasal hypoplasia with mid-face hypoplasia.
2/5 with developmental delay and abnormalities of the corpus callosum
4/5 with congenital heart disease

Biallelic variants also associated with congenital sideroblastic anaemia. Some patients with a a heterozygous LoF variant have developed congenital sideroblastic anaemia if a particular SNP is presence in trans correlating with reduced mRNA expression (pseudodominant pattern of inheritance)
Sources: Literature, Expert list
Fetal anomalies v0.1469 HAND2 Krithika Murali gene: HAND2 was added
gene: HAND2 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: HAND2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HAND2 were set to 26865696; 32134193; 26676105
Phenotypes for gene: HAND2 were set to Congenital heart defects
Review for gene: HAND2 was set to GREEN
Added comment: Heterozygous LoF variants associated with congenital heart defects reported in at least 3 unrelated families.
Sources: Literature, Expert list
Fetal anomalies v0.1469 HAND1 Krithika Murali gene: HAND1 was added
gene: HAND1 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: HAND1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HAND1 were set to 19586923; 28112363; 18276607; 27942761; 31286141
Phenotypes for gene: HAND1 were set to Congenital heart defects
Review for gene: HAND1 was set to GREEN
Added comment: Testing of hypoplastic human hearts (18276607) and those with septatation defects (19586923) demonstrated impairment in HAND1 function

Germline LoF variants associated with congenital heart defects
Sources: Literature, Expert list
Fetal anomalies v0.1469 GATA5 Krithika Murali gene: GATA5 was added
gene: GATA5 was added to Fetal anomalies. Sources: Literature,Expert list
Mode of inheritance for gene: GATA5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: GATA5 were set to 27066509; 23289003; 22961344; 23031282
Phenotypes for gene: GATA5 were set to Congenital heart defects, multiple types, 5 - #617912
Review for gene: GATA5 was set to GREEN
Added comment: Heterozygous variants asociated with multiple types of congenital heart defects (septal defects, ToF). Autosomal recessive inheritance also reported in a patient with double outflow right ventricle in a consanguineous Lebanese family
Sources: Literature, Expert list
Fetal anomalies v0.1469 FOXH1 Krithika Murali gene: FOXH1 was added
gene: FOXH1 was added to Fetal anomalies. Sources: Expert list,Literature
Mode of inheritance for gene: FOXH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXH1 were set to 19933292; 18538293; 19525021
Phenotypes for gene: FOXH1 were set to Congenital heart disease; holoprosencephaly
Review for gene: FOXH1 was set to GREEN
Added comment: Associated with congenital heart defects (including septal defects, tetralogy of fallot and transposition of the great arteries) as well as holoprosencephaly with supportive functional studies.
Sources: Expert list, Literature
Fetal anomalies v0.1469 FBRSL1 Krithika Murali gene: FBRSL1 was added
gene: FBRSL1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBRSL1 were set to 32424618; 34805182
Phenotypes for gene: FBRSL1 were set to Congenital malformations; congenital heart defect
Review for gene: FBRSL1 was set to GREEN
Added comment: Associated with novel malformation and intellectual disability syndrome. Three unrelated children with de novo PTCs that escape NMD, with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations - 2/3 had heart defects (ASD, VSD), cleft palate and hearing impairement. Supported by Xenopus oocyte functional studies
Sources: Literature
Fetal anomalies v0.1469 AKR1D1 Zornitza Stark Marked gene: AKR1D1 as ready
Fetal anomalies v0.1467 AK2 Zornitza Stark Marked gene: AK2 as ready
Fetal anomalies v0.1467 AK2 Zornitza Stark Phenotypes for gene: AK2 were changed from RETICULAR DYSGENESIS to Reticular dysgenesis, MIM# 267500; MONDO:0009973
Fetal anomalies v0.1465 AK2 Zornitza Stark reviewed gene: AK2: Rating: RED; Mode of pathogenicity: None; Publications: 19043416, 19043417; Phenotypes: Reticular dysgenesis, MIM# 267500, MONDO:0009973; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1465 AIRE Zornitza Stark Marked gene: AIRE as ready
Fetal anomalies v0.1464 CITED2 Krithika Murali gene: CITED2 was added
gene: CITED2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CITED2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CITED2 were set to 11694877; 16287139
Phenotypes for gene: CITED2 were set to Atrial septal defect 8 - MIM#614433; Ventricular septal defect 2 - MIM#614431; Congenital heart disease
Review for gene: CITED2 was set to GREEN
Added comment: Variants associated with congenital heart defects. Supportive functional evidence and animal models
Sources: Literature
Fetal anomalies v0.1464 BMPR2 Krithika Murali gene: BMPR2 was added
gene: BMPR2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: BMPR2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMPR2 were set to 31382961
Phenotypes for gene: BMPR2 were set to Persistent pulmonary hypertension of the neonate; Pulmonary hypertension, familial primary, 1, with or without HHT - MIM#178600; Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated- MIM#178600; Pulmonary venoocclusive disease 1-#265450
Penetrance for gene: BMPR2 were set to Incomplete
Review for gene: BMPR2 was set to AMBER
Added comment: BMPR2 gene variants known to be associated with sporadic/familial pulmonary hypertension and pulmonary venoocclusive disease. Fetal phenotype not reported but known to be associated with persistent pulmonary hypertension of the neonate - critical condition diagnosed in the early postnatal period.
Sources: Literature
Fetal anomalies v0.1464 AIPL1 Zornitza Stark Marked gene: AIPL1 as ready
Fetal anomalies v0.1461 AGXT Zornitza Stark Marked gene: AGXT as ready
Fetal anomalies v0.1461 AGXT Zornitza Stark Phenotypes for gene: AGXT were changed from HYPEROXALURIA, PRIMARY, TYPE 1 to Hyperoxaluria, primary, type 1, MIM# 259900 MONDO:0009823
Fetal anomalies v0.1459 AGXT Zornitza Stark reviewed gene: AGXT: Rating: RED; Mode of pathogenicity: None; Publications: 2039493, 19479957; Phenotypes: Hyperoxaluria, primary, type 1, MIM# 259900 MONDO:0009823; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1459 AGRN Zornitza Stark Marked gene: AGRN as ready
Fetal anomalies v0.1457 AGPAT2 Zornitza Stark Marked gene: AGPAT2 as ready
Fetal anomalies v0.1455 AGA Zornitza Stark Marked gene: AGA as ready
Fetal anomalies v0.1454 AGA Zornitza Stark Phenotypes for gene: AGA were changed from ASPARTYLGLUCOSAMINURIA to Aspartylglucosaminuria, MIM#208400
Fetal anomalies v0.1453 AFF2 Zornitza Stark Marked gene: AFF2 as ready
Fetal anomalies v0.1453 AFF2 Zornitza Stark Phenotypes for gene: AFF2 were changed from FRAGILE X-E MENTAL RETARDATION SYNDROME to Mental retardation, X-linked, FRAXE type 309548
Fetal anomalies v0.1451 AFF2 Zornitza Stark changed review comment from: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar. Missense variants found to be over-represented in an autism cohort.; to: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar. Missense variants found to be over-represented in an autism cohort.

Congenital anomalies are not a prominent feature of this disorder.
Fetal anomalies v0.1451 ADA Zornitza Stark Marked gene: ADA as ready