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| 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 |
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| 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 |
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| 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 |
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| 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 v1.140 | 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 |
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| 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 |
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| 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 v1.82 | 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 |
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| 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 |
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| 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 |
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| 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. |
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| 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 v1.22 | ATP11A | Zornitza Stark Phenotypes for gene: ATP11A were changed from Ventriculomegaly; cerebral atrophy; hypoplasia corpus callosum to Leukodystrophy, hypomyelinating, 24 , MIM# 619851 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v1.11 | 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 |
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| 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 v0.4729 | 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. --- 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 |
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| 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 |
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| 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 |
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| 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 v0.4666 | 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 v0.4532 | 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 |
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| Fetal anomalies v0.4457 | RFX6 | Zornitza Stark changed review comment from: ID is not part of the phenotype.; to: Intestinal atresia. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.4357 | 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 v0.4355 | 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 |
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| Fetal anomalies v0.4322 | EXOC7 | Zornitza Stark reviewed gene: EXOC7: Rating: GREEN; Mode of pathogenicity: None; Publications: 32103185; Phenotypes: Neurodevelopmental disorder with seizures and brain atrophy MIM#619072; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| Fetal anomalies v0.4284 | ATRIP | Zornitza Stark Marked gene: ATRIP as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4284 | ATRIP | Zornitza Stark Gene: atrip has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4284 | ATRIP | Zornitza Stark Classified gene: ATRIP as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4284 | ATRIP | Zornitza Stark Gene: atrip has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 |
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| 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 |
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| 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 |
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| Fetal anomalies v0.4273 | EXOC7 | Ain Roesley edited their review of gene: EXOC7: Changed publications: 32103185; Changed phenotypes: Neurodevelopmental disorder with seizures and brain atrophy MIM#619072 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 v0.4132 | 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 |
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| 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. |
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| 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 v0.4014 | 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 v0.3922 | 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 edited their review of gene: SCN1B: Changed phenotypes: Epileptic encephalopathy, early infantile, 52, MIM#617350, Atrial fibrillation, familial, 13, MIM# 615377 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3850 | NR2F1 | Zornitza Stark Phenotypes for gene: NR2F1 were changed from BOSCH-BOONSTRA OPTIC ATROPHY SYNDROME to Bosch-Boonstra-Schaaf optic atrophy syndrome, MIM# 615722 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
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| 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 v0.3721 | 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 v0.3656 | 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 v0.3532 | TBX20 | Zornitza Stark Phenotypes for gene: TBX20 were changed from ATRIAL SEPTAL DEFECT TYPE 4 to Atrial septal defect 4, MIM# 611363 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3529 | TBX20 | Zornitza Stark reviewed gene: TBX20: Rating: GREEN; Mode of pathogenicity: None; Publications: 17668378, 19762328, 33585493, 29089047; Phenotypes: Atrial septal defect 4, MIM# 611363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3493 | NDUFAF2 | Zornitza Stark changed review comment from: At least four unrelated families reported, complex neurological presentation with optic atrophy, nystagmus, ataxia in some, others described as ventilator-dependent. ID is unlikely to be the presenting or main feature.; to: At least four unrelated families reported, complex neurological presentation with optic atrophy, nystagmus, ataxia in some, others described as ventilator-dependent. Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 v0.3241 | 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. |
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| 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 |
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| 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 |
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| 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 v0.3084 | 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 |
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| Fetal anomalies v0.3031 | PTPN14 | Belinda Chong reviewed gene: PTPN14: Rating: GREEN; Mode of pathogenicity: None; Publications: 20826270, https://doi.org/10.1016/j.mgene.2017.07.006; Phenotypes: Choanal atresia and lymphedema MIM#613611; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
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| 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 |
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| 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 |
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| Fetal anomalies v0.2823 | SLC45A1 | Zornitza Stark Phenotypes for gene: SLC45A1 were changed from Intellectual disability and epilepsy to Intellectual developmental disorder with neuropsychiatric features, MIM# 617532 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
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| 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 |
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| 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 |
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| Fetal anomalies v0.2629 | MECR | Ain Roesley edited their review of gene: MECR: Changed phenotypes: Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities MIM#617282 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2619 | MECR | Zornitza Stark Phenotypes for gene: MECR were changed from Childhood-Onset Dystonia and Optic Atrophy to Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, MIM# 617282 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.2440 | UBTF | Zornitza Stark Phenotypes for gene: UBTF were changed from Childhood-Onset Neurodegeneration to Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672; MONDO:0044701 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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 v0.2343 | 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 v0.1973 | LAMA3 | Zornitza Stark reviewed gene: LAMA3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Epidermolysis bullosa, junctional, Herlitz type (MIM#226700), Epidermolysis bullosa, generalized atrophic benign (MIM#226650); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1933 | LAMA3 | Daniel Flanagan reviewed gene: LAMA3: Rating: AMBER; Mode of pathogenicity: None; Publications: 7633458, 8530087, 11810295, 10366601; Phenotypes: Epidermolysis bullosa, junctional, Herlitz type (MIM#226700), Epidermolysis bullosa, generalized atrophic benign (MIM#226650); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.1911 | 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 v0.1898 | 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 v0.1885 | TTC7A | Zornitza Stark Phenotypes for gene: TTC7A were changed from INTESTINAL ATRESIA, MULTIPLE to Gastrointestinal defects and immunodeficiency syndrome, MIM# 243150 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1877 | TUBB4A | Zornitza Stark Phenotypes for gene: TUBB4A were changed from HYPOMYELINATION WITH ATROPHY OF THE BASAL GANGLIA AND CEREBELLUM to Leukodystrophy, hypomyelinating, 6, MIM# 602662 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.1840 | 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 v0.1833 | 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 v0.1765 | 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 v0.1556 | 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 v0.1542 | 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 |
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| 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 v0.1469 | 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| Fetal anomalies v0.1423 | CTNND1 |
Zornitza Stark changed review comment from: 4 individuals from 3 unrelated families with blepharocheilodontic syndrome and mutations in the CTNND1 gene reported originally in PMID 28301459. All had eyelid anomalies, including ectropion of the lower lids, euryblepharon, lagophthalmia, and distichiasis. In addition, all 4 showed typical facial dysmorphism with hypertelorism, flat face, and high forehead, and all had conical teeth and tooth agenesis. Three had cleft lip and palate, 3 had hair anomalies, and 1 had hypothyroidism due to hypoplasia or aplasia of the thyroid gland. None of the patients exhibited anal atresia or neural tube defects. PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13). This more recent publication suggests a broader phenotype associated with CTNND1 variants including dev delay, ADHD/ASD, behavioural issues. Unclear from description whether significant ID present. Sources: Literature; to: 4 individuals from 3 unrelated families with blepharocheilodontic syndrome and mutations in the CTNND1 gene reported originally in PMID 28301459. All had eyelid anomalies, including ectropion of the lower lids, euryblepharon, lagophthalmia, and distichiasis. In addition, all 4 showed typical facial dysmorphism with hypertelorism, flat face, and high forehead, and all had conical teeth and tooth agenesis. Three had cleft lip and palate, 3 had hair anomalies, and 1 had hypothyroidism due to hypoplasia or aplasia of the thyroid gland. None of the patients exhibited anal atresia or neural tube defects. PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13). This more recent publication suggests a broader phenotype associated with CTNND1 variants including dev delay, ADHD/ASD, behavioural issues. Sources: Literature |
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| Fetal anomalies v0.1416 | CRELD1 | Zornitza Stark Phenotypes for gene: CRELD1 were changed from HETEROTAXY SYNDROME to Atrioventricular septal defect, partial, with heterotaxy syndrome 606217 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1262 | GATA4 | Zornitza Stark Phenotypes for gene: GATA4 were changed from ATRIAL SEPTAL DEFECT TYPE 2 to Atrial septal defect 2 MIM#607941; Atrioventricular septal defect 4 MIM#614430; Ventricular septal defect 1 MIM#614429 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1240 | GATA4 | Ain Roesley reviewed gene: GATA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12845333, 18055909, 15689439, 33413087, 30455927; Phenotypes: Atrial septal defect 2 MIM#607941, Atrioventricular septal defect 4 MIM#614430, Ventricular septal defect 1 MIM#614429; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1147 | CACNA1D | Zornitza Stark Phenotypes for gene: CACNA1D were changed from SINOATRIAL NODE DYSFUNCTION AND DEAFNESS; PRIMARY ALDOSTERONISM, SEIZURES, AND NEUROLOGIC ABNORMALITIES to Primary aldosteronism, seizures, and neurologic abnormalities, MIM# 615474 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1104 | B9D1 |
Zornitza Stark edited their review of gene: B9D1: Added comment: 3 unrelated cases with a syndromic phenotype and a supporting null mouse model PMID: 34338422 - compound het missense and frameshift variant in a proband with anal atresia with vestibular fistula, ventricular septal defect, and right renal agenesis (VACTERL cohort) PMID: 24886560 - 2 Joubert syndrome cases PMID: 21763481 - B9d1 -/- mouse displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction.; Changed rating: GREEN |
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| Fetal anomalies v0.1086 | DYNC1H1 | Zornitza Stark Phenotypes for gene: DYNC1H1 were changed from SPINAL MUSCULAR ATROPHY, LOWER EXTREMITY-PREDOMINANT, AD; SEVERE ID WITH NEURONAL MIGRATION DISORDER to Charcot-Marie-Tooth disease, axonal, type 20, MIM# 614228; Mental retardation, autosomal dominant 13, MIM# 614563; Spinal muscular atrophy, lower extremity-predominant 1, MIM# 158600 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1019 | NBAS | Seb Lunke Phenotypes for gene: NBAS were changed from ACUTE LIVER FAILURE (ALF) IN INFANCY AND CHILDHOOD to Short stature, optic nerve atrophy, and Pelger-Huet anomaly (MIM#614800); bone fragility; developmental delay; immunodeficiency; autism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.977 | ATR | Zornitza Stark Marked gene: ATR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.977 | ATR | Zornitza Stark Gene: atr has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.977 | ATR | Zornitza Stark Publications for gene: ATR were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.976 | ATR | Zornitza Stark Classified gene: ATR as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.976 | ATR | Zornitza Stark Gene: atr has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.975 | ATR | Zornitza Stark reviewed gene: ATR: Rating: GREEN; Mode of pathogenicity: None; Publications: 12640452, 19620979, 30199583, 23111928; Phenotypes: Seckel syndrome 1, MIM# 210600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.957 | NFIX |
Daniel Flanagan changed review comment from: Sotos syndrome-2 (SOTOS2) is clinically characterized by overgrowth, advanced bone age, macrocephaly, and dysmorphic facial features. Patients develop marfanoid habitus, with long and slender body, very low body mass, long narrow face, and arachnodactyly, with age. Impaired intellectual development and behavior anomalies are present. Well established gene-disease association. Marshall-Smith syndrome is allelic. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype (Malan syndrome). Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall-Smith syndrome. Atrial septal defect; to: Sotos syndrome-2 (SOTOS2) is clinically characterized by overgrowth, advanced bone age, macrocephaly, and dysmorphic facial features. Patients develop marfanoid habitus, with long and slender body, very low body mass, long narrow face, and arachnodactyly, with age. Impaired intellectual development and behavior anomalies are present. Well established gene-disease association. Marshall-Smith syndrome is allelic. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype (Malan syndrome). Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall-Smith syndrome. |
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| Fetal anomalies v0.957 | NBAS | Daniel Flanagan reviewed gene: NBAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 20577004, 27789416, 29955634, 26073778; Phenotypes: Short stature, optic nerve atrophy, and Pelger-Huet anomaly (MIM#614800), bone fragility, developmental delay, immunodeficiency, autism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.946 | AP3B2 | Zornitza Stark Phenotypes for gene: AP3B2 were changed from Epileptic Encephalopathy with Optic Atrophy to Developmental and epileptic encephalopathy 48, MIM# 617276 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.886 | ATP11A |
Krithika Murali gene: ATP11A was added gene: ATP11A was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATP11A were set to 34403372 Phenotypes for gene: ATP11A were set to Ventriculomegaly; cerebral atrophy; hypoplasia corpus callosum Review for gene: ATP11A was set to AMBER Added comment: PMID: 34403372 - Single de novo missense variant reported in a patient with developmental delay and neurological deterioration. Epilepsy diagnosed at 2 weeks of age followed by global developmental delay, mild hypothyroidism and cataracts. - Repeated MRI (earliest published is from age 2 yo) showed non-progressive severe cerebral atrophy, enlarged subarachnoid space, ventriculomegaly, hypomyelination leukodystrophy, thinned corpus callosum. - Axonal neuropathy suggested. - K/I heterozygous mice died perinatally. - Functional studies on missense variant show plasma membrane lipid content impairment, reduced ATPase activity etc. gnomAD: some NMD PTCs present, good quality variants found with 4-5 hets. Sources: Literature |
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| Fetal anomalies v0.825 | MAPKAPK5 |
Zornitza Stark gene: MAPKAPK5 was added gene: MAPKAPK5 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAPKAPK5 were set to 33442026 Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic Review for gene: MAPKAPK5 was set to GREEN Added comment: 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers. Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization. Sources: Expert Review |
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| Fetal anomalies v0.637 | KIAA1109 | Zornitza Stark Phenotypes for gene: KIAA1109 were changed from Brain atrophy, Dandy Walker and Contractures; Alkuraya-Kucinskas syndrome, 617822 to Alkuraya-Kucinskas syndrome MIM#617822 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.582 | KCNJ2 | Ain Roesley reviewed gene: KCNJ2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 20301441; Phenotypes: Andersen syndrome MIM#170390, Atrial fibrillation, familial, 9 MIM#613980, Short QT syndrome 3 MIM#609622; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.535 | MED17 | Zornitza Stark Phenotypes for gene: MED17 were changed from MICROCEPHALY, POSTNATAL PROGRESSIVE, WITH SEIZURES AND BRAIN ATROPHY to Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM#613668 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.496 | ITGB4 | Zornitza Stark Phenotypes for gene: ITGB4 were changed from Epidermolysis Bullosa with Pyloric Atresia. 226730 to Epidermolysis bullosa, junctional, with pyloric atresia MIM#226730 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.495 | ITGA6 | Zornitza Stark Phenotypes for gene: ITGA6 were changed from Epidermolysis Bullosa with Pyloric Atresia. 226730 to Epidermolysis bullosa, junctional, with pyloric stenosis MIM#226730 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.468 | IGHMBP2 | Zornitza Stark Phenotypes for gene: IGHMBP2 were changed from SPINAL MUSCULAR ATROPHY WITH RESPIRATORY DISTRESS 1 to Neuronopathy, distal hereditary motor, type VI MIM#604320 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.448 | ITGB4 | Ain Roesley reviewed gene: ITGB4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epidermolysis bullosa, junctional, with pyloric atresia MIM#226730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.448 | ITGA6 |
Ain Roesley changed review comment from: At least 4 probands reported Pyelonephrosis, Urethrovesical occlusion and Stenosis at the ureterovesical junctions are some other features in this condition; to: At least 4 probands reported Epidermolysis bullosa with pyloric atresia (EB-PA) is characterized by fragility of the skin and mucous membranes, manifested by blistering with little or no trauma; congenital pyloric atresia; and ureteral and renal anomalies (dysplastic/multicystic kidney, hydronephrosis/hydroureter, ureterocele, duplicated renal collecting system, absent bladder). |
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| Fetal anomalies v0.340 | BRAT1 | Zornitza Stark Phenotypes for gene: BRAT1 were changed from LETHAL NEONATAL RIGIDITY AND SEIZURE SYNDROME to Neurodevelopmental disorder with cerebellar atrophy and with or without seizures, MIM#618056; Rigidity and multifocal seizure syndrome, lethal neonatal, MIM# 614498 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.338 | BRAT1 |
Zornitza Stark edited their review of gene: BRAT1: Added comment: RMFSL: Lethal neonatal rigidity and multifocal seizure syndrome is a severe autosomal recessive epileptic encephalopathy characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within the first months or years of life. More than 5 unrelated families reported. Neurodevelopmental disorder with cerebellar atrophy, with or without seizures: at least 4 families reported with this milder disorder, which typically has onset in infancy. The two disorders likely represent a continuum. Both disorders associated with this gene have microcephaly as a feature.; Changed publications: 26483087, 26494257, 27282546, 22279524, 23035047, 25319849, 25500575 |
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| Fetal anomalies v0.338 | BRAT1 | Zornitza Stark edited their review of gene: BRAT1: Changed phenotypes: Neurodevelopmental disorder with cerebellar atrophy and with or without seizures, MIM#618056, Rigidity and multifocal seizure syndrome, lethal neonatal, MIM# 614498 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.247 | HR | Zornitza Stark Phenotypes for gene: HR were changed from ATRICHIA WITH PAPULAR LESIONS; ALOPECIA UNIVERSALIS to Atrichia with papular lesions MIM#209500 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.211 | ATRX | Zornitza Stark Marked gene: ATRX as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.211 | ATRX | Zornitza Stark Gene: atrx has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.211 | ATRX | Zornitza Stark Phenotypes for gene: ATRX were changed from ALPHA-THALASSEMIA MENTAL RETARDATION SYNDROME X-LINKED NON-DELETION TYPE; MENTAL RETARDATION SYNDROMIC X-LINKED WITH HYPOTONIC FACIES SYNDROME TYPE 1 to Alpha-thalassemia/mental retardation syndrome, MIM# 301040 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.210 | ATRX | Zornitza Stark Publications for gene: ATRX were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.209 | ATRX | Zornitza Stark edited their review of gene: ATRX: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.209 | ATP7A | Zornitza Stark Phenotypes for gene: ATP7A were changed from SPINAL MUSCULAR ATROPHY, DISTAL, X-LINKED 3; MENKES DISEASE; OCCIPITAL HORN SYNDROME to Menkes disease, MIM# 309400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.204 | ATAD3A | Zornitza Stark Phenotypes for gene: ATAD3A were changed from ATAD3A disorder - global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; Harel-Yoon syndrome, OMIM:617183 to Harel-Yoon syndrome, MIM# 617183; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal (PHRINL SYNDROME) 618810 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.190 | ASCC1 | Zornitza Stark Phenotypes for gene: ASCC1 were changed from spinal muscular atrophy; hypotonia; contractures; fetal akinesia; arthrogryposis to Spinal muscular atrophy with congenital bone fractures 2 MIM#616867 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.189 | ASAH1 | Zornitza Stark Phenotypes for gene: ASAH1 were changed from SPINAL MUSCULAR ATROPHY ASSOCIATED WITH PROGRESSIVE MYOCLONIC EPILEPSY; FARBER LIPOGRANULOMATOSIS to Farber lipogranulomatosis, MIM# 228000 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.161 | AR | Zornitza Stark Phenotypes for gene: AR were changed from SPINAL AND BULBAR MUSCULAR ATROPHY; ANDROGEN INSENSITIVITY SYNDROME to Androgen insensitivity, MIM# 300068 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.152 | HR | Ain Roesley reviewed gene: HR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrichia with papular lesions MIM#209500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.132 | BICD2 | Zornitza Stark Phenotypes for gene: BICD2 were changed from reduced fetal movements; PROXIMAL SPINAL MUSCULAR ATROPHY WITH AUTOSOMAL-DOMINANT INHERITANCE; Spinal muscular atrophy, lower extremity-predominant, 2B, autosomal dominant, 618291; arthrogryposis multiplex congenita (AMC); hydrops fetalis; Pterygium to Spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant 615290; Spinal muscular atrophy, lower extremity-predominant, 2B, autosomal dominant 618291 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.36 | ACTC1 | Zornitza Stark Phenotypes for gene: ACTC1 were changed from Atrial septal defect 5 612794 to Atrial septal defect 5 612794; Cardiomyopathy, hypertrophic, 11 612098 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.33 | ACTC1 | Zornitza Stark reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31430208, 17947298; Phenotypes: Cardiomyopathy, hypertrophic, 11 612098, Atrial septal defect; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.0 | NR2F1 |
Zornitza Stark gene: NR2F1 was added gene: NR2F1 was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: NR2F1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: NR2F1 were set to BOSCH-BOONSTRA OPTIC ATROPHY SYNDROME |
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| Fetal anomalies v0.0 | TRAPPC12 |
Zornitza Stark gene: TRAPPC12 was added gene: TRAPPC12 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: TRAPPC12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRAPPC12 were set to 28777934; 32347653 Phenotypes for gene: TRAPPC12 were set to Hydrocephaly; Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696 |
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| Fetal anomalies v0.0 | SIX6 |
Zornitza Stark gene: SIX6 was added gene: SIX6 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: SIX6 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SIX6 were set to Optic disc anomalies with retinal and/or macular dystrophy, OMIM:212550; Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome, MONDO:0008927 |
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| Fetal anomalies v0.0 | SCYL1 |
Zornitza Stark gene: SCYL1 was added gene: SCYL1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: SCYL1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SCYL1 were set to Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia |
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| Fetal anomalies v0.0 | QARS |
Zornitza Stark gene: QARS was added gene: QARS was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: QARS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: QARS were set to MICROCEPHALY, PROGRESSIVE, SEIZURES, AND CEREBRAL AND CEREBELLAR ATROPHY |
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| Fetal anomalies v0.0 | PTPN14 |
Zornitza Stark gene: PTPN14 was added gene: PTPN14 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: PTPN14 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PTPN14 were set to Lymphedema-posterior choanal atresia syndrome, MONDO:0013324; Choanal atresia and lymphedema, OMIM:613611 |
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| Fetal anomalies v0.0 | NONO |
Zornitza Stark gene: NONO was added gene: NONO was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: NONO was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: NONO were set to 32397791 Phenotypes for gene: NONO were set to Atresia; Ventricular septal defect (VSD); Pulmonary stenosis; Ebstein s anomaly; Left ventricular non-compaction cardiomyopathy (LVNC) |
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| Fetal anomalies v0.0 | MYL1 |
Zornitza Stark gene: MYL1 was added gene: MYL1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: MYL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYL1 were set to 30215711 Phenotypes for gene: MYL1 were set to Myopathy, congenital, with fast-twitch (type II) fiber atrophy, OMIM:618414; Congenital myopathy with reduced type 2 muscle fibers, MONDO:0034109 |
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| Fetal anomalies v0.0 | MED17 |
Zornitza Stark gene: MED17 was added gene: MED17 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: MED17 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MED17 were set to MICROCEPHALY, POSTNATAL PROGRESSIVE, WITH SEIZURES AND BRAIN ATROPHY |
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| Fetal anomalies v0.0 | MECR |
Zornitza Stark gene: MECR was added gene: MECR was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: MECR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MECR were set to Childhood-Onset Dystonia and Optic Atrophy |
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| Fetal anomalies v0.0 | GSC |
Zornitza Stark gene: GSC was added gene: GSC was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: GSC was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: GSC were set to Short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, MONDO:0011227; Short stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalities, OMIM:602471 |
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| Fetal anomalies v0.0 | GPAA1 |
Zornitza Stark gene: GPAA1 was added gene: GPAA1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: GPAA1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: GPAA1 were set to Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia |
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| Fetal anomalies v0.0 | EMC1 |
Zornitza Stark gene: EMC1 was added gene: EMC1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: EMC1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: EMC1 were set to Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy. |
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| Fetal anomalies v0.0 | CACNA1D |
Zornitza Stark gene: CACNA1D was added gene: CACNA1D was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: CACNA1D was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: CACNA1D were set to SINOATRIAL NODE DYSFUNCTION AND DEAFNESS; PRIMARY ALDOSTERONISM, SEIZURES, AND NEUROLOGIC ABNORMALITIES |
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| Fetal anomalies v0.0 | ATR |
Zornitza Stark gene: ATR was added gene: ATR was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: ATR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ATR were set to Seckel syndrome 1, MONDO:0008869; Seckel syndrome 1, OMIM:210600 |
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| Fetal anomalies v0.0 | AP3B2 |
Zornitza Stark gene: AP3B2 was added gene: AP3B2 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: AP3B2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: AP3B2 were set to Epileptic Encephalopathy with Optic Atrophy |
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| Fetal anomalies v0.0 | VPS53 |
Zornitza Stark gene: VPS53 was added gene: VPS53 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: VPS53 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS53 were set to 12920088; 24577744; 30100179 Phenotypes for gene: VPS53 were set to Progressive cerebella-cerebral atrophy type 2; PONTOCEREBELLAR HYPOPLASIA, TYPE 2E 615851 |
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| Fetal anomalies v0.0 | UBA1 |
Zornitza Stark gene: UBA1 was added gene: UBA1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: UBA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: UBA1 were set to Spinal muscular atrophy, X-linked 2, infantile 301830 |
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| Fetal anomalies v0.0 | TUBB4A |
Zornitza Stark gene: TUBB4A was added gene: TUBB4A was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TUBB4A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: TUBB4A were set to HYPOMYELINATION WITH ATROPHY OF THE BASAL GANGLIA AND CEREBELLUM |
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| Fetal anomalies v0.0 | TTC7A |
Zornitza Stark gene: TTC7A was added gene: TTC7A was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TTC7A was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TTC7A were set to INTESTINAL ATRESIA, MULTIPLE |
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| Fetal anomalies v0.0 | TRPV4 |
Zornitza Stark gene: TRPV4 was added gene: TRPV4 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TRPV4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: TRPV4 were set to METATROPIC DYSPLASIA; SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE |
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| Fetal anomalies v0.0 | TRIP4 |
Zornitza Stark gene: TRIP4 was added gene: TRIP4 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TRIP4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRIP4 were set to 26924529; 27008887 Phenotypes for gene: TRIP4 were set to 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 |
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| Fetal anomalies v0.0 | TBX20 |
Zornitza Stark gene: TBX20 was added gene: TBX20 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TBX20 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: TBX20 were set to ATRIAL SEPTAL DEFECT TYPE 4 |
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| Fetal anomalies v0.0 | TBCE |
Zornitza Stark gene: TBCE was added gene: TBCE was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TBCE was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TBCE were set to HYPOPARATHYROIDISM-RETARDATION-DYSMORPHISM SYNDROME; Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy; KENNY-CAFFEY SYNDROME TYPE 1 |
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| Fetal anomalies v0.0 | TBCD |
Zornitza Stark gene: TBCD was added gene: TBCD was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TBCD was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TBCD were set to Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646; Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193 |
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| Fetal anomalies v0.0 | SMN1 |
Zornitza Stark gene: SMN1 was added gene: SMN1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: SMN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SMN1 were set to 32644125; 11826188; 32644120 Phenotypes for gene: SMN1 were set to Spinal muscular atrophy 253400; Spinal muscular atrophy 271150; Spinal muscular atrophy 253550; Spinal muscular atrophy 253300 |
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| Fetal anomalies v0.0 | SLC39A8 |
Zornitza Stark gene: SLC39A8 was added gene: SLC39A8 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: SLC39A8 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SLC39A8 were set to Intellectual Disability with Cerebellar Atrophy |
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| Fetal anomalies v0.0 | NKX2-5 |
Zornitza Stark gene: NKX2-5 was added gene: NKX2-5 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: NKX2-5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: NKX2-5 were set to CONGENITAL HYPOTHYROIDISM NON-GOITROUS TYPE 5; TETRALOGY OF FALLOT; ATRIAL SEPTAL DEFECT WITH ATRIOVENTRICULAR CONDUCTION DEFECTS |
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| Fetal anomalies v0.0 | MYH6 |
Zornitza Stark gene: MYH6 was added gene: MYH6 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: MYH6 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MYH6 were set to ATRIAL SEPTAL DEFECT TYPE 3; CARDIOMYOPATHY FAMILIAL HYPERTROPHIC TYPE 14; CARDIOMYOPATHY DILATED TYPE 1EE |
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| Fetal anomalies v0.0 | KIAA1109 |
Zornitza Stark gene: KIAA1109 was added gene: KIAA1109 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: KIAA1109 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIAA1109 were set to 28749478; 30485398; 29290337 Phenotypes for gene: KIAA1109 were set to Brain atrophy, Dandy Walker and Contractures; Alkuraya-Kucinskas syndrome, 617822 |
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| Fetal anomalies v0.0 | ITGB4 |
Zornitza Stark gene: ITGB4 was added gene: ITGB4 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: ITGB4 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ITGB4 were set to Epidermolysis Bullosa with Pyloric Atresia. 226730 |
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| Fetal anomalies v0.0 | ITGA6 |
Zornitza Stark gene: ITGA6 was added gene: ITGA6 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: ITGA6 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ITGA6 were set to Epidermolysis Bullosa with Pyloric Atresia. 226730 |
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| Fetal anomalies v0.0 | IGHMBP2 |
Zornitza Stark gene: IGHMBP2 was added gene: IGHMBP2 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: IGHMBP2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IGHMBP2 were set to SPINAL MUSCULAR ATROPHY WITH RESPIRATORY DISTRESS 1 |
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| Fetal anomalies v0.0 | HR |
Zornitza Stark gene: HR was added gene: HR was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: HR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: HR were set to ATRICHIA WITH PAPULAR LESIONS; ALOPECIA UNIVERSALIS |
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| Fetal anomalies v0.0 | GDF1 |
Zornitza Stark gene: GDF1 was added gene: GDF1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: GDF1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: GDF1 were set to 17924340; PMID: 20413652; 28991257 Phenotypes for gene: GDF1 were set to Right atrial isomerism (Ivemark); Congenital heart defects, multiple types |
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| Fetal anomalies v0.0 | GATA6 |
Zornitza Stark gene: GATA6 was added gene: GATA6 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: GATA6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: GATA6 were set to ATRIOVENTRICULAR SEPTAL DEFECT 5; PANCREATIC AGENESIS, DIAPHRAGMATIC HERNIA AND CONGENITAL HEART DEFECTS; ATRIAL SEPTAL DEFECT 9 |
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| Fetal anomalies v0.0 | GATA4 |
Zornitza Stark gene: GATA4 was added gene: GATA4 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: GATA4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: GATA4 were set to ATRIAL SEPTAL DEFECT TYPE 2 |
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| Fetal anomalies v0.0 | DYNC1H1 |
Zornitza Stark gene: DYNC1H1 was added gene: DYNC1H1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: DYNC1H1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: DYNC1H1 were set to SPINAL MUSCULAR ATROPHY, LOWER EXTREMITY-PREDOMINANT, AD; SEVERE ID WITH NEURONAL MIGRATION DISORDER |
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| Fetal anomalies v0.0 | BICD2 |
Zornitza Stark gene: BICD2 was added gene: BICD2 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: BICD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: BICD2 were set to 27751653; 30054298; 29274205; 28635954 Phenotypes for gene: BICD2 were set to reduced fetal movements; PROXIMAL SPINAL MUSCULAR ATROPHY WITH AUTOSOMAL-DOMINANT INHERITANCE; Spinal muscular atrophy, lower extremity-predominant, 2B, autosomal dominant, 618291; arthrogryposis multiplex congenita (AMC); hydrops fetalis; Pterygium Mode of pathogenicity for gene: BICD2 was set to Other |
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| Fetal anomalies v0.0 | ATRX |
Zornitza Stark gene: ATRX was added gene: ATRX was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: ATRX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: ATRX were set to ALPHA-THALASSEMIA MENTAL RETARDATION SYNDROME X-LINKED NON-DELETION TYPE; MENTAL RETARDATION SYNDROMIC X-LINKED WITH HYPOTONIC FACIES SYNDROME TYPE 1 |
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| Fetal anomalies v0.0 | ATP7A |
Zornitza Stark gene: ATP7A was added gene: ATP7A was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: ATP7A was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: ATP7A were set to 23035047 Phenotypes for gene: ATP7A were set to SPINAL MUSCULAR ATROPHY, DISTAL, X-LINKED 3; MENKES DISEASE; OCCIPITAL HORN SYNDROME |
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| Fetal anomalies v0.0 | ATAD3A |
Zornitza Stark gene: ATAD3A was added gene: ATAD3A was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: ATAD3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATAD3A were set to 33845882; 28549128; 28158749; 29053797; 32607449; 32004445; 33575671; 31727539; 28327206; 27640307 Phenotypes for gene: ATAD3A were set to ATAD3A disorder - global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; Harel-Yoon syndrome, OMIM:617183 Mode of pathogenicity for gene: ATAD3A was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments |
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| Fetal anomalies v0.0 | ASCC1 |
Zornitza Stark gene: ASCC1 was added gene: ASCC1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: ASCC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ASCC1 were set to 28749478; 26924529; 30327447 Phenotypes for gene: ASCC1 were set to spinal muscular atrophy; hypotonia; contractures; fetal akinesia; arthrogryposis |
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| Fetal anomalies v0.0 | ASAH1 |
Zornitza Stark gene: ASAH1 was added gene: ASAH1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: ASAH1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ASAH1 were set to SPINAL MUSCULAR ATROPHY ASSOCIATED WITH PROGRESSIVE MYOCLONIC EPILEPSY; FARBER LIPOGRANULOMATOSIS |
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| Fetal anomalies v0.0 | AR |
Zornitza Stark gene: AR was added gene: AR was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: AR was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: AR were set to SPINAL AND BULBAR MUSCULAR ATROPHY; ANDROGEN INSENSITIVITY SYNDROME |
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| Fetal anomalies v0.0 | ACTC1 |
Zornitza Stark gene: ACTC1 was added gene: ACTC1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ACTC1 were set to 24461919 Phenotypes for gene: ACTC1 were set to Atrial septal defect 5 612794 |
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