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| Fetal anomalies v1.162 | CASP2 |
Zornitza Stark gene: CASP2 was added gene: CASP2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CASP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CASP2 were set to 37880421 Phenotypes for gene: CASP2 were set to neurodevelopmental disorder MONDO:0700092, CASP2-related Review for gene: CASP2 was set to GREEN Added comment: 7 individuals from 5 families: - 4 families homozygous for PTC. - 1 family compound heterozygote for splice site + PTC. RNA studies indicate usage of 2 cryptic splice donor sites. 5/5 have ID/dev delay 1/5 seizures 2/5 hypotonia 3/5 Lissencephaly (pachygyria + cortical thickening) Sources: Literature |
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| Fetal anomalies v1.129 | STX5 |
Ain Roesley gene: STX5 was added gene: STX5 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: STX5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STX5 were set to 34711829 Phenotypes for gene: STX5 were set to congenital disorder of glycosylation MONDO#0015286, STX5-related Review for gene: STX5 was set to AMBER gene: STX5 was marked as current diagnostic Added comment: 1x family with 3x deceased shortly after death + 3x spontaneous abortions + 2x abortions due to abnormal fatal ultrasound (US). Hom for NM_003164.4:c.163 A > G p.(Met55Val), which results in complete loss of short isoform (which uses Met55 as the start) phenotype: short long bones on US, dysmorphism, skeletal dysplasia, profound hypotonia, hepatomegaly elevated cholesterol. Post-natally they died of progressive liver failure with cholestasis and hyperinsulinemic hypoglycemias Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking Sources: Literature |
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| Fetal anomalies v0.4665 | NPC2 | Zornitza Stark Phenotypes for gene: NPC2 were changed from NIEMANN-PICK DISEASE, TYPE C2 to Niemann-pick disease, type C2, MIM# 607625 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4349 | SMPD1 | Zornitza Stark Phenotypes for gene: SMPD1 were changed from NIEMANN-PICK DISEASE TYPE B; NIEMANN-PICK DISEASE TYPE A to Niemann-Pick disease, type A, MIM# 257200; MONDO:0009756 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4305 | VPS50 |
Chirag Patel gene: VPS50 was added gene: VPS50 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS50 were set to PMID: 34037727 Phenotypes for gene: VPS50 were set to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis , MIM#619685 Review for gene: VPS50 was set to AMBER Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants. Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging. Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)). VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor. As discussed by Schneeberger et al (refs provided in text): - VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development. - Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality. Studies performed by Schneeberger et al included: - Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del). - Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels. - Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts. - Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function. As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders". There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes. Sources: Expert list |
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| Fetal anomalies v0.4273 | ENO1 |
Daniel Flanagan gene: ENO1 was added gene: ENO1 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: ENO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ENO1 were set to 32488097 Phenotypes for gene: ENO1 were set to Polymicrogyria; microcephaly Review for gene: ENO1 was set to RED Added comment: ENO1 identified as a polymicrogyria candidate gene from the smallest case of 1p36 duplication reported to date, in a 35yo F (onset at 8mo) presenting intellectual disability, microcephaly, epilepsy and perisylvian polymicrogyria. The duplication only encompassed 2 genes, ENO1 and RERE, and gene expression analysis performed using the patient cells revealed reduced expression, mimicking haploinsufficiency. Eno1 inactivation in rats was shown to cause a brain development defect. According to OMIM, ENO1 is deleted in glioblastoma, which is tolerated by the expression of ENO2. Sources: Expert list |
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| Fetal anomalies v0.3934 | SLC2A2 | Zornitza Stark Phenotypes for gene: SLC2A2 were changed from FANCONI-BICKEL SYNDROME to Fanconi-Bickel syndrome, MIM# 227810 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3914 | PLOD3 | Zornitza Stark Phenotypes for gene: PLOD3 were changed from Lysyl hydroxylase 3 deficiency - MIM#612394 to Lysyl hydroxylase 3 deficiency - MIM#612394; Stickler-syndrome like | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3908 | PLOD3 | Krithika Murali reviewed gene: PLOD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18834968, 30237576, 30463024, 31129566; Phenotypes: Lysyl hydroxylase 3 deficiency - MIM#612394, Stickler-syndrome like; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3908 | PLOD3 |
Krithika Murali gene: PLOD3 was added gene: PLOD3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PLOD3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLOD3 were set to 30237576; 18834968 Phenotypes for gene: PLOD3 were set to Lysyl hydroxylase 3 deficiency - MIM#612394 Review for gene: PLOD3 was set to GREEN Added comment: 4 unrelated families reported with biallelic PLOD3 variants and Stickler-syndrome like phenotype including antenatal phenotype of IUGR in one family. -- PMID 30237576 Maddirevula et al 2019 - report homozygous nonsense variant in a proband with dysmorphic facies, microcephaly, ptosis and contractures. No antenatal information provided. PMID 31129566 Ewans et al 2019 - report 3 affected siblings with a Stickler-syndrome like disorder. - Patient 1 had congenital nystagmus and presented with hearing loss and myopia. On examination aged 2, noted to have dysmorphic features - prominent eyes, hypertelorism, malar hypoplasia, an upturned nose, low-set ears and microretrognathia. - Patient 2 noted to have camptodactyly and clinodactyly postnatally. On examination age 5 noted to have DIP joint contractures and mild skin syndactyly. - Patient 3 - breech delivery. bilateral hand foot camptodactyly, facial dysmorphism. - No antenatal features reported. PMID 30463024 Vahidnehzad et al 2019 - report a male proband from a consanguineous Iranian Baloch family referred for assessment age 4.5. Noted to have developmental delay, musculoskeletal manifestations including scoliosis, flexion contractions, cutaneous syndactyly, right diaphragmatic eventration, ocular anomalies, growth failure and skin blisters. No concerns antenatally. Postnatally noted to have cataract and facial dysmorphism (midface hypoplasia). Homozygous PLOD3 missense variant identified, parents unaffected carriers. PLOD3 mRNA levels in the patient’s fibroblasts measured by whole-transcriptome sequencing and confirmed by RT-PCR, were the same as in control cells, however, the expression of type VII collagen was reduced significantly. No antenatal features reported. PMID: 18834968 Salo et al 2008 - a female proband with significant IUGR, characteristic craniofacial profile, diaphragm eventration, skeletal anomalies (bilateral talipes equinovarus, flexion contractures, scoliosis from age 7), skin anomalies incl blistering and ocular anomalies. One 28 week male stillborn sibling noted to have significant IUGR and skeletal anomalies on post-mortem. Supportive functional evidence. Compound het PLOD3 variants. Sources: Literature |
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| Fetal anomalies v0.3908 | LOXL3 |
Krithika Murali gene: LOXL3 was added gene: LOXL3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LOXL3 were set to 25663169; 26307084; 26957899; 29802726; 30362103; 34787502 Phenotypes for gene: LOXL3 were set to Stickler syndrome; cleft lip/palate Review for gene: LOXL3 was set to AMBER Added comment: Biallelic variants reported in association with Stickler syndrome in 2 unrelated families. Also identified in one individual with non-syndromic Pierre Robin sequence who had a CNV also. --- PMID 34787502 Sood et al 2021 - proband with non-syndromic Pierre Robin sequence - homozygous missense LOXL3 variant identified. Sibling also had non-syndromic PRS, but genetic testing declined by family. In addition 551 kb chr10q26.2 duplication identified, no parental testing information provided, not previously reported to be associated with CL/P. PMID 30362103 Chan et al 2019 - report father and son with Stickler syndrome and homozygous LOXL3 missense variants. Predominantly ocular phenotype with no antenatal features reported. PMID: 29802726 Khan et al 2018 - genotyping of 258 probands with non-syndromic cleft palate (nsCP) and their parents, focusing in particular on common missense variant p.Ile615Phe. Identified four Phe/Phe homozygotes, report significant association between infant’s homozygote Phe/Phe genotype and the risk of nsCP, compared to common Ile/Ile homozygotes PMID 26957899 Li et al 2016 - A homozygous frameshift mutation (c.39dup; p.L14Afs*21) and a compound heterozygous frameshift mutation (c.39dup; p.L14Afs*21 and c.594delG; p.Q199Kfs*35) in LOXL3 were separately identified in two of 298 probands with early-onset high myopia. PMID: 26307084 Zhang et al 2015 - Mice lacking LOXL3 exhibited perinatal lethality and were noted to have cleft palate and spinal deformity. PMID: 25663169 Alzahrani et al 2015 - homozygous variant identified in 2 children with Stickler syndrome from the same family, both children had cleft lip/palate. Sources: Literature |
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| Fetal anomalies v0.3825 | TSHR |
Krithika Murali changed review comment from: Heterozygous variants associated with hyperthyroidism. De novo GoF variants in particular associated with more severe, non-autoimmune congenital hyperthyroidism. Biallelic LoF variants associated with congenital hypothyroidism. Premature delivery, IUGR and fetal tachycardia are reported antenatal phenotypes. Goitre also noted at birth in some cases. Craniosynostosis also a feature, but diagnosed postnatally in the context of rapidly advancing bone age. --- PMID: 9360555 Holzapfel 1997 - report IUGR and antenatal fetal tachycardia PMID: 7800007 Kopp et al 1995 - proband born prematurely at 32 weeks gestation with BW of 1660g. Fetal tachycardia and diffuse goitre noted postnatally. PMID: 18655531 Chester et al 2008 - proband born at 34 weeks. Antenatal ultrasound had shown thickened nuchal fold. PMID: 15163335 Vaidya et al 2004 - report two siblings born premature with IUGR, heterozygous variant inherited from affected father. Sources: Literature; to: Heterozygous variants associated with hyperthyroidism. De novo GoF variants in particular associated with more severe, non-autoimmune congenital hyperthyroidism. Biallelic LoF variants associated with congenital hypothyroidism. Premature delivery, IUGR and fetal tachycardia are reported antenatal phenotypes. Goitre also noted at birth in some cases. Craniosynostosis also a feature, but diagnosed postnatally in the context of rapidly advancing bone age. --- PMID: 9360555 Holzapfel 1997 - report IUGR and antenatal fetal tachycardia PMID: 7800007 Kopp et al 1995 - proband born prematurely at 32 weeks gestation with BW of 1660g. Fetal tachycardia and diffuse goitre noted postnatally. PMID: 18655531 Chester et al 2008 - proband born at 34 weeks. Antenatal ultrasound had shown thickened nuchal fold. PMID: 15163335 Vaidya et al 2004 - report two siblings born premature with IUGR, heterozygous variant inherited from affected father. PMID: 11081252 M Tonacchera et al 2000 - report SGA PMID: 16960398 Nishihara et al 2006 - proband born 32 weeks with 1860g birthweight, postnatal goitre and craniosynostosis Sources: Literature |
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| Fetal anomalies v0.3825 | TSHR |
Krithika Murali gene: TSHR was added gene: TSHR was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TSHR was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TSHR were set to 23295291; 9360555; 7800007; 18655531; 15163335 Phenotypes for gene: TSHR were set to Hyperthyroidism, nonautoimmune - MIM#609152; Hypothyroidism, congenital, nongoitrous, 1 - MIM#275200 Review for gene: TSHR was set to GREEN Added comment: Heterozygous variants associated with hyperthyroidism. De novo GoF variants in particular associated with more severe, non-autoimmune congenital hyperthyroidism. Biallelic LoF variants associated with congenital hypothyroidism. Premature delivery, IUGR and fetal tachycardia are reported antenatal phenotypes. Goitre also noted at birth in some cases. Craniosynostosis also a feature, but diagnosed postnatally in the context of rapidly advancing bone age. --- PMID: 9360555 Holzapfel 1997 - report IUGR and antenatal fetal tachycardia PMID: 7800007 Kopp et al 1995 - proband born prematurely at 32 weeks gestation with BW of 1660g. Fetal tachycardia and diffuse goitre noted postnatally. PMID: 18655531 Chester et al 2008 - proband born at 34 weeks. Antenatal ultrasound had shown thickened nuchal fold. PMID: 15163335 Vaidya et al 2004 - report two siblings born premature with IUGR, heterozygous variant inherited from affected father. Sources: Literature |
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| Fetal anomalies v0.3630 | ENPP1 | Zornitza Stark Phenotypes for gene: ENPP1 were changed from HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL RECESSIVE, 2; ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1 to Arterial calcification, generalized, of infancy, 1, MIM3 208000; Hypophosphatemic rickets, autosomal recessive, 2, MIM# 613312 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3627 | ENPP1 | Zornitza Stark reviewed gene: ENPP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19521093; Phenotypes: Arterial calcification, generalized, of infancy, 1, MIM3 208000, Hypophosphatemic rickets, autosomal recessive, 2, MIM# 613312; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3623 | DMP1 | Zornitza Stark Phenotypes for gene: DMP1 were changed from HYPOPHOSPHATEMIC RICKETS, AR to Hypophosphatemic rickets, AR MIM#241520 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3544 | DMP1 | Belinda Chong reviewed gene: DMP1: Rating: RED; Mode of pathogenicity: None; Publications: 17033625, 17033621, 31843680; Phenotypes: Hypophosphatemic rickets, AR MIM#241520; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3400 | PHEX |
Krithika Murali gene: PHEX was added gene: PHEX was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PHEX was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: PHEX were set to 29791829; 16055933; 19219621; 9106524 Phenotypes for gene: PHEX were set to Hypophosphatemic rickets, X-linked dominant - MIM#307800 Review for gene: PHEX was set to GREEN Added comment: Well-known association with hypophosphataemic rickets with some phenotypic features potentially detectable antenatally (skeletal, craniosynostosis). Early therapeutic interventions available. Sources: Literature |
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| Fetal anomalies v0.3292 | ICK | Zornitza Stark Marked gene: ICK as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3292 | ICK | Zornitza Stark Gene: ick has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3292 | ICK | Zornitza Stark Publications for gene: ICK were set to 24853502; 19185282; 27466187; 27069622 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3291 | ICK | Zornitza Stark Classified gene: ICK as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3291 | ICK | Zornitza Stark Gene: ick has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3290 | ICK |
Zornitza Stark changed review comment from: 6 affected individuals from 2 Amish families reported originally (founder effect); another Turkish family reported since. However, renal cysts only reported in the Amish families, emerging ciliopathy gene, renal phenotype remains to be elucidated. Sources: Expert list; to: Ciliopathy phenotype. Sources: Expert list |
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| Fetal anomalies v0.3290 | ICK | Zornitza Stark edited their review of gene: ICK: Changed rating: GREEN; Changed phenotypes: Endocrine-cerebroosteodysplasia, MIM# 612651 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3140 | COL9A3 |
Krithika Murali gene: COL9A3 was added gene: COL9A3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: COL9A3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: COL9A3 were set to 33570243; 31090205; 30450842; 25381065; 24273071; 15551337 Phenotypes for gene: COL9A3 were set to Epiphyseal dysplasia, multiple, 3, with or without myopathy - MIM#600969; Stickler syndrome Review for gene: COL9A3 was set to GREEN Added comment: 6 patients from 4 families reported with biallelic variants associated with a Stickler syndrome like phenotype. All of these cases characterised by the absence of cleft palate, which is noted more commonly in other autosomal dominant forms of Stickler syndrome. Potential antenatally detectable features described with biallelic COL9A3 variants include fetal growth restriction (1/6), midface hypoplasia (6/6), tibial and femoral bowing (1/6) PMID 33570243 Markova et al 2021 - report a patient with novel Class 4 compound heterozygous COL9A3 variants confirmed to be in trans. Antenatal USS identified fetal growth restriction in the third trimester. Examination findings by clinical geneticist aged 2 provided, including dysmorphic facial features noted - slightly flattened nasal bridge, small nose, mild mid-facial hypoplasia, high palate. PMID 31090205 – Nixon et al 2019 - homozygous COL9A3 variant identified in proband, consanguineous family. Antenatal phenotype not provided, mid-facial hypoplasia noted. PMID: 30450842 – Hanson-Kahn et al 2018 - proband homozygous for LoF COL9A3 variants. Phenotypic features included moderate to severe sensorineural hearing loss, high myopia, mid-face hypoplasia and both tibial and femoral bowing at birth. PMID 24273071 Faletra et al 2014 - first reported family with AR COL9A3 associated Stickler syndrome due to homozygous LoF variants. 3 siblings with hearing loss, midface hypoplasia, high myopia, variable severity ID from consanguineous Moroccan family. -- Variants in COL9A3 have previously been associated with autosomal dominant multiple epiphyseal dysplasia, susceptibility to an intervertebral disc disease, and hearing loss. Generally milder phenotype than individuals with biallelic variants. However, PMID 33633367 Nash et al 2021 - report 2 families with heterozygous COL9A3 variants with a more severe Stickler-like phenotype including severe peripheral lattice vitreoretinal abnormalities and mild/moderate sensorineural hearing loss in some cases. No antenatal information provided Sources: Literature |
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| Fetal anomalies v0.2892 | UROS |
Krithika Murali gene: UROS was added gene: UROS was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: UROS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UROS were set to 34187847; 34828434; 15065102 Phenotypes for gene: UROS were set to Porphyria, congenital erythropoietic - MIM#263700; hydrops fetalis; multiple congenital anomalies Review for gene: UROS was set to GREEN Added comment: Biallelic variants associated with congenital erytropoietic porphyria (CEP). PMID 34187847 Khalouaoui A et al 2021 report one infant with CEP secondary to homozygous UROS variants. Prenatal ultrasound at 25 weeks of gestation revealed an increased nuchal translucency and myocardial hypertrophy. PMID: 34828434 Arnaud et al 2021 - report one fetus miscarried in the 2nd trimester with 22 weeks ultrasound showing hyperechogenic small intestine with short femurs. Subsequent pregnancy MTOP after antenatal USS showed hygroma coli, ascites, short femurs, double outlet right ventricle. Genomic sequencing on stored fetal DNA samples confirmed homozygous UROS p.Cys73Arg variants in both fetuses. PMID 15065102 Lazebnik et al 2004 reported the prenatal findings of two siblings with CEP secondary to homozygous pathogenic C73R variants. 1st child - USS at 17.5 weeks gestation showed increased nuchal thickness (9.7mm) with mild ascites, pericardial effusion, and skin oedema which persisted on subsequent scans. 2nd child - 16 week USS showed increased nuchal thickness (8.7mm) with scalp oedema, ascites, pericardial effusion, skin oedema and hepatomegaly. Other cases with antenatal features, particularly non-immune hydrops, secondary to suspected CEP reported but not confirmed molecularly. Sources: Literature |
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| Fetal anomalies v0.2845 | MKKS | Alison Yeung Phenotypes for gene: MKKS were changed from BARDET-BIEDL SYNDROME TYPE 6; MCKUSICK-KAUFMAN SYNDROME to McKusick-Kaufman syndrome, MIM# 236700; Bardet-Biedl syndrome 6, MIM# 605231 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2728 | MAST1 |
Krithika Murali gene: MAST1 was added gene: MAST1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MAST1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAST1 were set to 32818970; 32198973; 31721002; 30449657 Phenotypes for gene: MAST1 were set to Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations - #61827; corpus callosum anomalies; cortical malformations; cerebellar hypoplasia Review for gene: MAST1 was set to GREEN Added comment: Neurodevelopmental disorder with muscular hypotonia and varying brain anomalies which may be diagnosed antenatally. Reported cases include x1 individual reported to have hydrocephalus antenatally (PMID 32818970). MRI-B at 17 months demonstrated polymicrogyria, hyperplastic corpus callosum, progressive pontine hypoplasia and enlarged ventricles. Another female patient reported with antenatal findings of increased nuchal translucency in a pregnancy complicated by oligohydramnios, IUGR, pre-eclampsia and pre-term delivery at 32 weeks (PMID 32198973). Postnatally diagnosed with cortical malformations without cerebellar hypoplasia. 6 unrelated patients with mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCHCM) with de novo heterozygous mutations in MAST1 gene (30449657). In vitro functional studies showed that 1 of the variants (lys276del) increased MAST1 binding to microtubules compared to controls. Mutant mice heterozygous for a Mast1 leu278del allele showed a thicker corpus callosum compared to wildtype, and an overall reduction in cortical volume and thickness and decreased cerebellar volume and number of granule and Purkinje cells due to increased apoptosis compared to controls. 1 Emirati patient with ID, microcephaly, and dysmorphic features, with missense variant in MAST1 (30449657) Sources: Literature |
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| Fetal anomalies v0.2526 | VDR | Zornitza Stark Phenotypes for gene: VDR were changed from RICKETS VITAMIN D-DEPENDENT TYPE 2A to Rickets, vitamin D-resistant, type IIA, MIM# 277440 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2360 | TBX22 | Zornitza Stark Phenotypes for gene: TBX22 were changed from CLEFT PALATE, X-LINKED; ?Abruzzo-Erickson syndrome, 302905 to Cleft palate with ankyloglossia, MIM# 303400; Abruzzo-Erickson syndrome, MIM# 302905 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2357 | TBX22 |
Zornitza Stark edited their review of gene: TBX22: Added comment: More than 10 families reported with cleft palate/ankyloglossia and variants in this gene. Single family reported with Abruzzo-Erickson syndrome, a syndromic form of cleft palate.; Changed publications: 11559848, 12374769, 14729838, 17868388, 22784330, 22784330 |
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| Fetal anomalies v0.2357 | TBX22 | Zornitza Stark edited their review of gene: TBX22: Changed rating: GREEN; Changed phenotypes: Cleft palate with ankyloglossia, MIM# 303400, Abruzzo-Erickson syndrome, MIM# 302905; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2215 | SMS | Chirag Patel changed review comment from: Snyder-Robinson X-linked syndromic intellectual developmental disorder (MRXSSR) is an X-linked intellectual disability syndrome with characteristic features including facial asymmetry, marfanoid habitus, unsteady gait, thickened lower lip, nasal dysarthric speech, narrow or cleft palate, diminished muscle mass, osteoporosis, kyphoscoliosis, long great toes, short stature, pectus carinatum, and myopia. Does not present antenatally/perinatally. Not suitable for fetal anomalies panel.; to: X-linked syndromic intellectual developmental disorder with characteristic features including dysmorphism, marfanoid habitus, unsteady gait, nasal dysarthric speech, diminished muscle mass, osteoporosis, kyphoscoliosis, long great toes, short stature, pectus carinatum, and myopia. Does not present antenatally. Not suitable for fetal anomalies panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1604 | FLNA | Zornitza Stark Phenotypes for gene: FLNA were changed from PERIVENTRICULAR NODULAR HETEROTOPIA TYPE 1; EPILEPTIC ENCEPHALOPATHY; FG SYNDROME TYPE 2; X-LINKED CONGENITAL IDIOPATHIC INTESTINAL PSEUDOOBSTRUCTION; MELNICK-NEEDLES SYNDROME; FRONTOMETAPHYSEAL DYSPLASIA; OTOPALATODIGITAL SYNDROME TYPE 2; TERMINAL OSSEOUS DYSPLASIA; OTOPALATODIGITAL SYNDROME TYPE 1 to Melnick-Needles syndrome, 309350; Otopalatodigital syndrome, type I 311300; Otopalatodigital syndrome, type II 304120; Terminal osseous dysplasia 300244; Heterotopia, periventricular, 1 MIM# 300049 Cardiac valvular dysplasia, X-linked MIM# 314400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1602 | FLNA |
Zornitza Stark changed review comment from: Melnick-Needles associated with radial shortening in affected women. Male fetuses reported with absent thumbs Sources: Expert list; to: Multiple FLNA-related disorders are relevant to this panel. Melnick-Needles associated with radial shortening in affected women. Male fetuses reported with absent thumbs Sources: Expert list |
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| Fetal anomalies v0.1602 | FLNA | Zornitza Stark edited their review of gene: FLNA: Changed phenotypes: Melnick-Needles syndrome, 309350, Otopalatodigital syndrome, type I 311300, Otopalatodigital syndrome, type II 304120, Terminal osseous dysplasia 300244, Heterotopia, periventricular, 1 MIM# 300049 Cardiac valvular dysplasia, X-linked MIM# 314400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1361 | ADAMTS19 |
Krithika Murali gene: ADAMTS19 was added gene: ADAMTS19 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: ADAMTS19 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAMTS19 were set to 32323311; 31844321 Phenotypes for gene: ADAMTS19 were set to Heart valve disease (HVD) Review for gene: ADAMTS19 was set to GREEN Added comment: PMID 32323311 reports 3 additional consanguineous families (2 affected sibs in each) with anomalies of the aortic/pulmonary valves, which included thickening of valve leaflets, stenosis and insufficiency. All 3 families had homozygous LoF variants in ADAMTS19, which segregated with disease. No functional studies. Previously reported 4 affected in 2 unrelated consanguineous families with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Carriers unaffected. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype Sources: Expert list, Literature |
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| Fetal anomalies v0.1257 | NPC1 | Zornitza Stark Phenotypes for gene: NPC1 were changed from NIEMANN-PICK DISEASE, TYPE C1 to Niemann-Pick disease, type C1/ type D (MIM#257220) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1240 | NPC1 | Daniel Flanagan reviewed gene: NPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12408188, 12408188; Phenotypes: Niemann-Pick disease, type C1/ type D (MIM#257220); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.761 | DARS |
Zornitza Stark changed review comment from: Onset typically in infancy with lower limb spasticity. Brain MRI shows extensive white matter abnormalities involving the supratentorial white matter, brainstem, cerebellar peduncles, and dorsal columns and lateral corticospinal tracts of the spinal cord. However, two individuals with adolescent onset described in 25527264, mimicking steroid-responsive neuroinflammatory disorder. HGNC approved name DARS1.; to: Onset typically in infancy with lower limb spasticity. Brain MRI shows extensive white matter abnormalities involving the supratentorial white matter, brainstem, cerebellar peduncles, and dorsal columns and lateral corticospinal tracts of the spinal cord. HGNC approved name DARS1. |
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| Fetal anomalies v0.595 | COL9A2 | Zornitza Stark Phenotypes for gene: COL9A2 were changed from STICKLER SYNDROME, TYPE V; MULTIPLE EPIPHYSEAL DYSPLASIA TYPE 2 to Stickler syndrome, type V, MIM# 614284 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.592 | COL9A2 | Zornitza Stark reviewed gene: COL9A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21671392, 31090205, 33356723; Phenotypes: Stickler syndrome, type V, MIM# 614284; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.592 | COL9A1 | Zornitza Stark Phenotypes for gene: COL9A1 were changed from MULTIPLE EPIPHYSEAL DYSPLASIA TYPE 6; STICKLER SYNDROME TYPE 4 to Stickler syndrome, type IV, MIM# 614134 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.589 | COL9A1 | Zornitza Stark reviewed gene: COL9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16909383, 21421862, 31090205; Phenotypes: Stickler syndrome, type IV, MIM# 614134; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.573 | COL2A1 | Zornitza Stark Phenotypes for gene: COL2A1 were changed from KNIEST DYSPLASIA; SPONDYLOEPIMETAPHYSEAL DYSPLASIA STRUDWICK TYPE; PLATYSPONDYLIC LETHAL SKELETAL DYSPLASIA TORRANCE TYPE; STICKLER SYNDROME TYPE 1 NON-SYNDROMIC OCULAR; RHEGMATOGENOUS RETINAL DETACHMENT AUTOSOMAL DOMINANT; SPONDYLOEPIPHYSEAL DYSPLASIA CONGENITA; ACHONDROGENESIS TYPE 2; SPONDYLOPERIPHERAL DYSPLASIA to Collagenopathy type 2 alpha 1, MONDO:0022800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.567 | COL11A2 | Zornitza Stark Phenotypes for gene: COL11A2 were changed from DEAFNESS AUTOSOMAL DOMINANT TYPE 13; AUTOSOMAL RECESSIVE OTOSPONDYLOMEGAEPIPHYSEAL DYSPLASIA; WEISSENBACHER-ZWEYMUELLER SYNDROME; STICKLER SYNDROME TYPE 3; DEAFNESS AUTOSOMAL RECESSIVE TYPE 53 to Fibrochondrogenesis 2, MIM# 614524; Otospondylomegaepiphyseal dysplasia, autosomal recessive, MIM# 215150 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.566 | COL11A1 | Zornitza Stark Phenotypes for gene: COL11A1 were changed from FIBROCHONDROGENESIS; STICKLER SYNDROME, TYPE II to Fibrochondrogenesis 1, MIM# 228520; Marshall syndrome, MIM# 154780 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.558 | COG7 |
Zornitza Stark changed review comment from: CDG IIe is caused by variants that impair the integrity of the conserved oligomeric Golgi (COG) complex and alter Golgi trafficking, resulting in the disruption of multiple glycosylation pathways. Three families reported, IVS1+4A-C variant is recurrent, supportive functional data.; to: CDG IIe is caused by variants that impair the integrity of the conserved oligomeric Golgi (COG) complex and alter Golgi trafficking, resulting in the disruption of multiple glycosylation pathways. Three families reported, IVS1+4A-C variant is recurrent, supportive functional data. IUGR is a feature. |
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| Fetal anomalies v0.132 | FAM111A |
Zornitza Stark changed review comment from: Kenny-Caffey syndrome is characterized by severe proportionate short stature, cortical thickening and medullary stenosis of the tubular bones, delayed closure of the anterior fontanel, eye abnormalities including microphthalmia/nanophthalmos, and transient hypocalcemia. Sources: Literature; to: Kenny-Caffey syndrome is characterized by severe proportionate short stature, cortical thickening and medullary stenosis of the tubular bones, delayed closure of the anterior fontanel, eye abnormalities including microphthalmia/nanophthalmos, and transient hypocalcemia. Prenatal presentation reported. Sources: Literature |
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| Fetal anomalies v0.0 | SLC2A2 |
Zornitza Stark gene: SLC2A2 was added gene: SLC2A2 was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: SLC2A2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SLC2A2 were set to FANCONI-BICKEL SYNDROME |
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| Fetal anomalies v0.0 | ENPP1 |
Zornitza Stark gene: ENPP1 was added gene: ENPP1 was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: ENPP1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ENPP1 were set to HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL RECESSIVE, 2; ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1 |
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| Fetal anomalies v0.0 | DMP1 |
Zornitza Stark gene: DMP1 was added gene: DMP1 was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: DMP1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DMP1 were set to HYPOPHOSPHATEMIC RICKETS, AR |
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| Fetal anomalies v0.0 | VDR |
Zornitza Stark gene: VDR was added gene: VDR was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: VDR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: VDR were set to RICKETS VITAMIN D-DEPENDENT TYPE 2A |
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| Fetal anomalies v0.0 | TBX22 |
Zornitza Stark gene: TBX22 was added gene: TBX22 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: TBX22 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: TBX22 were set to 22784330 Phenotypes for gene: TBX22 were set to CLEFT PALATE, X-LINKED; ?Abruzzo-Erickson syndrome, 302905 |
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| Fetal anomalies v0.0 | ICK |
Zornitza Stark gene: ICK was added gene: ICK was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: ICK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ICK were set to 24853502; 19185282; 27466187; 27069622 Phenotypes for gene: ICK were set to Endocrine-cerebroosteodysplasia, OMIM:612651; Endocrine-cerebro-osteodysplasia syndrome, MONDO:0012980 |
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| Fetal anomalies v0.0 | SMPD1 |
Zornitza Stark gene: SMPD1 was added gene: SMPD1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: SMPD1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SMPD1 were set to NIEMANN-PICK DISEASE TYPE B; NIEMANN-PICK DISEASE TYPE A |
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| Fetal anomalies v0.0 | NPC2 |
Zornitza Stark gene: NPC2 was added gene: NPC2 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: NPC2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: NPC2 were set to NIEMANN-PICK DISEASE, TYPE C2 |
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| Fetal anomalies v0.0 | NPC1 |
Zornitza Stark gene: NPC1 was added gene: NPC1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: NPC1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: NPC1 were set to NIEMANN-PICK DISEASE, TYPE C1 |
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| Fetal anomalies v0.0 | MKKS |
Zornitza Stark gene: MKKS was added gene: MKKS was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: MKKS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MKKS were set to BARDET-BIEDL SYNDROME TYPE 6; MCKUSICK-KAUFMAN SYNDROME |
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| Fetal anomalies v0.0 | FLNA |
Zornitza Stark gene: FLNA was added gene: FLNA was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: FLNA was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: FLNA were set to 30712878; 28425981 Phenotypes for gene: FLNA were set to PERIVENTRICULAR NODULAR HETEROTOPIA TYPE 1; EPILEPTIC ENCEPHALOPATHY; FG SYNDROME TYPE 2; X-LINKED CONGENITAL IDIOPATHIC INTESTINAL PSEUDOOBSTRUCTION; MELNICK-NEEDLES SYNDROME; FRONTOMETAPHYSEAL DYSPLASIA; OTOPALATODIGITAL SYNDROME TYPE 2; TERMINAL OSSEOUS DYSPLASIA; OTOPALATODIGITAL SYNDROME TYPE 1 |
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| Fetal anomalies v0.0 | COL9A2 |
Zornitza Stark gene: COL9A2 was added gene: COL9A2 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: COL9A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: COL9A2 were set to STICKLER SYNDROME, TYPE V; MULTIPLE EPIPHYSEAL DYSPLASIA TYPE 2 |
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| Fetal anomalies v0.0 | COL9A1 |
Zornitza Stark gene: COL9A1 was added gene: COL9A1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: COL9A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: COL9A1 were set to MULTIPLE EPIPHYSEAL DYSPLASIA TYPE 6; STICKLER SYNDROME TYPE 4 |
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| Fetal anomalies v0.0 | COL2A1 |
Zornitza Stark gene: COL2A1 was added gene: COL2A1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: COL2A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: COL2A1 were set to KNIEST DYSPLASIA; SPONDYLOEPIMETAPHYSEAL DYSPLASIA STRUDWICK TYPE; PLATYSPONDYLIC LETHAL SKELETAL DYSPLASIA TORRANCE TYPE; STICKLER SYNDROME TYPE 1 NON-SYNDROMIC OCULAR; RHEGMATOGENOUS RETINAL DETACHMENT AUTOSOMAL DOMINANT; SPONDYLOEPIPHYSEAL DYSPLASIA CONGENITA; ACHONDROGENESIS TYPE 2; SPONDYLOPERIPHERAL DYSPLASIA |
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| Fetal anomalies v0.0 | COL11A2 |
Zornitza Stark gene: COL11A2 was added gene: COL11A2 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: COL11A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: COL11A2 were set to DEAFNESS AUTOSOMAL DOMINANT TYPE 13; AUTOSOMAL RECESSIVE OTOSPONDYLOMEGAEPIPHYSEAL DYSPLASIA; WEISSENBACHER-ZWEYMUELLER SYNDROME; STICKLER SYNDROME TYPE 3; DEAFNESS AUTOSOMAL RECESSIVE TYPE 53 |
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| Fetal anomalies v0.0 | COL11A1 |
Zornitza Stark gene: COL11A1 was added gene: COL11A1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: COL11A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: COL11A1 were set to FIBROCHONDROGENESIS; STICKLER SYNDROME, TYPE II |
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