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| Fetal anomalies v1.311 | ITGAV |
Zornitza Stark gene: ITGAV was added gene: ITGAV was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ITGAV was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ITGAV were set to 39526957 Phenotypes for gene: ITGAV were set to Syndromic disease, MONDO:0002254, ITGAV-related Review for gene: ITGAV was set to AMBER Added comment: Three unrelated families reported: two with affected children (one hmz missense; other compound het LoF with missense) and one family with four affected fetuses. Clinical features included brain and eye anomalies and IBD/immune dysregulation. TGF-beta signalling pathway affected. The deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation. Sources: Literature |
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| Fetal anomalies v1.309 | C1orf127 |
Zornitza Stark gene: C1orf127 was added gene: C1orf127 was added to Fetal anomalies. Sources: Literature new gene name tags were added to gene: C1orf127. Mode of inheritance for gene: C1orf127 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C1orf127 were set to 39753129 Phenotypes for gene: C1orf127 were set to Heterotaxy, visceral, MONDO:0018677, CIROZ-related Review for gene: C1orf127 was set to GREEN Added comment: 16 individuals from 10 families reported with bi-allelic variants in this gene and heterotaxy, including CHD. Supportive mouse model. CIROZ is absent or obsolete in select animals with motile cilia at their left-right organiser, including Carnivora, Atherinomorpha fish, or jawless vertebrates. Knockouts in zebrafish and Xenopus did not have observable LR anomalies. Approved HGNC name is CIROZ. Sources: Literature |
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| Fetal anomalies v1.307 | PPFIBP1 |
Krithika Murali changed review comment from: Fetal microcephaly and IUGR are reported features. Sources: Literature; to: Fetal microcephaly and IUGR are reported features. Sources: Literature |
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| Fetal anomalies v1.307 | PPFIBP1 |
Krithika Murali gene: PPFIBP1 was added gene: PPFIBP1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPFIBP1 were set to PMID: 35830857; PMID: 37229200 Phenotypes for gene: PPFIBP1 were set to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities - MIM#620024 Review for gene: PPFIBP1 was set to GREEN Added comment: Fetal microcephaly and IUGR are reported features. Sources: Literature |
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| Fetal anomalies v1.304 | KDM6B |
Zornitza Stark gene: KDM6B was added gene: KDM6B was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: KDM6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: KDM6B were set to Stolerman neurodevelopmental syndrome, MIM# 618505 Review for gene: KDM6B was set to GREEN Added comment: Well established gene-disease association. A proportion of individuals have congenital anomalies, including cleft palate, skeletal anomalies and congenital heart disease. Sources: Expert Review |
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| Fetal anomalies v1.292 | GON4L |
Bryony Thompson gene: GON4L was added gene: GON4L was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: GON4L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GON4L were set to 39500882; 21937992 Phenotypes for gene: GON4L were set to complex neurodevelopmental disorder MONDO:0100038 Review for gene: GON4L was set to GREEN Added comment: 2 LoF variants in 4 cases from 3 unrelated consanguineous families, and supporting null zebrafish model PMID: 39500882 - 2 homozygous truncating GON4L variants [NM_001282860.2: c.62_63del, p.(Gln21Argfs*12) and c.5517+1G>A] in 3 patients from 2 consanguineous families with prenatal-onset growth impairment, developmental delay, mild intellectual disability, speech impairment, progressive and disproportionate microcephaly, facial asymmetry, congenital heart anomaly, and brain structure abnormalities. Null zebrafish model had distinct morphological and size abnormalities in the craniofacial cartilage of zebrafish larvae Heterozygous carriers in biallelic families were unaffected PMID: 21937992 - a case from Iran from a consanguineous family homozygous for c.5517+1G>A with syndromic ID. No other clinical details provided Sources: Literature |
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| Fetal anomalies v1.285 | RREB1 |
Krithika Murali gene: RREB1 was added gene: RREB1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: RREB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RREB1 were set to PMID: 32938917; 38332451 Phenotypes for gene: RREB1 were set to Rasopathy, MONDO:0021060, RREB1-related Review for gene: RREB1 was set to AMBER Added comment: PMID 38332451: de novo LoF variant in an individual with Noonan syndrome-like features. No prenatal phenotype reported in this individual, however, prenatal phenotype has been reported with other RASopathies. Sources: Literature |
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| Fetal anomalies v1.283 | DHRSX |
Zornitza Stark gene: DHRSX was added gene: DHRSX was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: DHRSX was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DHRSX were set to 38821050 Phenotypes for gene: DHRSX were set to congenital disorder of glycosylation, MONDO:0015286, DHRSX-related Review for gene: DHRSX was set to GREEN Added comment: PMID:38821050 reported the identification of biallelic missense variants in DHRSX gene in four patients from three unrelated families with a congenital disorder of glycosylation. They displayed distinct facial features, severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss. These patients also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs. In PAR. Contractures and brain anomalies may be detectable antenatally. Sources: Literature |
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| Fetal anomalies v1.275 | RPL26 |
Zornitza Stark gene: RPL26 was added gene: RPL26 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: RPL26 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RPL26 were set to 22431104; 39268718 Phenotypes for gene: RPL26 were set to Diamond-Blackfan anaemia 11, MIM# 614900 Review for gene: RPL26 was set to GREEN Added comment: Four unrelated families reported, radial ray defects are part of the phenotype. Sources: Literature |
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| Fetal anomalies v1.267 | NME8 | Achchuthan Shanmugasundram changed review comment from: The phenotype listed in the review below, namely, CINCA syndrome, OMIM:607115 is associated with NLRP3 gene rather than NME8 in OMIM. The publications listed below (PMIDs: 12032915, 12483741, 12928894) also reports cases with NLRP3 variants (gene alias: CIAS1) rather than NME8 variants. Hence, this gene should be demoted from green rating and NLRP3 should be added to this panel.; to: The phenotype listed in the review below, namely, CINCA syndrome, OMIM:607115 is associated with NLRP3 gene rather than NME8 in OMIM. The publications listed below (PMIDs: 12032915, 12483741, 12928894) also report cases with NLRP3 variants (gene alias: CIAS1) rather than NME8 variants. Hence, this gene should be demoted from green rating and NLRP3 should be added to this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.264 | CSMD1 |
Krithika Murali gene: CSMD1 was added gene: CSMD1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CSMD1 were set to PMID: 38816421 Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038 Review for gene: CSMD1 was set to GREEN Added comment: Prenatal features reported include polyhydramnios, IUGR, preterm labour. Other reported features such as brain anomalies, arthrogryposis have the potential to be ascertained prenatally also. -- PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected. Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autism and ID GCEP. Sources: Literature |
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| Fetal anomalies v1.257 | GLIS2 | Zornitza Stark edited their review of gene: GLIS2: Added comment: Five individuals from three unrelated families reported, albeit with homozygous variants. Functional data.; Changed rating: GREEN; Changed publications: 31676329, 17618285, 23559409 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.256 | SRPK3 |
Zornitza Stark gene: SRPK3 was added gene: SRPK3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SRPK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: SRPK3 were set to 39073169 Phenotypes for gene: SRPK3 were set to Neurodevelopmental disorder, MONDO:0700092, SRPK3-related Review for gene: SRPK3 was set to AMBER Added comment: PMID 39073169: 9 individuals from 5 unrelated families reported with 4 missense and 1 putative truncating variant and a neurodevelopmental phenotype. The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Supportive animal model data (mouse and zebrafish). Sources: Literature |
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| Fetal anomalies v1.254 | PSMF1 |
Zornitza Stark gene: PSMF1 was added gene: PSMF1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PSMF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PSMF1 were set to https://www.medrxiv.org/content/10.1101/2024.06.19.24308302v1 Phenotypes for gene: PSMF1 were set to Complex neurodevelopmental disorder with motor features, MONDO:0100516, PSMF1-related Review for gene: PSMF1 was set to GREEN Added comment: 22 individuals from 15 families reported with a range of neurological phenotypes ranging from early-onset Parkinson's disease; childhood conditions typified by ID and a range of movement disorders; through to perinatal lethal presentations with arthrogryposis multiplex. Genotype-phenotype correlation: biallelic missense variants resulted in the milder phenotypes, while bi-allelic LoF variants in the more severe phenotypes. Supportive functional data. Sources: Literature |
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| Fetal anomalies v1.242 | HOXD12 |
Zornitza Stark gene: HOXD12 was added gene: HOXD12 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: HOXD12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HOXD12 were set to 38663984 Phenotypes for gene: HOXD12 were set to Clubfoot (non-syndromic) MONDO:0007342 Review for gene: HOXD12 was set to AMBER Added comment: Identified as a candidate gene in a large cohort due to enrichment of rare variants. PMID: 38663984 Around 9 individuals from 4 unrelated families have been reported with clubfoot and the variants were shown to segregate. Cohort of over 1000 individuals, with several novel candidates identified. N-terminal region and C-terminal homeobox domain of HOXD12 are known to be clusters for pathogenic variants related to clubfoot. Loss of function variants are less likely to contribute to clubfoot pathogenesis therefore mechanism of disease is suggested as dominant negative but is not confirmed. Sources: Literature |
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| Fetal anomalies v1.234 | CNOT1 |
Zornitza Stark edited their review of gene: CNOT1: Added comment: LIMITED by ClinGen for holoprosencephaly 12 with or without pancreatic agenesis, MONDO:0032787 ClinGen curation: CNOT1 was originally reported in cases of holoprosencephaly and/or pancreatic agenesis/insufficiency in 2019 (PMID: 31006513, 31006510). One of the papers included 3 individuals with heterozygous p.Arg535Cys (PMID: 31006513), confirmed to be de novo in 2 individuals. One of these individuals was not scored due to a lack of documentation of holoprosencephaly. The other paper included 2 individuals with de novo p.Arg535Cys, both of whom with holoprosencephaly. A knock-in mouse model of this variant showed neurological and pancreatic abnormalities at E14.5, and this evidence was used to augment the genetic evidence. A mouse brain expression study (PMID: 31006510) was scored as functional evidence. In total, there is Limited evidence to support the gene-disease relationship between CNOT1 and holoprosencephaly with or without pancreatic agenesis. Of note, this gene has also been implicated in Vissers-Bodmer syndrome, which is characterized by global developmental delay and behavioral abnormalities apparent from infancy. As the condition is clinically distinct from holoprosencephaly and/or pancreatic agenesis/insufficiency, lacks specific structural brain anomalies, and likely has different molecular mechanisms, this will be/have been assessed separately.; Changed rating: AMBER; Changed phenotypes: Holoprosencephaly 12 with or without pancreatic agenesis MONDO:0032787 |
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| Fetal anomalies v1.225 | DISP1 |
Zornitza Stark edited their review of gene: DISP1: Added comment: PMID: 38529886 25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE). A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense). 14 heterozygous individuals , 5 compound heterozygous individuals, 6 homozygous individuals (5 of the individuals were from 3 unrelated consanguineous families). HPE phenotype was also seen prenatally as one of the reported monoallelic individuals was a fetus at 20+6 GW prior to passing due to MTP.; Changed rating: GREEN; Changed publications: 19184110, 26748417, 23542665, 38529886; Changed phenotypes: Holoprosencephaly (MONDO:0016296), DISP1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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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 v1.223 | MAP3K20 | Zornitza Stark edited their review of gene: MAP3K20: Added comment: PMID 38451290: five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20.; Changed publications: 38451290; Changed phenotypes: Syndromic disease, MONDO:0002254, MAP3K20-related, Centronuclear myopathy 6 with fiber-type disproportion MIM#617760, Split-foot malformation with mesoaxial polydactyly MIM#616890; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.206 | AMOTL1 |
Ain Roesley gene: AMOTL1 was added gene: AMOTL1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: AMOTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AMOTL1 were set to 36751037 Phenotypes for gene: AMOTL1 were set to Orofacial clefting syndrome, MONDO:0015335, AMOTL1-related Review for gene: AMOTL1 was set to GREEN gene: AMOTL1 was marked as current diagnostic Added comment: PMID: 36751037- 16 individuals from 12 families with orofacial clefting syndrome and het variants in AMOTL1. Many in 1 hotspot: 5 individuals from 3 families have R157C, 6 individuals from another 4 families have R157H, 1 has P160L, and another has Q161R. Out of this hostpaot- 1 with P368A, 1 with E507K, 1 with E579K. 7 are de novo. All but 2 have clefting, 7 are dysmorphic, 5 have hearing loss, 9 have CHD, 7 have tall stature, 6 have dev delay. Other features include liver disease, myopia, scoliosis and immune involvement. Another 2 families have been previously reported (described in the panelapp review below) with variants in this hotspot 1 has 2 individuals with R157C, the other has 1 individual with P160L. All hotspot are absent from gnomad v2. Sources: Literature |
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| Fetal anomalies v1.201 | CELSR3 |
Zornitza Stark gene: CELSR3 was added gene: CELSR3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CELSR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CELSR3 were set to 38429302 Phenotypes for gene: CELSR3 were set to Neurodevelopmental disorder (MONDO#0700092), CELSR3-related Added comment: PMID: 38429302:12 affected individuals from 11 families reported with bi-allelic variants. Phenotype ranged from CNS anomalies (7/12), CNS and CAKUT (3/12) and CAKUT only (2/12). 8/12 has ID/DD. Only missense variants reported and 1 inframe variant. Functional studies done in zebrafish demonstrate similar structural anomalies of the developing pronephros and neuronal abnormalities to affected individuals Sources: Literature |
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| Fetal anomalies v1.197 | THSD1 |
Zornitza Stark gene: THSD1 was added gene: THSD1 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: THSD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: THSD1 were set to 33569873; 27895300 Phenotypes for gene: THSD1 were set to Lymphatic malformation 13, MIM# 620244 Review for gene: THSD1 was set to GREEN Added comment: PMID: 33569873 - 1 fetus with a homozygous PTC and nonimmune hydrops fetalis (NIHF), congenital heart disease and hemangiomas. FHx of 1/3 triplets with severe hydrops fetalis, not sequenced. - Paper reviews previous NIHF cases and reports another homozygous PTC in two families ( and a recurring homozygous missense (p.Cys206Tyr) in three families. PMID: 27895300- Mouse model has hydrocephaly with poor perfusion. Sources: Expert Review |
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| Fetal anomalies v1.186 | DLG5 |
Zornitza Stark gene: DLG5 was added gene: DLG5 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: DLG5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DLG5 were set to 32631816 Phenotypes for gene: DLG5 were set to Yuksel-Vogel-Bauer syndrome, MIM#620703 Review for gene: DLG5 was set to GREEN Added comment: Four unrelated families reported, supportive Xenopus animal model data. Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. Sources: Expert Review |
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| Fetal anomalies v1.182 | WDR44 |
Andrew Fennell gene: WDR44 was added gene: WDR44 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: WDR44 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: WDR44 were set to PMID: 38191484 Phenotypes for gene: WDR44 were set to Ciliopathy, MONDO:0005308, WDR44-related Review for gene: WDR44 was set to GREEN Added comment: 11 male patients with 6 missense and 1 nonsense variant in WDR44 displaying a wide range of cognitive impairment and variable congenital anomalies associated with primary cilium dysfunction. All patients had learning difficulties with 8 labelled as intellectually disabled (mild-moderate). Other clinical features included anomalies of craniofacial, musculoskeletal, brain, renal and cardiac development. WDR44 is a negative regulator of ciliogenesis. Increased binding is hypothesised to underlie the pathogenicity of WDR44 variants identified in this cohort. Functional data supported impaired ciliogenesis initiation in patient fibroblasts and a zebrafish model. A zebrafish model recapitulated the human phenotype when morphants expressed WDR44 L668S, D669N, S764F, G782C, H839R, and R733* variants. Of note, D648G or N840S did not recapitulate the phenotype in the zebrafish model. The studies supported a GoF mechanism, but the authors could not rule out that LoF of WDR44 contributes to the ciliopathy-like phenotype observed, because protein expression data was only available for a limited number of patients. Sources: Literature |
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| Fetal anomalies v1.179 | MAX |
Rylee Peters gene: MAX was added gene: MAX was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MAX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAX were set to 38141607 Phenotypes for gene: MAX were set to Syndromic disease (MONDO:0002254), MAX-related Review for gene: MAX was set to GREEN Added comment: Three individuals who each share a recurrent de novo germline variant in the MAX gene, resulting in a p.Arg60Gln substitution in the loop of the b-HLH-LZ domain. Affected individuals have a complex disorder consisting primarily of macrocephaly, polydactyly, and delayed ophthalmic development. Other phenotypes reported include intellectual disability, perianal abscesses, pectus carinatum, hypospadias, renal agenesis, single umbilical artery, flattened thoracic vertebrae. Functional analysis of the p.Arg60Gln variant shows a significant increase in CCND2 protein and a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc. Sources: Literature |
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| Fetal anomalies v1.179 | CACHD1 |
Suliman Khan gene: CACHD1 was added gene: CACHD1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CACHD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CACHD1 were set to PMID: 38158856 Phenotypes for gene: CACHD1 were set to syndromic complex neurodevelopmental disorder MONDO:0800439 Penetrance for gene: CACHD1 were set to unknown Review for gene: CACHD1 was set to GREEN Added comment: PMID: 38158856 - Six affected individuals from four unrelated families with homozygous CACHD1 variants (3 splice, 2 frameshift and 1 nonsense variant). Excluding the two fatal cases, all other were affected by syndromic neurodevelopmental abnormalities, multiple organ systems featuring global impairment of psychomotor development, dysmorphic facial features, genitourinary abnormalities, oculo-auricular and congenital malformation. Seizure was reported in one case. Whole exome sequencing identified bi-allelic loss of function variants in the CACHD1 gene. In vitro human neural models of CACHD1 depletion displayed dysregulated of Wnt signaling in the developing brain. Sources: Literature |
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| Fetal anomalies v1.167 | PKP2 |
Suliman Khan changed review comment from: PMID: 30562116: PMID: 30562116 reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed. PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD). PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In case 1, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case 2 had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consistent to Wolff Parkinson-White syndrome. Sources: Literature; to: PMID: 30562116: reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed. PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD). PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In case 1, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case 2 had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consistent to Wolff Parkinson-White syndrome. Sources: Literature |
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| Fetal anomalies v1.167 | PKP2 |
Suliman Khan changed review comment from: PMID: 30562116: PMID: 30562116 reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed. PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD). PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In case 1, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case 2 had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consist to Wolff Parkinson-White syndrome. Sources: Literature; to: PMID: 30562116: PMID: 30562116 reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed. PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD). PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In case 1, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case 2 had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consistent to Wolff Parkinson-White syndrome. Sources: Literature |
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| Fetal anomalies v1.167 | PKP2 |
Suliman Khan changed review comment from: PMID: 30562116: PMID: 30562116 reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed. PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD). PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In cases, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consist to Wolff Parkinson-White syndrome. Sources: Literature; to: PMID: 30562116: PMID: 30562116 reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed. PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD). PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In case 1, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case 2 had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consist to Wolff Parkinson-White syndrome. Sources: Literature |
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| Fetal anomalies v1.167 | PKP2 |
Suliman Khan gene: PKP2 was added gene: PKP2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PKP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PKP2 were set to PMID: 30562116; PMID: 35059364; PMID: 38050058 Phenotypes for gene: PKP2 were set to dilated cardiomyopathy; hypoplastic left heart syndrome; hydrops fetalis; ventricular septal defect; left ventricular non-compaction Penetrance for gene: PKP2 were set to unknown Review for gene: PKP2 was set to GREEN Added comment: PMID: 30562116: PMID: 30562116 reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed. PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD). PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In cases, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consist to Wolff Parkinson-White syndrome. Sources: Literature |
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| Fetal anomalies v1.166 | PLS3 | Zornitza Stark Phenotypes for gene: PLS3 were changed from Bone mineral density QTL18, osteoporosis - MIM#300910; congenital diaphragmatic hernia MONDO:0005711, PLS3-related to Bone mineral density QTL18, osteoporosis - MIM#300910; Diaphragmatic hernia 5, X-linked, MIM# 306950 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.164 | TRIT1 |
Zornitza Stark gene: TRIT1 was added gene: TRIT1 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: TRIT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRIT1 were set to 36049610; 32088416 Phenotypes for gene: TRIT1 were set to Combined oxidative phosphorylation deficiency 35, MIM#617873 Review for gene: TRIT1 was set to GREEN Added comment: Presentations with IUGR reported. Sources: Expert Review |
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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 v1.155 | PLS3 | Ain Roesley Phenotypes for gene: PLS3 were changed from Bone mineral density QTL18, osteoporosis - MIM#300910 to Bone mineral density QTL18, osteoporosis - MIM#300910; congenital diaphragmatic hernia MONDO:0005711, PLS3-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.151 | MYCN | Elena Savva Added comment: Comment on phenotypes: Three individuals now reported with gain-of-function missense variants (identical variant in two individuals). Clinical presentation includes megalencephaly, hypoplastic corpus callosum, postaxial polydactyly, intellectual disability and motor delay. Knock-in mouse model showed morphological manifestations in multiple tissues including digits, female reproductive system and kidney. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.146 | GNPNAT1 |
Zornitza Stark gene: GNPNAT1 was added gene: GNPNAT1 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: GNPNAT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GNPNAT1 were set to 36097642; 35427807; 32591345 Phenotypes for gene: GNPNAT1 were set to Rhizomelic dysplasia, Ain-Naz type, MIM#619598 Review for gene: GNPNAT1 was set to AMBER Added comment: 3 unrelated families reported with a skeletal dysplasia characterised by severe short stature and rhizomelic shortening. No antenatal features reported. The parents in PMID 36097642 had a medical termination of pregnancy at 4 months gestation for a fetus with skeletal anomalies - not genotyped. Sources: Expert Review |
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| Fetal anomalies v1.142 | DBR1 |
Chern Lim edited their review of gene: DBR1: Added comment: PMID: 37656279: - A homozygous missense as a founder recessive DBR1 variant in four consanguineous families. - Total of 7 affected children. WES done for one proband from each family. - Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life. - RNA and protein studies using fibroblasts derived from a patient are supportive of pathogenicity: RNA-seq, rt-qPCR and western blotting, showing marked reduction of DBR1 level and intronic RNA lariat accumulation in the patient sample. - Haplotype analysis revealed that the four families all share a haplotype extending at least 2.27 Mb around the c.200A>G p.(Tyr67Cys) DBR1 founder variant. - Authors proposed this is a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility, and highlighted the apparent lack of correlation with the degree of DBR1 deficiency.; Changed phenotypes: Ichthyosis (MONDO#0019269), DBR1-related |
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| Fetal anomalies v1.140 | DBR1 |
Chern Lim gene: DBR1 was added gene: DBR1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: DBR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DBR1 were set to 37656279 Phenotypes for gene: DBR1 were set to Prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation, and death before the first year of life Review for gene: DBR1 was set to AMBER gene: DBR1 was marked as current diagnostic Added comment: PMID: 37656279: - A homozygous missense as a founder recessive DBR1 variant in four consanguineous families. - Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life. - RNA and protein studies using fibroblasts derived from a patient are supportive of pathogenicity: RNA-seq, rt-qPCR and western blotting, showing marked reduction of DBR1 level and intronic RNA lariat accumulation in the patient sample. - Haplotype analysis revealed that the four families all share a haplotype extending at least 2.27 Mb around the c.200A>G p.(Tyr67Cys) DBR1 founder variant. - Authors proposed this is a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility, and highlighted the apparent lack of correlation with the degree of DBR1 deficiency. Sources: Literature |
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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 v1.138 | ATP5O |
Zornitza Stark gene: ATP5O was added gene: ATP5O was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: ATP5O was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATP5O were set to 35621276; 34954817 Phenotypes for gene: ATP5O were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, MIM# 620359 Review for gene: ATP5O was set to GREEN Added comment: Prenatal phenotypes reported (IUGR, CHD, oligohydramnios) Sources: Expert list |
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| Fetal anomalies v1.131 | SENP7 |
Elena Savva gene: SENP7 was added gene: SENP7 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SENP7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SENP7 were set to PMID: 37460201 Phenotypes for gene: SENP7 were set to Arthrogryposis multiplex congenita, MONDO:0015168, SENP7-related Review for gene: SENP7 was set to AMBER Added comment: PMID: 37460201 - 1 family (4 affecteds, sibling pair and 1st cousin) with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia. Fetus could not be tested, so 3 confirmed genetically. - Homozygous for a PTC, decreased mRNA from one sample supports an NMD outcome. - Additional studies performed supporting downstream proteins expression being affected - Neutropenia observed in 2/3 patients Sources: Literature |
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| Fetal anomalies v1.110 | MAP4K4 |
Zornitza Stark gene: MAP4K4 was added gene: MAP4K4 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MAP4K4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAP4K4 were set to 37126546 Phenotypes for gene: MAP4K4 were set to RASopathy, MONDO:0021060, MAP4K4-related Review for gene: MAP4K4 was set to GREEN Added comment: 26 individuals from 21 families reported with Rasopathy-like phenotype, comprising ID/DD, dysmorphic features and congenital anomalies. Sources: Literature |
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| Fetal anomalies v1.93 | FILIP1 |
Paul De Fazio gene: FILIP1 was added gene: FILIP1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FILIP1 were set to 36943452 Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168 Penetrance for gene: FILIP1 were set to unknown Review for gene: FILIP1 was set to GREEN gene: FILIP1 was marked as current diagnostic Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings. Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism. Sources: Literature |
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| Fetal anomalies v1.93 | SLC31A1 | Zornitza Stark Phenotypes for gene: SLC31A1 were changed from Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092) to Neurodegeneration and seizures due to copper transport defect, MIM# 620306 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.92 | SLC31A1 | Zornitza Stark reviewed gene: SLC31A1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration and seizures due to copper transport defect, MIM# 620306; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.84 | GOLGA2 | Zornitza Stark edited their review of gene: GOLGA2: Added comment: Third family reported but again hypoplasia of CC which may be difficult to detect. Onset of microcephaly uncertain.; Changed publications: 34424553; Changed phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v1.71 | FOSL2 |
Krithika Murali gene: FOSL2 was added gene: FOSL2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FOSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FOSL2 were set to 36197437 Phenotypes for gene: FOSL2 were set to Neurodevelopmental disorder, MONDO:0700092, FOSL2-related Review for gene: FOSL2 was set to GREEN Added comment: PMID 36197437 Cospain et al 2022 report 11 individuals from 10 families with heterozygous PTC variants in exon 4/4 of the FOSL2 gene. All variants were predicted to escape NMD resulting in a truncated protein, with the truncation occurring proximal to the C-terminal domain (supportive functional studies). In 10/11 families the variant occurred de novo in a single affected proband. In one family with 2 affected siblings, the variant was present in the siblings but absent in the unaffected parent likely due to gonadal mosaicism. Clinical features included: - Cutis aplasia congenital of the scalp (10/11) - Tooth enamel hypoplasia and discolouration (8/9) - Multiple other ectodermal features also noted e.g. small brittle nails, hypotrichosis/hypertrichosis, lichen sclerosis - 5 individuals had cataracts (mostly bilateral, congenital/early childhood onset) - 6/9 IUGR - 5/9 postnatal growth restriction - 7/9 developmental delay/ID - 5/7 ADHD/ASD - 2/9 seizures Sources: Literature |
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| Fetal anomalies v1.71 | KCNK3 |
Krithika Murali gene: KCNK3 was added gene: KCNK3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: KCNK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNK3 were set to 36195757 Phenotypes for gene: KCNK3 were set to Neurodevelopmental disorder, MONDO:0700092, KCNK3-related; developmental delay with sleep apnoea (DDSA) Review for gene: KCNK3 was set to GREEN Added comment: PMID 36195757 Sörmann et al 2022 report 9 unrelated individuals with de novo heterozygous KCNK3 missense variants (21 weeks to 25 years old). All 8 living probands (3-25 years) had hypotonia, global developmental delay, central and/or obstructive sleep apnoea and feeding difficulties. 7/9 probands had additional anomalies including microcephaly (at least 3/9), arthrogryposis/flexion contractures/foot deformities (7/9), scoliosis, cleft palate (2/9), and ambiguous genitalia/undescended testes (5/6) and dysmorphism. IUGR reported in 3/9 probands and polyhdramnios in 2/9. KCNK3 encodes the TASK-1 K2P channel expressed throughout the central nervous system. All identified variants clustered near the X-gate and are involved in inter- or intra-subunit interaction likely to hold the X-gate closed. Individuals with variants located in the M2 transmembrane helix had a more severe phenotype than those with variants in the M4 helix. Functional studies support a gain of function disease mechanism with increased channel activation. TASK-1 K+ channel inhibitors (some in clinical use) have been raised as a possible therapeutic strategy. ---- Heterozygous LoF variants associated with a different disorder - primary pulmonary arterial hypertension Sources: Literature |
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| Fetal anomalies v1.70 | ATP7A |
Zornitza Stark changed review comment from: Well established gene-disease association, IUGR is a feature.; to: Well established gene-disease association, IUGR is a feature. Treatment: subcutaneous injections of copper histidine or copper chloride ClinGen has assessed as moderate evidence for actionability. Neonatal treatment with subcutaneous copper-histidine (initiated before 30 days of life) is recommended for asymptomatic males with a diagnosis of MD, but is not recommended for symptomatic boys or after 30 days of life. Treatment should be continued indefinitely. In an open-label clinical trial, 12 patients with MD treated with copper-histidine within 22 days of life had 92% survival after a mean follow-up of 4.6 years compared to 13% in a historical control group of 15 patients treated after a late diagnosis (mean age at diagnosis: 163 ± 113 days, range: 42 to 390). Two of the 12 patients with earlier treatment had normal neurological development. A second open-label trial of 35 presymptomatic patients receiving copper-histidine at less than a month of age reported significant improvement of four major neurodevelopmental (gross motor, fine motor/adaptive, personal/social, and language) domains and a non-significant lower mortality (28.5% vs 50%) at age of 3 years (or age of death) compared to 22 patients treated later and after onset of symptoms. |
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| Fetal anomalies v1.67 | NODAL |
Zornitza Stark edited their review of gene: NODAL: Added comment: NODAL is a good biological candidate for heterotaxy disorders, and this is supported by animal models. The gene is depleted for LoF variants in gnomad. The missense variants reported in PMIDs 9354794 and 19064609 are present at a high population frequency in gnomad, including some in homozygous case: their association with disease is DISPUTED. A total of at least 7 families reported with severe CHD and high impact variants (stop gain, frameshift and canonical splice site). However, almost invariably these were inherited from unaffected or questionably affected parents (e.g. self reports of heart murmur in childhood), raising questions about whether these variants contribute to disease under a monogenic or polygenic model and/or about penetrance. Discussed at GenCC on 13/9/2022 and agreed on MODERATE assessment.; Changed rating: AMBER; Changed publications: 9354794, 19064609, 29368431, 19933292, 11311163, 30293987 |
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| Fetal anomalies v1.64 | ADAMTS15 |
Zornitza Stark gene: ADAMTS15 was added gene: ADAMTS15 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ADAMTS15 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAMTS15 were set to 35962790 Phenotypes for gene: ADAMTS15 were set to Arthrogryposis (MONDO:0008779), ADMATS15-related Review for gene: ADAMTS15 was set to GREEN Added comment: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: contractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5). Sources: Literature |
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| Fetal anomalies v1.54 | ZMYND8 |
Zornitza Stark gene: ZMYND8 was added gene: ZMYND8 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZMYND8 were set to 35916866; 32530565 Phenotypes for gene: ZMYND8 were set to Neurodevelopmental disorder, MONDO:0700092, ZMYND8-related; Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures Review for gene: ZMYND8 was set to GREEN Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565). Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11). As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression. The protein is broadly expressed in brain and shows highest expression in early development. Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain). Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning. Sources: Expert Review |
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| Fetal anomalies v1.51 | BMP3 |
Seb Lunke gene: BMP3 was added gene: BMP3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: BMP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BMP3 were set to 35089417 Phenotypes for gene: BMP3 were set to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129 Added comment: Single missense variant identified segregating with disease following WES screen in a family with coloboma and/or microphthalmia in BMP3. Two additional unrelated patients identified with different missense in BMP3. Pathogenicity however largely on in-silicos, with one of the 3 missense having 29 hets in gnomAD. Additional functional work in bmp3 -/- zebra fish and some supporting evidence but not conclusive. Sources: Literature |
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| Fetal anomalies v1.49 | SPTA1 |
Zornitza Stark gene: SPTA1 was added gene: SPTA1 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: SPTA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: SPTA1 were set to 34132406; 35483216; 31333484; 29594000 Phenotypes for gene: SPTA1 were set to Spherocytosis type 3 #270970; Elliptocytosis-2 #130600; pyropoikilocytosis #266140 Review for gene: SPTA1 was set to GREEN Added comment: Severe presentations with hydrops reported. Sources: Expert Review |
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| Fetal anomalies v1.47 | GINS3 |
Zornitza Stark gene: GINS3 was added gene: GINS3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: GINS3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GINS3 were set to 35603789 Phenotypes for gene: GINS3 were set to Meier-Gorlin syndrome, MONDO:0016817, GINS3-related Review for gene: GINS3 was set to GREEN Added comment: 7 individuals from 5 families reported, presenting with prenatal and postnatal growth deficiency as well as other features. Three unique missense variants identified, two affecting p.Asp24. These variants are thought to be hypomorphic. Supportive mouse model. Sources: Literature |
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| Fetal anomalies v1.42 | TTC25 | Zornitza Stark edited their review of gene: TTC25: Added comment: At least 7 families reported now.; Changed rating: GREEN; Changed publications: 27486780, 31765523, 33715250, 33746037, 34215651 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.41 | WNT7B |
Zornitza Stark gene: WNT7B was added gene: WNT7B was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: WNT7B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WNT7B were set to 35790350 Phenotypes for gene: WNT7B were set to Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects syndrome; Multiple congenital anomalies/dysmorphic features syndrome MONDO:0043005, WNT7B-related Review for gene: WNT7B was set to GREEN Added comment: Three families reported with fetuses with multiple congenital anomalies and bi-allelic LoF variants. Two of the families had at the same variant. Supportive zebrafish model. Sources: Literature |
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| Fetal anomalies v1.39 | PAN2 |
Naomi Baker gene: PAN2 was added gene: PAN2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PAN2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PAN2 were set to PMID:35304602; 29620724 Phenotypes for gene: PAN2 were set to Syndromic disease MONDO:0002254 Added comment: PMID:35304602 reports five individuals from 3 families with biallelic (homozygous) loss-of-function variants. Clinical presentation incudes mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck. PMID:29620724 reports one individual with biallelic (homozygous) loss-of-function variant who presented with global developmental delay, mild hypotonia, craniosynostosis, severe early-onset scoliosis, imperforate anus, and double urinary collecting system. Sources: Literature |
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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 v1.25 | ODC1 |
Lucy Spencer gene: ODC1 was added gene: ODC1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ODC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ODC1 were set to 30475435; 30239107 Phenotypes for gene: ODC1 were set to Bachmann-Bupp syndrome (MIM#619075) Review for gene: ODC1 was set to GREEN Added comment: Polyhydraminos are a common prenatal finding in individuals with ODC1 variants. Malformations of cortical development and intracranial calcification have also been reported. Sources: Literature |
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| Fetal anomalies v1.19 | CDK10 |
Ain Roesley gene: CDK10 was added gene: CDK10 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CDK10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK10 were set to 28886341; 34974531 Phenotypes for gene: CDK10 were set to Al Kaissi syndrome MIM#617694 Review for gene: CDK10 was set to GREEN gene: CDK10 was marked as current diagnostic Added comment: 6 families reported 1x with IUGR, 1x hydrocephalus and 1x with fetal hydrops, hydrocephalus, multicystic, dysplastic kidneys, lung hypoplasia, cardiomyopathy, retrognathia Small birth weight/sizes reported in all Sources: Literature |
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| Fetal anomalies v1.13 | TNNI1 |
Krithika Murali gene: TNNI1 was added gene: TNNI1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TNNI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TNNI1 were set to 34934811 Phenotypes for gene: TNNI1 were set to arthrogryposis; joint contractures Review for gene: TNNI1 was set to AMBER Added comment: No OMIM gene disease association reported PMID 34934811 Nishimori et al report 2 individuals from a Japanese family with joint contractures, elevated CK and a novel heterozygous TNNI1 variant. The proband was born with clasped thumbs (gestational age not stated) requiring surgical correction at 5 months of age. At age 14 was diagnosed with contractures of the neck, trunk, hip and knee with elevated serum CK (1689 IU/L). No muscle weakness noted. Muscle biopsy showed moth-eaten appearance of type I fibres and electron microscopy showed type 1 fibre Z disk streaming. Trio exome sequencing identified a paternally heterozygous nonsense TNNI1 variant (c.523A>T p.K175*). The proband's father and paternal grandfather (not genotyped) also have a history of joint contractures with elevated CK. The affected amino acid residue is in the tropomyosin binding site near the C-terminus and is highly conserved. The variant is absent from gnomAD. rt-PCR products of mRNA from the patient's muscle biopsy showed presence of both mutated and normal transcripts. Sources: Literature |
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| 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 v1.5 | NAA15 |
Zornitza Stark changed review comment from: Typically presents post-natally.; to: Congenital heart defects in 4 of 19 individuals reported with the neurodevelopmental syndrome. PMID 33557580 - WES of 4511 patients with CHD identified 4 subjects with a rare LoF variant (allele frequency <0.00005) in the NAA15 gene, resulting in NAA15 haploinsufficiency. Parental analyses indicated that 3 of these LoF variants (p.Ser761*, p.Lys336Lys fs*6, and p.Arg470*) arose de novo in the probands. The inheritance of the p.Ala718fs variant is uncertain, as parental samples were unavailable. The authors also reference their previous studies identifying 2 other patients with CHD and LoF NAA15 heterozygous variants. |
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| Fetal anomalies v1.4 | NARS |
Krithika Murali gene: NARS was added gene: NARS was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: NARS were set to 32738225; 32788587 Phenotypes for gene: NARS were set to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive - MIM#619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant - MIM#619092 Review for gene: NARS was set to GREEN Added comment: HGNC approved gene symbol - NARS1 Both mono allelic and biallelic variants associated with a progressive neurological disorder with onset in infancy. Antenatal features reported. PMID 32738225 - reports roband with de novo heterozygous variant - IUGR and oligohydramnios noted prenatally. At birth noted to have low weight and OFC for gestational age. Proband with homozygous variant diagnosed with microcephaly, seizures and FTT in the neonatal period. Proband with compound het variants born with a low weight (-2.38 SD) and height (-3.76 SD) for gestational age. Review of supplementary material table - microcephaly at birth reported in 17 unrelated families. Sources: Literature |
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| Fetal anomalies v1.3 | IRX5 | Zornitza Stark edited their review of gene: IRX5: Added comment: Third family with Hamamy syndrome and homozygous missense variant reported, p.Arg168His. Two cousins, >4 meioses, good segregation data.; Changed rating: GREEN; Changed publications: 22581230, 27453922, 34899143 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.2 | ZNF335 |
Zornitza Stark gene: ZNF335 was added gene: ZNF335 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: ZNF335 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF335 were set to 23178126; 27540107; 29652087; 34982360 Phenotypes for gene: ZNF335 were set to Microcephaly 10, primary, autosomal recessive (MIM#615095) Review for gene: ZNF335 was set to GREEN Added comment: Microcephaly is generally primary, including reports of -9SD at birth. Sources: Expert Review |
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| 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 v0.4729 | MED27 |
Krithika Murali gene: MED27 was added gene: MED27 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MED27 were set to 33443317 Phenotypes for gene: MED27 were set to Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia - MIM#619286 Review for gene: MED27 was set to GREEN Added comment: Severe neurodevelopmental disorder with onset in infancy associated with multiple, significant brain anomalies which may be detectable antenatally (although antenatal phenotype not reported in published cases) Sources: Literature |
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| Fetal anomalies v0.4729 | EXOSC9 |
Krithika Murali gene: EXOSC9 was added gene: EXOSC9 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: EXOSC9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EXOSC9 were set to 33040083; 30690203; 29727687 Phenotypes for gene: EXOSC9 were set to Pontocerebellar hypoplasia, type 1D - MIM#618065 Review for gene: EXOSC9 was set to GREEN Added comment: Multiple antenatal features reported including IUGR, reduced fetal movements, oligohydramnios, congenital fractures and contractures. Sources: Literature |
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| Fetal anomalies v0.4725 | RBP4 |
Zornitza Stark gene: RBP4 was added gene: RBP4 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: RBP4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RBP4 were set to 25910211; 29178648 Phenotypes for gene: RBP4 were set to Microphthalmia, isolated, with coloboma 10 MIM#616428 Review for gene: RBP4 was set to GREEN Added comment: At least 3 unrelated microphthalmia, anophthalmia and coloboma families and supporting functional assays. Study established an uncharacterized mode of maternal inheritance, distinct from imprinting and oocyte-derived mRNA. Sources: Expert Review |
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| Fetal anomalies v0.4723 | PRR12 |
Zornitza Stark gene: PRR12 was added gene: PRR12 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: PRR12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PRR12 were set to 33314030; 29556724 Phenotypes for gene: PRR12 were set to Neuroocular syndrome, MIM#619539; Complex microphthalmia Review for gene: PRR12 was set to GREEN Added comment: PMID 33314030: Four unrelated families reported with unilateral or bilateral microphthalmia +/- Peters anomaly. In addition, 3 unrelated families reported with more complex phenotype including ID in PMID 29556724. Sources: Expert Review |
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| Fetal anomalies v0.4722 | EXOSC8 |
Krithika Murali changed review comment from: Severe autosomal recessive neurodegenerative disorder. PMID 24989451 report polyhydramnios, vermis hypoplasia, mega cisterna magna and corpus callosum anomalies in affectd individuals Sources: Literature; to: Severe autosomal recessive neurodegenerative disorder. PMID 24989451 (more info in supplementary material) report polyhydramnios, vermis hypoplasia, mega cisterna magna and corpus callosum anomalies in affectd individuals Sources: Literature |
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| Fetal anomalies v0.4722 | EXOSC8 |
Krithika Murali gene: EXOSC8 was added gene: EXOSC8 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: EXOSC8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EXOSC8 were set to 34210538; 24989451 Phenotypes for gene: EXOSC8 were set to Pontocerebellar hypoplasia, type 1C - MIM#616081 Review for gene: EXOSC8 was set to GREEN Added comment: Severe autosomal recessive neurodegenerative disorder. PMID 24989451 report polyhydramnios, vermis hypoplasia, mega cisterna magna and corpus callosum anomalies in affectd individuals Sources: Literature |
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| Fetal anomalies v0.4721 | MAB21L1 |
Zornitza Stark gene: MAB21L1 was added gene: MAB21L1 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: MAB21L1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAB21L1 were set to 30487245 Phenotypes for gene: MAB21L1 were set to Cerebellar, ocular, craniofacial, and genital syndrome OMIM#618479 Review for gene: MAB21L1 was set to GREEN Added comment: Pontocerebellar hypoplasia, Dandy-Walker malformation, microcephaly reported. Sources: Expert Review |
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| Fetal anomalies v0.4717 | CAPN15 |
Zornitza Stark gene: CAPN15 was added gene: CAPN15 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CAPN15 were set to 32885237 Phenotypes for gene: CAPN15 were set to Oculogastrointestinal neurodevelopmental syndrome, MIM# 619318; microphthalmia HP:0000568; coloboma HP:0000589 Review for gene: CAPN15 was set to GREEN Added comment: PMID: 32885237 - Zha et al 2020 - report 5 individuals with microphthalmia and/or coloboma from 4 independent families who, through WES, were identified as carrying homozygous or compound heterozygous missense variants in CAPN15 that are predicted to be damanging. the variants segregated with the disease in all 4 families, with parents being unaffected heterozygous carriers. Several individuals had additional phenotypes including growth deficits (2 families), developmental delay (2 families) and hearing loss (2 families). Capn15 knockout mice showed similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth. Sources: Expert Review |
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| Fetal anomalies v0.4715 | C16orf62 |
Zornitza Stark changed review comment from: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475;31712251). Microphthalmia and multiple other anomalies. Sources: Expert Review; to: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impaired autophagy and VPS35L knockout mouse resulted in early embryonic lethality (PMID 25434475;31712251). Microphthalmia and multiple other anomalies. Sources: Expert Review |
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| Fetal anomalies v0.4715 | C16orf62 |
Zornitza Stark gene: C16orf62 was added gene: C16orf62 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: C16orf62 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C16orf62 were set to 25434475; 31712251 Phenotypes for gene: C16orf62 were set to Ritscher-Schinzel syndrome-3 (RTSC3), MIM#619135 Review for gene: C16orf62 was set to AMBER Added comment: HGNC approved name: VPS35L. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 25434475;31712251). Microphthalmia and multiple other anomalies. Sources: Expert Review |
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| Fetal anomalies v0.4702 | TMEM218 |
Krithika Murali gene: TMEM218 was added gene: TMEM218 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TMEM218 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM218 were set to 33791682; 25161209 Phenotypes for gene: TMEM218 were set to Joubert syndrome 39 - MIM#619562 Review for gene: TMEM218 was set to GREEN Added comment: Associated with Jouberty syndrome. Occipital encephalocele reported in 5 fetuses. Sources: Literature |
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| Fetal anomalies v0.4702 | KIAA0556 |
Krithika Murali gene: KIAA0556 was added gene: KIAA0556 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: KIAA0556 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIAA0556 were set to 26714646; 27245168 Phenotypes for gene: KIAA0556 were set to Joubert syndrome 26 - MIM#616784 Review for gene: KIAA0556 was set to GREEN Added comment: Associated with Joubert syndrome. 5 individuals from two families reported, supportive mouse model. New HGNC approved name is KATNIP. Sources: Literature |
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| Fetal anomalies v0.4702 | IFT74 |
Krithika Murali gene: IFT74 was added gene: IFT74 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: IFT74 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IFT74 were set to 33531668; 27486776; 32144365 Phenotypes for gene: IFT74 were set to ?Bardet-Biedl syndrome 22 - MIM#617119; Joubert syndrome 40 - MIM#619582 Review for gene: IFT74 was set to GREEN Added comment: Biallelic variants associated with both Joubert and Bardet-Biedl syndrome phenotype - multiple congenital anomalies reported. Sources: Literature |
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| Fetal anomalies v0.4702 | FAM149B1 |
Krithika Murali gene: FAM149B1 was added gene: FAM149B1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAM149B1 were set to 30905400 Phenotypes for gene: FAM149B1 were set to Joubert syndrome 36 - MIM#618763 Review for gene: FAM149B1 was set to GREEN Added comment: Biallelic variants associated with Joubert syndrome in 4 unrelated families. Reported characteristics in published cases includes macrocephaly, mesoaxial polydactyly and cleft lip Sources: Literature |
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| Fetal anomalies v0.4700 | MORC2 |
Krithika Murali gene: MORC2 was added gene: MORC2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MORC2 were set to 32693025 Phenotypes for gene: MORC2 were set to Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy - MIM#619090 Review for gene: MORC2 was set to RED Added comment: No new publications since last PanelApp review Dec 2020. No antenatal features reported. --- MORC2 variants have commonly been associated with CMT, presenting axonal neuropathy with progressive weakness, muscle cramps and sensory impairment. However, Sacoto et al (2020) (PMID: 32693025) present a cohort of 20 individuals (19 kindreds) with a neurodevelopmental disorder characterised by DD, ID (18/20 - mild to severe), short stature (18/20), microcephaly (15/20) and variable craniofacial dysmorphisms. Hearing loss was observed in 11/19 subjects, primarily SNHL. Sources: Literature |
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| Fetal anomalies v0.4699 | MINPP1 |
Krithika Murali gene: MINPP1 was added gene: MINPP1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MINPP1 were set to 33257696; 33168985 Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia, type 16 - MIM#619527 Review for gene: MINPP1 was set to GREEN Added comment: Biallelic LoF variants associated with pontocerebellar hypoplasia. Early-onset progressive microcephaly is a phenotypic feature with one affected individual reported to have prenatal evidence of microcephaly associated with increased thalami echogenicity (PMID 33257696) Sources: Literature |
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| Fetal anomalies v0.4699 | NCAPD2 |
Zornitza Stark gene: NCAPD2 was added gene: NCAPD2 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: NCAPD2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NCAPD2 were set to 31056748; 27737959; 28097321 Phenotypes for gene: NCAPD2 were set to Microcephaly 21, primary, autosomal recessive; OMIM #617983 Review for gene: NCAPD2 was set to GREEN Added comment: Three families reported: 1 family with 2 sibs with microcephaly and ID, and homozygous NCAPD2 mutation, which segregated with disease. No functional evidence. 1 family with 1 affected and homozygous NCAPD2 mutation, which segregated with disease. Patient fibroblasts showed impaired chromosome segregation and abnormal recovery from mitotic condensation compared to controls. 1 family with 2 sibs with microcephaly, growth retardation, and ID, and homozygous NCAPD2 mutation, which segregated with disease. Functional studies of the variants and studies of patient cells were not performed. IUGR reported. Sources: Expert Review |
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| Fetal anomalies v0.4697 | NSRP1 |
Zornitza Stark gene: NSRP1 was added gene: NSRP1 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NSRP1 were set to 34385670 Phenotypes for gene: NSRP1 were set to Neurodevelopmental disorder, MONDO:0700092, NSRP1-related; Epilepsy; Cerebral palsy; microcephaly; Intellectual disability Review for gene: NSRP1 was set to GREEN Added comment: Novel gene regulating splicing. Biallelic LoF pathogenic variants reported in 6 individuals from 3 unrelated families associated with a phenotype characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy. Structural brain abnormalities. Sources: Expert Review |
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| Fetal anomalies v0.4694 | NUP188 |
Zornitza Stark gene: NUP188 was added gene: NUP188 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: NUP188 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NUP188 were set to 32021605; 28726809; 32275884 Phenotypes for gene: NUP188 were set to Sandestig-Stefanova syndrome, 618804; microcephaly; ID; cataract; structural brain abnormalities Review for gene: NUP188 was set to GREEN Added comment: 8 unrelated individuals reported. Sources: Expert Review |
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| Fetal anomalies v0.4692 | NUP85 |
Zornitza Stark gene: NUP85 was added gene: NUP85 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: NUP85 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NUP85 were set to 34170319 Phenotypes for gene: NUP85 were set to Microcephaly, MONDO:0001149, NUP85-related Review for gene: NUP85 was set to AMBER Added comment: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction. In the second family, compound heterozygous missense variants in NUP85 were detected (c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle. Variants in this gene are also associated with nephrotic syndrome. Sources: Expert Review |
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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 v0.4686 | PPP1R15B |
Belinda Chong gene: PPP1R15B was added gene: PPP1R15B was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PPP1R15B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPP1R15B were set to 26159176; 26307080; 27640355 Phenotypes for gene: PPP1R15B were set to Microcephaly, short stature, and impaired glucose metabolism 2, MIM# 616817 Review for gene: PPP1R15B was set to AMBER gene: PPP1R15B was marked as current diagnostic Added comment: Three unrelated families reported, two with the same variant. Phenotype in family reported in PMID 27640355 included infantile cirrhosis requiring transplantation. Sources: Literature |
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| Fetal anomalies v0.4686 | PPIL1 |
Belinda Chong gene: PPIL1 was added gene: PPIL1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPIL1 were set to 33220177 Phenotypes for gene: PPIL1 were set to Pontocerebellar hypoplasia, type 14, MIM# 619301; microcephaly; seizures Review for gene: PPIL1 was set to GREEN gene: PPIL1 was marked as current diagnostic Added comment: The patients presented at birth with severe microcephaly (-2 to -6 SD), which progressed postnatally (-4 to -8 SD) 17 individuals from 9 unrelated families reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID. Mouse models support gene-disease association. Sources: Literature |
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| Fetal anomalies v0.4686 | SYNCRIP |
Zornitza Stark gene: SYNCRIP was added gene: SYNCRIP was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SYNCRIP were set to 34157790 Phenotypes for gene: SYNCRIP were set to SYNCRIP-related neurodevelopmental disorder Review for gene: SYNCRIP was set to RED Added comment: One of 8 individuals reported so far had PVNH. Other features present post-natally. Sources: Expert Review |
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| Fetal anomalies v0.4632 | PDHA1 |
Zornitza Stark changed review comment from: Variants in this gene can cause congenital anomalies. Sources: Literature; to: Variants in this gene can cause congenital anomalies, primarily affecting the brain. One report of CDH. Sources: Literature |
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| Fetal anomalies v0.4632 | PDHA1 |
Zornitza Stark changed review comment from: Single individual reported as part of a cohort. Note variants in this gene can cause congenital anomalies. Sources: Literature; to: Variants in this gene can cause congenital anomalies. Sources: Literature |
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| Fetal anomalies v0.4600 | PGAP2 |
Zornitza Stark changed review comment from: Bi-allelic variants in this gene are typically associated with severe DD/ID, hypotonia with very poor motor development, poor speech, and increased serum alkaline phosphatase, although presentations with milder ID have also been reported. More than 10 unrelated families reported.; to: Bi-allelic variants in this gene are typically associated with severe DD/ID, hypotonia with very poor motor development, poor speech, and increased serum alkaline phosphatase, although presentations with milder ID have also been reported. More than 10 unrelated families reported. Microcephaly is a feature. |
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| Fetal anomalies v0.4598 | PGAP3 |
Zornitza Stark changed review comment from: Bi-allelic variants in this gene are associated with severe DD/ID, lack of speech acquisition, seizures, and dysmorphic facial features. Laboratory studies show increased serum alkaline phosphatase. More than 15 unrelated families reported.; to: Bi-allelic variants in this gene are associated with severe DD/ID, lack of speech acquisition, seizures, and dysmorphic facial features. Laboratory studies show increased serum alkaline phosphatase. More than 15 unrelated families reported. Microcephaly, CC abnormalities reported. |
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| Fetal anomalies v0.4596 | PGM1 | Zornitza Stark changed review comment from: The most common features include cleft lip and bifid uvula, apparent at birth, followed by hepatopathy, intermittent hypoglycemia, short stature, and exercise intolerance, often accompanied by increased serum creatine kinase. Less common features include rhabdomyolysis, dilated cardiomyopathy, and hypogonadotropic hypogonadism; to: Over 50 individuals reported. The most common features include cleft lip and bifid uvula, apparent at birth, followed by hepatopathy, intermittent hypoglycemia, short stature, and exercise intolerance, often accompanied by increased serum creatine kinase. Less common features include rhabdomyolysis, dilated cardiomyopathy, and hypogonadotropic hypogonadism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4585 | PIEZO2 | Zornitza Stark changed review comment from: Gene is associated with several phenotypes. The other two DA phenotypes do not have ID as a feature. Mild ID is part of the phenotype of some individuals with DA type 3. ID is part of the phenotype of Marden-Walker, however only one individual with PIEZO2 variant has been reported to date.; to: Gene is associated with several phenotypes, contractures are a key feature. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4572 | PIK3CA |
Zornitza Stark changed review comment from: Single case report of MCAP with fetal hydrops presentation, PIK3CA variant identified. Sources: Expert list; to: Multiple congenital anomalies. Sources: Expert list |
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| Fetal anomalies v0.4554 | PLK1 |
Belinda Chong gene: PLK1 was added gene: PLK1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PLK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLK1 were set to 33875846 Phenotypes for gene: PLK1 were set to Epilepsy; microcephaly; intellectual disability Review for gene: PLK1 was set to AMBER gene: PLK1 was marked as current diagnostic Added comment: Five individuals reported with microcephaly. However, unclear if microcephaly is pre or post natal. Sources: Literature |
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| Fetal anomalies v0.4553 | POGZ |
Zornitza Stark changed review comment from: White-Sutton syndrome is a neurodevelopmental disorder characterized by delayed psychomotor development apparent in infancy and a characteristic constellation of dysmorphic facial features. Additional features may include hypotonia, sensorineural hearing impairment, visual defects, joint laxity, and gastrointestinal difficulties, such as poor feeding. More than 40 individuals reported.; to: White-Sutton syndrome is a neurodevelopmental disorder characterized by delayed psychomotor development apparent in infancy and a characteristic constellation of dysmorphic facial features. Additional features may include hypotonia, sensorineural hearing impairment, visual defects, joint laxity, and gastrointestinal difficulties, such as poor feeding. More than 40 individuals reported. Microcephaly is a feature, congenital heart disease rarely reported. |
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| Fetal anomalies v0.4551 | POLR1C |
Zornitza Stark changed review comment from: 8 unrelated individuals reported, ID is part of the phenotype. Sources: Expert list; to: Treacher Collins more likely to be detected antenatally. Sources: Expert list |
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| Fetal anomalies v0.4546 | PIGH |
Belinda Chong gene: PIGH was added gene: PIGH was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PIGH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGH were set to 29573052; 33156547; 29603516 Phenotypes for gene: PIGH were set to Glycosylphosphatidylinositol biosynthesis defect 17, MIM# 618010 Review for gene: PIGH was set to AMBER gene: PIGH was marked as current diagnostic Added comment: Microcephaly appears to present at postnatal in these individuals. Three further families reported, including two sibs with microcephaly. Sources: Literature |
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| Fetal anomalies v0.4546 | PHC1 |
Belinda Chong gene: PHC1 was added gene: PHC1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PHC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PHC1 were set to 23418308 Phenotypes for gene: PHC1 were set to Microcephaly 11, primary, autosomal recessive, MIM#615414 Review for gene: PHC1 was set to RED gene: PHC1 was marked as current diagnostic Added comment: Short stature and microcephaly, currently not enough information. Single family reported with functional data. Sources: Literature |
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| Fetal anomalies v0.4546 | POR | Zornitza Stark Marked gene: POR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4546 | POR | Zornitza Stark Gene: por has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4546 | PORCN | Zornitza Stark Marked gene: PORCN as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4546 | PORCN | Zornitza Stark Gene: porcn has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4546 | PORCN | Zornitza Stark Phenotypes for gene: PORCN were changed from FOCAL DERMAL HYPOPLASIA to Focal dermal hypoplasia, MIM# 305600 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4545 | PORCN | Zornitza Stark Publications for gene: PORCN were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4542 | POU1F1 | Zornitza Stark changed review comment from: Hypotonia with untreated hypothyroidism, not truly ID.; to: Presentation with hydrops reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4535 | PPP2R5D |
Zornitza Stark changed review comment from: (P/LP in ClinVar): >15 missense, 1 PTC DN missense mechanism suspected: Functional studies showed defective holoenzyme assembly in transfected HEK293 cells and mutant subunits hindering dephosphorylation of B56δ-anchored substrates. Moreover,. p.P53S was the only variant to not show defective binding - authors speculate an alternative mechanism. Unknown mechanism for PTCs: pLI = 1 and very few in gnomAD. Missense variants cluster p.198-207 (Decipher).; to: (P/LP in ClinVar): >15 missense, 1 PTC DN missense mechanism suspected: Functional studies showed defective holoenzyme assembly in transfected HEK293 cells and mutant subunits hindering dephosphorylation of B56δ-anchored substrates. Moreover,. p.P53S was the only variant to not show defective binding - authors speculate an alternative mechanism. Unknown mechanism for PTCs: pLI = 1 and very few in gnomAD. Missense variants cluster p.198-207 (Decipher). Hydrocephalus reported in some. |
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| 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 v0.4532 | PCDH12 |
Belinda Chong gene: PCDH12 was added gene: PCDH12 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PCDH12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PCDH12 were set to 27164683; 30178464 Phenotypes for gene: PCDH12 were set to Diencephalic-mesencephalic junction dysplasia syndrome 1, MIM# 251280 Review for gene: PCDH12 was set to GREEN gene: PCDH12 was marked as current diagnostic Added comment: Brain malformations were detectable antenatally. Diencephalic-mesencephalic junction dysplasia syndrome-1 (DMJDS1) is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, severely delayed or even absent psychomotor development with profound intellectual disability, and spasticity or dystonia. Some patients may have seizures and/or visual impairment. Brain imaging shows a characteristic developmental malformation of the midbrain; subtle intracranial calcifications may also be present. At least 12 families reported. Sources: Literature |
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| Fetal anomalies v0.4532 | PARP6 |
Belinda Chong gene: PARP6 was added gene: PARP6 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PARP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PARP6 were set to 34067418 Phenotypes for gene: PARP6 were set to Intellectual disability; Epilepsy; Microcephaly Review for gene: PARP6 was set to GREEN gene: PARP6 was marked as current diagnostic Added comment: IUGR and partial agenesis of the corpus callosum has been observed. Four unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype. Supportive functional data. One pair of siblings with a homozygous missense: limited evidence for bi-allelic variants causing disease. Sources: Literature |
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| Fetal anomalies v0.4513 | PRKD1 |
Zornitza Stark edited their review of gene: PRKD1: Added comment: PMID: 27479907 (2016): three individuals reported, two with the c.1774G>A variant and one with the c.896T>G variant. All had congenital heart disease, two had some developmental delay, and two had variable features of ectodermal dysplasia, including sparse hair, dry skin, thin skin, fragile nails, premature loss of primary teeth, and small widely spaced teeth; the third individuals had a 'disorganized eyebrow.' PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation. c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.; Changed publications: 27479907, 32817298; Changed phenotypes: Congenital heart defects and ectodermal dysplasia, MIM#617364; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Fetal anomalies v0.4486 | RARS2 | Zornitza Stark changed review comment from: Progressive microcephaly is part of the phenotype. At least three unrelated families reported.; to: Progressive microcephaly, PCH. At least three unrelated families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4483 | RASA1 |
Zornitza Stark changed review comment from: Single individual reported as part of a cohort. Sources: Literature; to: AV malformations/fistulas, which can be large. Sources: Literature |
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| Fetal anomalies v0.4478 | MCM7 |
Krithika Murali gene: MCM7 was added gene: MCM7 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MCM7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MCM7 were set to 33654309; 34059554 Phenotypes for gene: MCM7 were set to Meier-Gorlin syndrome; Microcephaly; Intellectual disability; Lipodystrophy; Adrenal insufficiency Review for gene: MCM7 was set to AMBER Added comment: Association with congenital microcephaly. No new publications since last PanelApp review --- MCM7 is a component of the MCM complex, a DNA helicase which is essential for DNA replication. Other components have been linked to disease with phenotypes including microcephaly and ID. MCM7 is not associated with any phenotype in OMIM or G2P at present. ------ Currently there are 3 unrelated pedigrees in literature with different biallelic MCM7 variants associated with disease (see below). Although there is some functional data in support of variant-level deleteriousness or gene-level pathogenicity, the clinical gestalt is very different between the 3 families. - PMID: 33654309 (2021) - Two unrelated individuals with different compound het variants in MCM7 but disparate clinical features. One patient had typical Meier-Gorlin syndrome (including growth retardation, microcephaly, congenital lung emphysema, absent breast development, microtia, facial dysmorphism) whereas the second case had a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. While small at birth, the second patient did not demonstrate reduced stature or microcephaly at age 14.5 years. Both individuals had normal neurodevelopment. Functional studies using patient-derived fibroblasts demonstrate that the identified MCM7 variants were deleterious at either transcript or protein levels and through interfering with MCM complex formation, impact efficiency of S phase progression. - PMID: 34059554 (2021) - Homozygous missense variant identified in three affected individuals from a consanguineous family with severe primary microcephaly, severe ID and behavioural abnormalities. Knockdown of Mcm7 in mouse neuroblastoma cells lead to reduced cell viability and proliferation with increased apoptosis, which were rescued by overexpression of wild-type but not mutant MCM7. Sources: Literature |
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| Fetal anomalies v0.4478 | LMNB2 |
Krithika Murali gene: LMNB2 was added gene: LMNB2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: LMNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LMNB2 were set to 33033404 Phenotypes for gene: LMNB2 were set to Microcephaly 27, primary, autosomal dominant - MIM#619180 Review for gene: LMNB2 was set to GREEN Added comment: Almost all reported individuals had congenital microcephaly. Sources: Literature |
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| Fetal anomalies v0.4478 | LMNB1 |
Krithika Murali gene: LMNB1 was added gene: LMNB1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LMNB1 were set to 32910914 Phenotypes for gene: LMNB1 were set to Microcephaly 26, primary, autosomal dominant - MIM#619179 Review for gene: LMNB1 was set to GREEN Added comment: Monoallelic variants associated with profound microcephaly - this was noted antenatally in 5 unrelated individuals (total of 8 individuals from 5 families reported) Sources: Literature |
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| Fetal anomalies v0.4478 | LINGO1 |
Krithika Murali gene: LINGO1 was added gene: LINGO1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: LINGO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LINGO1 were set to 28837161; 31668702 Phenotypes for gene: LINGO1 were set to Mental retardation, autosomal recessive 64 - MIM#618103 Review for gene: LINGO1 was set to AMBER Added comment: 5 individuals reported from 2 families. 4 out of the 5 individuals had microcephaly. ID, developmentatl delay, spasticity, hypertonia, feeding problems also reported features. No antenatal information or birth growth parameters provided, but it is possible that microcephaly was antenatal/congenital in onset based on other phenotypic features reported. Sources: Literature |
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| Fetal anomalies v0.4478 | KIF21B |
Krithika Murali gene: KIF21B was added gene: KIF21B was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: KIF21B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KIF21B were set to 32415109 Phenotypes for gene: KIF21B were set to Global developmental delay; Intellectual disability; Abnormality of brain morphology; Microcephaly Review for gene: KIF21B was set to GREEN Added comment: Monoallelic variants associated with a neurodevelopmental disorder. Phenotypic features include ID, corpus callosum anomalies and microcephaly. PMID 32415109 report 4 unrelated individuals, 2 had IUGR +/- oligohydramnios. Sources: Literature |
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| Fetal anomalies v0.4459 | SNORD118 | Zornitza Stark changed review comment from: Many reported individuals have ID; however overall this is a progressive neurological disorder with variable onset, including in late adulthood.; to: Variable onset, including in infancy with brain abnormalities detectable by imaging. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4450 | RNU4ATAC | Zornitza Stark changed review comment from: ID is reported as part of the phenotype. NOTE this gene codes for snRNA, not protein.; to: IUGR. NOTE this gene codes for snRNA, not protein. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4443 | ROGDI |
Zornitza Stark changed review comment from: Kohlschutter-Tonz syndrome (KTZS) is an autosomal recessive disorder characterized by severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting both primary and secondary teeth and causing yellow or brown discolouration of the teeth. More than 10 families reported.; to: Kohlschutter-Tonz syndrome (KTZS) is an autosomal recessive disorder characterized by severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting both primary and secondary teeth and causing yellow or brown discolouration of the teeth. More than 10 families reported. Cerebellar hypoplasia and ventriculomegaly described. |
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| Fetal anomalies v0.4422 | RTTN | Zornitza Stark changed review comment from: More than 10 unrelated families reported, severe microcephaly, ID.; to: More than 10 unrelated families reported, severe microcephaly, PMG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4405 | SEC23B | Zornitza Stark changed review comment from: Over 20 families reported. Clinical presentation is typically post-natal.; to: Over 20 families reported. Clinical presentation is typically post-natal. However, at least two families reported with fetal hydrops. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4404 | SEC23B | Zornitza Stark changed review comment from: Over 20 families reported.; to: Over 20 families reported. Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4404 | TBC1D7 |
Krithika Murali gene: TBC1D7 was added gene: TBC1D7 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TBC1D7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TBC1D7 were set to 23687350; 24515783 Phenotypes for gene: TBC1D7 were set to Macrocephaly/megalencephaly syndrome, autosomal recessive - MIM#248000 Review for gene: TBC1D7 was set to AMBER Added comment: PMID: 24515783 report 2 siblings with biallelic variants. One noted to be macrosomic at birth and parents reported macrocephaly. PMID: 23687350 report 2 affected siblings. One was noted to be macrocephalic at birth. Sources: Literature |
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| Fetal anomalies v0.4404 | TAOK1 |
Krithika Murali gene: TAOK1 was added gene: TAOK1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TAOK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TAOK1 were set to 35091509; 31230721; 33565190 Phenotypes for gene: TAOK1 were set to Developmental delay with or without intellectual impairment or behavioral abnormalities - MIM#619575 Review for gene: TAOK1 was set to GREEN Added comment: Heterozygous TAOK1 variants associated with developmental delay PMID 35091509 - complication of polyhydramnios noted in 2 pregnancies in unrelated families PMID 33565190: - 1 patient with ventriculomegaly detected 28 week USS and polyhydramnios with secondary complication of multi-suture craniosynostosis - 1 infant with low birth weight. - 1 individual - antenatal history includes polyhydramnios at 5 months gestation PMID 31230721 - report one individual noted to be macrocephalic at birth with cleft palate Sources: Literature |
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| Fetal anomalies v0.4404 | STT3A |
Krithika Murali gene: STT3A was added gene: STT3A was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: STT3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: STT3A were set to 34653363; 23842455; 30701557; 28424003 Phenotypes for gene: STT3A were set to Congenital disorder of glycosylation, type Iw, autosomal dominant - MIM#619714; Congenital disorder of glycosylation, type Iw, autosomal recessive - MIM#615596 Review for gene: STT3A was set to GREEN Added comment: Biallelic variants associated with an earlier onset of symptoms. PMID: 23842455 report IUGR in one infant. PMID: 28424003 - report 5 affected individuals from one family, birth growth parameters of 4/5 individuals suggestive of growth restriction/relative microcephaly. --- ID/DD reported in all cases (at least 7 individuals from 3 unrelated families, with 2 different homozygous variants in STT3A) PMID: 34653363 - 16 patients from 9 families with new AD mode of inheritance (both de novo and inherited). All variants were missense within/around acritical active/catalytic sites. Patients aged 3-55yo, with children noted to be "healthy" until reaching young adulthood Clinical features include dysmorphic features, macrocephaly (6/16), mild-moderate ID/DD (10/16), short stature (8/16), skeletal abnormalities (10/16), muscle cramps (7/16). Functional studies verifies AR disease is caused by LOF variants, whereas the AD variants cause DN proven by cotransfection in WT yeast resulting in impaired glycosylation (protein levels unchanged). Sources: Literature |
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| Fetal anomalies v0.4404 | RHEB |
Krithika Murali gene: RHEB was added gene: RHEB was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: RHEB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RHEB were set to 29051493; 31337748 Phenotypes for gene: RHEB were set to Intellectual disability; Macrocephaly; Focal cortical dysplasia Review for gene: RHEB was set to GREEN Added comment: No new publications since last PanelApp review. Reviewed PMID: 29051493 supplementary information - three individuals with short stature and macrocephaly. Limited antenatal information provided/birth HC parameters, but one of the affected individuals was noted to have a large head circumference from 20 weeks gestation. PMID 31337748: Somatic variant in this gene found in one individual with focal cortical dysplasia. --- 3 individuals from two families with heterozygous RHEB variants. Two siblings carried the c.110 C > T (p.Pro37Leu) variant, and a sporadic individual carried the c.202 T>C (p.Ser68Pro) allele. All 3 individuals had short stature (−2 to −3 SD) and early brain overgrowth with pronounced macrocephaly during childhood (+2.5/+3 SD). They had severe to profound ID with hypotonia, as well as autism spectrum disorder. 2 of 3 individuals were reported to have epilepsy. In a zebrafish model, overexpression of RHEB produced megalencephaly, supporting a hyperactivating effect. This is supported in mice where loss of RHEB activity does not cause an overt neurological phenotype Single individual with somatic variants in this gene and focal cortical dysplasia also reported. Sources: Literature |
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| Fetal anomalies v0.4381 | SLC13A5 | Zornitza Stark changed review comment from: At least 7 unrelated families reported.; to: At least 7 unrelated families reported. Microcephaly is a feature. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4381 | SLC16A2 | Zornitza Stark Phenotypes for gene: SLC16A2 were changed from MCT8 (SLC16A2)-SPECIFIC THYROID HORMONE CELL TRANSPORTER DEFICIENCY to Allan-Herndon-Dudley syndrome, MIM# 300523 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4372 | SLC35C1 |
Zornitza Stark changed review comment from: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe DD/ID, mild dysmorphism, and impaired neutrophil motility. More than 5 unrelated families reported, note immune dysfunction is not always present. Microcephaly is a feature.; to: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe DD/ID, mild dysmorphism, and impaired neutrophil motility. More than 5 unrelated families reported, note immune dysfunction is not always present. Microcephaly is a feature. Variable severity, some present in childhood. |
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| Fetal anomalies v0.4372 | SLC35C1 |
Zornitza Stark changed review comment from: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe DD/ID, mild dysmorphism, and impaired neutrophil motility. More than 5 unrelated families reported, note immune dysfunction is not always present.; to: Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe DD/ID, mild dysmorphism, and impaired neutrophil motility. More than 5 unrelated families reported, note immune dysfunction is not always present. Microcephaly is a feature. |
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| Fetal anomalies v0.4368 | SLC39A8 | Zornitza Stark changed review comment from: 6 individuals from Hutterite descent and two other unrelated families reported. ID a consistent feature.; to: 6 individuals from Hutterite descent and two other unrelated families reported. Craniosynostosis; brain abnormalities. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4360 | SMARCA4 |
Zornitza Stark changed review comment from: Single individual reported as part of a CDH cohort. Sources: Literature; to: IUGR and multiple congenital anomalies. Sources: Literature |
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| Fetal anomalies v0.4359 | SMC1A | Zornitza Stark changed review comment from: CDH is a feature of CdL, but cannot find a report specifically with SMC1A variant.; to: Multiple congenital anomalies syndrome. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4357 | SMC3 | Zornitza Stark changed review comment from: CDH is a feature of CdL but cannot find specific reports of SMC3 variants.; to: Multiple congenital anomalies syndrome. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4355 | 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 v0.4305 | 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 v0.4303 | 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 v0.4301 | WDR37 |
Chirag Patel gene: WDR37 was added gene: WDR37 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: WDR37 were set to PMID: 31327508, 31327510 Phenotypes for gene: WDR37 were set to Neurooculocardiogenitourinary syndrome MIM#618652 Review for gene: WDR37 was set to GREEN Added comment: Neurooculocardiogenitourinary syndrome (NOCGUS) is a multisystem disorder characterized by poor growth and anomalies of the ocular, craniofacial, neurologic, cardiovascular, genitourinary, skeletal, and gastrointestinal systems. Lethality before 2 years of age has been observed. Nine unrelated patients reported with de novo missense mutations in the WDR37 gene. Sources: Expert list |
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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 v0.4294 | NFIB |
Krithika Murali gene: NFIB was added gene: NFIB was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: NFIB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NFIB were set to 30388402; 33130023; 32902921 Phenotypes for gene: NFIB were set to Macrocephaly, acquired, with impaired intellectual development - MIM#618286 Review for gene: NFIB was set to GREEN Added comment: NFIB haploinsufficiency associated with syndromic ID. Macrocephaly and corpus callosum anomalies are recurrent phenotypic features. OMIM notes macrocephaly postnatal in onset, but review of published cases shows some instances of relative macrocephaly at birth. Also corpus callosal anomalies - agenesis and dysgenesis, noted on MRI-B in childhood but possibility of detecting this antenatally in future cases. 2 unrelated individuals reported with minor cardiac anomalies also. --- OMIM notes macrocephaly postnatal in onset. PMID: 30388402 - 18 individuals reported, of whom 11 had deletions of this gene and the rest had SNVs. Relative macrocephaly noted based on growth parameters in 4 individuals (e.g. x1 male with BW 22nd centile and HC 99th centile in an apparently uncomplicated pregnancy) - macrocephaly became more pronounced with age. In addition, 2 individuals had congenital cardiac anomalies (x1 small VSD and x1 narrow pulmonary artery) and 2 individuals had complete agenesis of the corpus callosum. 33130023 - Report one affected individual. Birth weight was 4.13 kg (Z-score 1.50, 93rd percentile), length was 52 cm (Z-score 1.12, 87th percentile) and his head circumference was 37 cm (Z-score 2.00, 98th percentile). MRI-B at 12 months confirmed agenesis of the corpus callosum 32902921 - report one patient with normal antenatal history, no birth HC provided, macrocephaly noted at 7 months. MRI-B showed mild dysgensis of the corpus callosum age 5. 2nd unrelated patient's birth weight 3.43 kg(57th centile,Zscore 0.17), length 52.8 cm (94th centile, Zscore1.54), and OFC 37.5 cm (99th centile,Zscore 2.39). MRI-B age 5 showed dysgenesis of the corpus callosum. Sources: Literature |
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| Fetal anomalies v0.4293 | YRDC |
Chirag Patel gene: YRDC was added gene: YRDC was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: YRDC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: YRDC were set to PMID: 31481669, 34545459 Phenotypes for gene: YRDC were set to Galloway-Mowat syndrome 10, OMIM # 619609 Review for gene: YRDC was set to GREEN Added comment: Galloway-Mowat syndrome-10 (GAMOS10) is a severe autosomal recessive disorder characterized by onset of symptoms soon after birth. Affected individuals have progressive renal dysfunction with proteinuria associated with diffuse mesangial sclerosis (DMS) on renal biopsy. Other features include global developmental delay, microcephaly, hypothyroidism, arachnodactyly, and dysmorphic facial features. Some patients may have seizures or abnormalities on brain imaging. All reported patients have died in infancy. 4 individuals from 3 unrelated families with typical features of Galloway-Mowat syndrome including proteinuria, microcephaly, developmental delay and brain malformations. Supportive functional data. Sources: Expert list |
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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 v0.4289 | ZNF668 |
Chirag Patel gene: ZNF668 was added gene: ZNF668 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF668 were set to PMID: 34313816, 26633546 Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism Review for gene: ZNF668 was set to AMBER Added comment: 2 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts. Sources: Expert list |
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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 v0.4275 | HEXB |
Krithika Murali gene: HEXB was added gene: HEXB was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: HEXB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HEXB were set to 23046579; 24613245; 33407268; 27697305; 11869411; 33363784 Phenotypes for gene: HEXB were set to Sandhoff disease, infantile, juvenile, and adult forms-MIM#268800 Review for gene: HEXB was set to RED Added comment: Biallelic variants associated with Sandhoff disease which includes a severe, infantile onset form. Authors of reported cases note normal antenatal and immediate postnatal course with onset of phenotypic features generally from 2 months of age onwards. Note subset with cardiomyopathy and secondary valvular incompetence, not congenital heart defects. Sources: Literature |
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| Fetal anomalies v0.4273 | GTPBP2 |
Ain Roesley gene: GTPBP2 was added gene: GTPBP2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: GTPBP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GTPBP2 were set to 26675814; 29449720; 30790272 Phenotypes for gene: GTPBP2 were set to Jaberi-Elahi syndrome MIM#617988 Review for gene: GTPBP2 was set to GREEN gene: GTPBP2 was marked as current diagnostic Added comment: Nine individuals from six unrelated families microcephaly noted but measurements at birth not provided. 1x weight 5th percentile and OFC 25-50 percentile scoliosis consistently reported Other features include clenched hands, talipes, abnormal brain imaging, pectus excavatum Sources: Literature |
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| Fetal anomalies v0.4273 | MCF2 |
Daniel Flanagan gene: MCF2 was added gene: MCF2 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: MCF2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: MCF2 were set to 31846234 Phenotypes for gene: MCF2 were set to Perisylvian polymicrogyria Review for gene: MCF2 was set to RED Added comment: Single individual reported, inherited missense variant from unaffected mother, some support from mouse model. Sources: Expert list |
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| Fetal anomalies v0.4273 | GRM7 |
Ain Roesley gene: GRM7 was added gene: GRM7 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: GRM7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GRM7 were set to 32286009; 32248644 Phenotypes for gene: GRM7 were set to Neurodevelopmental disorder with seizures, hypotonia, and brain abnormalities MIM#618922 Review for gene: GRM7 was set to GREEN gene: GRM7 was marked as current diagnostic Added comment: progressive/post-natal microcephaly consistently reported 6 families with 11 affecteds 5 of the pregnancies were complicated by polyhydramnios/decreased fetal movements Sources: Literature |
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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 | 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 v0.4273 | CEP85L |
Daniel Flanagan gene: CEP85L was added gene: CEP85L was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: CEP85L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CEP85L were set to 32097630 Phenotypes for gene: CEP85L were set to Lissencephaly 10, posterior predominant (MIM618873) Review for gene: CEP85L was set to RED Added comment: Thirteen individuals reported with mono allelic variants in this gene, inherited in two of the families. Mouse model had neuronal migration defects. Earliest symptom onset 5 months, most develop seizures after several years. Sources: Expert list |
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| Fetal anomalies v0.4273 | HEXA |
Krithika Murali gene: HEXA was added gene: HEXA was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: HEXA was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: HEXA were set to Tay-Sachs disease - MIM#272800 Review for gene: HEXA was set to RED Added comment: Associated features not reported prenatally or at birth. Sources: Literature |
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| Fetal anomalies v0.4273 | HERC1 |
Krithika Murali gene: HERC1 was added gene: HERC1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: HERC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HERC1 were set to 28323226; 27108999; 26153217; 26138117 Phenotypes for gene: HERC1 were set to Macrocephaly, dysmorphic facies, and psychomotor retardation - MIM#617011 Review for gene: HERC1 was set to GREEN Added comment: Multiple individuals reported with macrosomia and macrocephaly detected at birth. Sources: Literature |
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| Fetal anomalies v0.4273 | CDK5 |
Daniel Flanagan gene: CDK5 was added gene: CDK5 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CDK5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK5 were set to 25560765 Phenotypes for gene: CDK5 were set to Lissencephaly 7 with cerebellar hypoplasia (MIM#616342) Review for gene: CDK5 was set to RED Added comment: Single consanguineous family with multiple affected individuals reported, lissencephaly prominent. Head circumference at the low-normal range (5th–25th percentile). Sources: Literature |
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| Fetal anomalies v0.4273 | FIBP |
Krithika Murali gene: FIBP was added gene: FIBP was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FIBP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FIBP were set to 27183861; 26660953 Phenotypes for gene: FIBP were set to Thauvin-Robinet-Faivre syndrome - MIM#617107 Review for gene: FIBP was set to AMBER Added comment: Thauvin-Robinet-Faivre syndrome is an autosomal recessive disorder characterized by generalized overgrowth, mainly of height, and mildly delayed psychomotor development with mild or severe learning difficulties. More variable features may include congenital heart defects, kidney abnormalities, and skeletal defects. Patients may have an increased risk for Wilms tumor. 2 unrelated families reported. 27183861 - report one family with 3 affected children. Prenatally relevant phenotypic features include: - congenital heart disease in one child - preterm delivery and bilateral talipes equinovarus 2nd child - cystic kidney disease, nephromegaly and polyhydramnios 3rd child 26660953 - report one child with ventricular septal defect, mitral valve prolapse, renal malrotation with left bifid ureter, macrocephaly and macrosomia noted at birth. Sources: Literature |
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| Fetal anomalies v0.4273 | B3GNT2 |
Daniel Flanagan gene: B3GNT2 was added gene: B3GNT2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: B3GNT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: B3GNT2 were set to 23359570; 23877401 Phenotypes for gene: B3GNT2 were set to Walker-Warburg syndrome Review for gene: B3GNT2 was set to AMBER Added comment: Only 2 families reported PMID: 23877401. Homozygous frameshift in B3GNT1 identified in a proband born with occipital encephalocele, anencephaly, cloudy cornea, proptotic eyes, spastic posture and micropenis. PMID: 23359570. Family with two homozygous B3GNT1 missense in affected. 4 pregnancies with abnormalities identified by ultrasound, including: hydrocephalus with the lateral ventricles, severe cerebral ventriculomegaly, cystic dysplastic kidney Sources: Literature |
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| Fetal anomalies v0.4273 | CTNNA2 |
Ain Roesley gene: CTNNA2 was added gene: CTNNA2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CTNNA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTNNA2 were set to 30013181 Phenotypes for gene: CTNNA2 were set to Cortical dysplasia, complex, with other brain malformations 9, MIM#618174 Review for gene: CTNNA2 was set to GREEN gene: CTNNA2 was marked as current diagnostic Added comment: acquired microcephaly. Pachygyria is also a feature, which can be detectable in a prenatal MRI, though none of the reports thus far were diagnosed antenatally 3 families with 7 affecteds Sources: Literature |
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| Fetal anomalies v0.4273 | DICER1 |
Krithika Murali gene: DICER1 was added gene: DICER1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DICER1 were set to 27960159; 29343557; 26227654; 33208384; 35114704; 31232238; 24676357 Phenotypes for gene: DICER1 were set to GLOW syndrome, somatic mosaic - MIM#618272; Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors - MIM#138800; Pleuropulmonary blastoma - MIM#601200 Review for gene: DICER1 was set to GREEN Added comment: Heterozygous pathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic somatic missense DICER1 variants in the RNase IIIb domain are linked to GLOW syndrome (global developmental delay, lung cysts, overgrowth, and Wilms’ tumor) syndrome. While the DICER1 syndrome is classically caused by frameshift, nonsense or other mutations that ablate DICER1 function in a true heterozygous state, GLOW-syndrome mutations occur at specific residues within the RNase IIIb domain that only affect the function of this domain. Both syndromes have been reported to have features that can be detected prenatally. PMID 33208384 - report a patient with heterozygous germline DICER1 variant. The patient was born at gestational week 39 after a difficult delivery due to macrocephaly. Clinical findings at birth included two blood vessels in the umbilical cord, undescended testis, inguinal hernia, postaxial polydactyly, ear pits and rocker bottom feet. PMID: 34331184 - report 4 unrelated families with germline DICER1 variants. In family 1 - one child was born with Pierre Robin sequence, shortening of the left arm and leg and bilateral hip dysplasia. In Family 2 a child had macrosomia and macrocephaly at birth. Family 4 - born at 33 weeks, dysmorphic facies including hypertelorism and macroglossia. PMID 24676357 - report 2 unrelated children with GLOW syndrome. Patient 1 was noted to have enlarged kidneys on 24 week ultrasound. At birth was found to have renal and pulmonary cysts. Patient 2 - macrocephaly was noted at birth. DICER1 implicated in ~60% of PPB - reports of PPB detecteed antenatally, although no reports in the context of confirmed DICER1 syndrome. Sources: Literature |
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| Fetal anomalies v0.4271 | COLGALT1 | Zornitza Stark commented on gene: COLGALT1: 3 unrelated cases with biallelic variants, and supporting functional assays. The main features of the cases were porencephalic cysts, leukoencephalopathy, lacunar infarcts, cerebral microbleeds/haemorrhages and calcifications. A null mouse model was embryonic lethal, but had defects in the vascular networks of the embryos. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4266 | ARF1 |
Daniel Flanagan gene: ARF1 was added gene: ARF1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ARF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARF1 were set to 28868155; 34353862 Phenotypes for gene: ARF1 were set to Periventricular nodular heterotopia 8 (MIM#618185) Review for gene: ARF1 was set to RED Added comment: Three unrelated individuals reported with de novo missense in this gene. PMID: 34353862: Additional report of affected parent and child. 1 patient had microcephaly in teens but normal head circumference at first examination. Sources: Literature |
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| Fetal anomalies v0.4266 | ATXN2L |
Krithika Murali gene: ATXN2L was added gene: ATXN2L was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ATXN2L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATXN2L were set to 33283965; 33057194 Phenotypes for gene: ATXN2L were set to macrocephaly; intellectual disability Review for gene: ATXN2L was set to AMBER Added comment: Combined data from three large exome groups identified several de novo variants, including frameshift and missense, in ATXN2L in patients with developmental delay (Kaplanis et al., 2020). pLI=1.0 33283965 - Single case report of a novel de novo missense variant in a child with macrocephaly and developmental delay. No functional work. Macrocephaly was detected prenatally. This together with breech presentation resulted in elective C-section at 36 weeks. Sources: Literature |
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| Fetal anomalies v0.4266 | COPB1 |
Ain Roesley gene: COPB1 was added gene: COPB1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: COPB1 were set to Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts Review for gene: COPB1 was set to RED gene: COPB1 was marked as current diagnostic Added comment: Two unrelated families, some supportive functional data. Microcephaly is not a consistent feature in the families reported to date. Cataracts were also post-natal Sources: Literature |
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| Fetal anomalies v0.4266 | CENPE |
Ain Roesley gene: CENPE was added gene: CENPE was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CENPE was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CENPE were set to 24748105; 30086807 Phenotypes for gene: CENPE were set to Microcephaly 13, primary, autosomal recessive (MIM#616051) Review for gene: CENPE was set to RED gene: CENPE was marked as current diagnostic Added comment: PMID: 24748105; - 2 siblings from non-consanguineous family of European descent - patient A: at birth, OFC of -5SD which progressed to -9SD at 5 years of age - patient B: no measurement at birth but OFC was -7SD at 3 years of age - cHet for 2 missense *no new reports since. A review of AR primary microcephaly in 2018 still states just 1 family (PMID: 30086807) Sources: Literature |
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| Fetal anomalies v0.4264 | C7orf43 |
Ain Roesley gene: C7orf43 was added gene: C7orf43 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: C7orf43 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C7orf43 were set to 30715179 Phenotypes for gene: C7orf43 were set to Microcephaly 25, primary, autosomal recessive, MIM# 618351 Penetrance for gene: C7orf43 were set to Complete Review for gene: C7orf43 was set to AMBER gene: C7orf43 was marked as current diagnostic Added comment: HGNC approved name TRAPPC14 Single family reported: three affected siblings with homozygous truncating variant. Supportive zebrafish model. Occipital-frontal circumferences were below2 SD at birth, with microcephaly progressing later in life Sources: Literature |
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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 v0.4264 | AGMO |
Ain Roesley gene: AGMO was added gene: AGMO was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: AGMO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AGMO were set to 31555905; 27000257 Phenotypes for gene: AGMO were set to neurodevelopmental disorder, AGMO-related MONDO#0700092 Penetrance for gene: AGMO were set to Complete Review for gene: AGMO was set to RED gene: AGMO was marked as current diagnostic Added comment: syndromic neurodevelopmental disorder with ID, microcephaly and epilesy reported 1x oligo-hydramnios, maternal hypothyroidism, and decreased fetal movement birth weight was 2892 g (23%) and length was 49.5 cm (50%). Head circumference was not known but noted to be 5–10% 1x uneventful pregnancy birth weight was 2977 g (55%) and length was 53.3 cm (98%) 1x siblings with post natal microcephaly Sources: Literature |
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| Fetal anomalies v0.4256 | COLGALT1 |
Chloe Stutterd gene: COLGALT1 was added gene: COLGALT1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: COLGALT1 was set to BIALLELIC, autosomal or pseudoautosomal Added comment: Antenatal features: porencephalic cyst, calcifications Sources: Literature |
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| Fetal anomalies v0.4253 | UNC13A |
Belinda Chong gene: UNC13A was added gene: UNC13A was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: UNC13A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: UNC13A were set to 27648472; 28192369 Phenotypes for gene: UNC13A were set to Congenital myasthenia; dyskinesia; autism; developmental delay Review for gene: UNC13A was set to RED Added comment: One individual described with biallelic variants in this gene and a myasthenic syndrome; another individual reported with de novo variant in this gene and a different neurological phenotype (abnormal movements, developmental delay and autism). Sources: Literature |
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| Fetal anomalies v0.4253 | SYT2 |
Belinda Chong gene: SYT2 was added gene: SYT2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SYT2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: SYT2 were set to 25192047; 32776697; 32250532; 30533528 Phenotypes for gene: SYT2 were set to Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040; Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461 Review for gene: SYT2 was set to GREEN gene: SYT2 was marked as current diagnostic Added comment: Myasthenic syndrome bi-allelic #619461- Decreased fetal movements Mono-allelic disease, PMID 25192047 and 30533528: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in three families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function. Sources: Literature |
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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 v0.4235 | NACC1 | Alison Yeung Added comment: Comment on phenotypes: Fetal anomalies reported include cataracts (5/7 patients) and microcephaly (5/7) patients | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4229 | MYT1 | Alison Yeung changed review comment from: Associated with OAV spectrum / hemifacial microsomia; to: Reported in patients with OAV spectrum / hemifacial microsomia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4205 | GDF3 |
Zornitza Stark changed review comment from: The variants originally reported are present at a high frequency in gnomad which is not consistent with a rare Mendelian disorder.; to: The variants originally reported are present at a high frequency in gnomad which is not consistent with a rare Mendelian disorder. Some individuals had skeletal features. More recent publication PMID 29260090: variant inherited from phenotypically normal parent, leading authors to speculate about reduced penetrance. |
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| Fetal anomalies v0.4192 | SEMA3E |
Krithika Murali gene: SEMA3E was added gene: SEMA3E was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SEMA3E was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SEMA3E were set to 31691538; 31464029; 15235037 Phenotypes for gene: SEMA3E were set to ?CHARGE syndrome - MIM#214800 Review for gene: SEMA3E was set to AMBER Added comment: Heterozygous variant identified in a fetus given a clinical diagnosis of CHARGE syndrome. One individual with a translocation and one individual with a missense variant reported in 2004; some functional data. Sources: Literature |
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| Fetal anomalies v0.4192 | TMEM53 |
Krithika Murali gene: TMEM53 was added gene: TMEM53 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TMEM53 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM53 were set to 33824347 Phenotypes for gene: TMEM53 were set to Craniotubular dysplasia, Ikegawa type - MIM#619727 Review for gene: TMEM53 was set to RED Added comment: 33824347 Guo et al 2021 report 5 individuals from 4 unrelated Indian families with a sclerosing bone disorder. Authors report normal prenatal and early postnatal development. Sources: Literature |
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| Fetal anomalies v0.4192 | SGMS2 |
Krithika Murali gene: SGMS2 was added gene: SGMS2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SGMS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SGMS2 were set to 34236445; 32028018; 30779713; 34761145; 34504906 Phenotypes for gene: SGMS2 were set to Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia - MIM#126550 Review for gene: SGMS2 was set to RED Added comment: Heterozygous variants in SGMS2 associated with childhood-onset osteoporosis and skeletal dysplasia. Evidence suggests that some heterozygous missense variants have a dominant negative effect and lead to severe bone fragility and spondylometaphyseal dysplasia, while one recurrent nonsense variant (c.148C > T, p.Arg50*) has been associated with milder bone fragility with or without cranial sclerosis (cranial doughnut lesions). No antenatal features reported in published cases including growth parameters. --- PMID 32028018 Robinson et al 2020 - provide phenotypic information for 2 unrelated individuals with c.148C > T, p.Arg50* variant. No antenatal history reported. PMID: 30779713 Pekkinen et al 2019 - identified heterozygous SGMS2 variants in 13 individuals from 6 unrelated families with early-onset osteoporosis and skeletal dysplasia. Identified recurrent nonsense variant in 4 families ( p.Arg50*) presented with childhood-onset osteoporosis with or without cranial sclerosis. 2 families had p.Ile62Ser or p.Met64Arg and. more severe phenotype including with neonatal fracture (clavicular fracture at birth), severe short stature, and spondylometaphyseal dysplasia. No antenatal phenotype/birth growth parameters provided. PMID: 34761145 Makitie et al 2021 - further examination of bone changes in two individuals already reported in Pekkinen et al 2019 paper with recurrent nonsense variant. PMID: 34504906 Basalom et al 2021 - no antenatal features reported Sources: Literature |
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| Fetal anomalies v0.4191 | UBA2 |
Chirag Patel gene: UBA2 was added gene: UBA2 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: UBA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: UBA2 were set to PMID: 31332306; 31587267 Phenotypes for gene: UBA2 were set to Split-Hand/Foot Malformation; Aplasia Cutis Congenita; Ectrodactyly Review for gene: UBA2 was set to GREEN Added comment: 2x unrelated probands with isolated split hand malformation. fs variants - 1x de novo and 1x inherited from apparent unaffected mother (no radiographs of her hand available. 1x proband with unilateral split-hand malformation (missense). Her daughter and grandson reported to have ectrofactyly but were unavailable for testing PMID: 31332306 - a single individual with a de novo PTC and split hand/foot malformation (SHFM). Additional two multigenic CNVs including this gene in individuals with SHFM and ectrodactyly. Authors mention an additional de novo missense but the patient didnt have SHFM, argue low penetrance PMID: 31587267 - a mother and son with aplasia cutis congenita (ACC), with a heterozygous PTC. Son also has ectrodactyly. Authors note an additional de novo missense in a patient with ACC. Sources: Expert list |
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| Fetal anomalies v0.4189 | SCNN1B |
Chirag Patel gene: SCNN1B was added gene: SCNN1B was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SCNN1B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: SCNN1B were set to PubMed: 8589714 Phenotypes for gene: SCNN1B were set to Pseudohypoaldosteronism, type I - MIM#264350 Review for gene: SCNN1B was set to GREEN Added comment: Autosomal recessive pseudohypoaldosteronism type I caused by homozygous or compound heterozygous mutation in SCNN1B is characterized by renal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder involves multiple organ systems and is especially threatening in the neonatal period. Multiple patients reported. Sources: Literature |
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| Fetal anomalies v0.4187 | SCNN1A |
Chirag Patel gene: SCNN1A was added gene: SCNN1A was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SCNN1A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: SCNN1A were set to PubMed: 8589714, 31301676 Phenotypes for gene: SCNN1A were set to Pseudohypoaldosteronism, type I - MIM#264350 Review for gene: SCNN1A was set to GREEN Added comment: Autosomal recessive pseudohypoaldosteronism type I caused by homozygous or compound heterozygous mutation in SCNN1A is characterized by renal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder involves multiple organ systems and is especially threatening in the neonatal period. Multiple patients reported. Sources: Literature |
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| Fetal anomalies v0.4180 | MIA3 |
Chirag Patel gene: MIA3 was added gene: MIA3 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MIA3 were set to PMID: 32101163, 33778321 Phenotypes for gene: MIA3 were set to Ondontochondrodysplasia 2 with hearing loss and diabetes , MIM#619269 Review for gene: MIA3 was set to AMBER Added comment: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability. Four affected siblings reported, homozygous variant affecting splicing. Mouse model has absence of bone mineralization. Can present with IUGR antenatally. Suitable for fetal anomalies panel. Sources: Expert list |
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| Fetal anomalies v0.4178 | MBTPS1 |
Chirag Patel gene: MBTPS1 was added gene: MBTPS1 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: MBTPS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MBTPS1 were set to PMID: 32857899; 32420688; 30046013 Phenotypes for gene: MBTPS1 were set to Skeletal dysplasia, no OMIM # Review for gene: MBTPS1 was set to GREEN Added comment: Three unrelated individuals reported with bi-allelic variants in this gene and a skeletal dysplasia, one described with SRS-like features. Elevated blood lysosomal enzymes are also a feature. Sources: Expert list |
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| Fetal anomalies v0.4172 | COL27A1 |
Chirag Patel gene: COL27A1 was added gene: COL27A1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: COL27A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COL27A1 were set to PubMed: 24986830, 28276056, 28322503 Phenotypes for gene: COL27A1 were set to Steel syndrome, OMIM #615155 Review for gene: COL27A1 was set to GREEN Added comment: Steel syndrome is characterized by characteristic facies, congenital dislocated hips and radial heads, carpal coalition (fusion of carpal bones), short stature, scoliosis, and cervical spine anomalies. The dislocated hips are resistant to surgical intervention. 3 families with biallelic variants reported. Sources: Literature |
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| Fetal anomalies v0.4170 | CHST11 |
Chirag Patel gene: CHST11 was added gene: CHST11 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: CHST11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHST11 were set to PMID: 26436107; 29514872 Phenotypes for gene: CHST11 were set to Osteochondrodysplasia, brachydactyly, and overlapping malformed digits, MIM# 618167 Review for gene: CHST11 was set to GREEN Added comment: Osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD) is characterized by bilateral symmetric skeletal defects that primarily affect the limbs. Affected individuals have mild short stature due to shortening of the lower leg bones, as well as hand and foot malformations, predominantly brachydactyly and overlapping digits. Other skeletal defects include scoliosis, dislocated patellae and fibulae, and pectus excavatum. Two unrelated families reported, note one had a homozygous deletion. Sources: Expert list |
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| Fetal anomalies v0.4168 | PRDM15 |
Chirag Patel gene: PRDM15 was added gene: PRDM15 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: PRDM15 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRDM15 were set to PMID: 31950080 Phenotypes for gene: PRDM15 were set to Holoprosenephaly; Steroid resistant nephrotic syndrome; Multiple congenital anomalies Review for gene: PRDM15 was set to AMBER Added comment: Four consanguineous families reported with same homozygous variant, C844Y, shown to be LoF. Syndromic HPE including SRNS, brain malformations, polydactyly, congenital heart disease. Mouse model, extensive functional data. Two additional homozygous missense identified with isolated SRNS. Sources: Expert list |
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| Fetal anomalies v0.4165 | RNF113A |
Chirag Patel gene: RNF113A was added gene: RNF113A was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: RNF113A was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: RNF113A were set to PMID: 25612912; 31793730; 31880405 Phenotypes for gene: RNF113A were set to Trichothiodystrophy 5, nonphotosensitive; OMIM #300953 Review for gene: RNF113A was set to GREEN Added comment: Four families reported, two with same variant. Clinical features include ID, microcephaly, IUGR/growth failure, hypogonadism, and sparse/brittle hair. One of the families had antenatal presentation. Sources: Expert list |
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| Fetal anomalies v0.4163 | RAP1B |
Chirag Patel gene: RAP1B was added gene: RAP1B was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RAP1B were set to PMID: 32627184; 26280580 Phenotypes for gene: RAP1B were set to Syndromic intellectual disability; short stature Review for gene: RAP1B was set to GREEN Added comment: Three unrelated individuals reported, Kabuki-like disorder (multiple malformations, microcephaly, learning difficulties, dysmorphism and other features). Sources: Literature |
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| Fetal anomalies v0.4161 | RAD50 |
Chirag Patel gene: RAD50 was added gene: RAD50 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: RAD50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RAD50 were set to PMID: 19409520; 32212377; 33378670 Phenotypes for gene: RAD50 were set to Nijmegen breakage syndrome-like disorder, MIM# 613078; MONDO:0013118 Review for gene: RAD50 was set to GREEN Added comment: Nijmegen breakage syndrome-like disorder (NBSLD) is an autosomal recessive disorder characterized by severe prenatal growth retardation and persistent postnatal growth restriction, congenital microcephaly, borderline to mildly impaired intellectual development, normal sexual development, and radioresistant DNA synthesis with no immunodeficiency, myelodysplasia, or early neurodegeneration. Three unrelated families reported. Sources: Expert list |
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| Fetal anomalies v0.4157 | FRA10AC1 |
Chirag Patel gene: FRA10AC1 was added gene: FRA10AC1 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: FRA10AC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FRA10AC1 were set to PMID: 34694367 Phenotypes for gene: FRA10AC1 were set to Neurodevelopmental disorder, MONDO:0700092, FRA10AC1-related Review for gene: FRA10AC1 was set to GREEN Added comment: 5 individuals from 3 unrelated families reported. Variable ID, possibly related to variant type with LoF variants associated with more severe ID. All individuals had microcephaly, hypoplasia or agenesis of the corpus callosum, growth retardation, and craniofacial dysmorphism. Sources: Expert list |
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| Fetal anomalies v0.4153 | BRD4 |
Chirag Patel gene: BRD4 was added gene: BRD4 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: BRD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BRD4 were set to PMID: 29379197, 30302754, 11997514, 34035299 Phenotypes for gene: BRD4 were set to Cornelia de Lange syndrome (no OMIM# yet) Review for gene: BRD4 was set to GREEN Added comment: Cornelia de Lange syndrome is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Affected individuals have dysmorphic facial features, cleft palate, distal limb defects, prenatal onset growth retardation, and developmental delay. About 1% of patients have mutations in the BRD4 gene. % patients reported with functional evidence. Sources: Expert list |
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| Fetal anomalies v0.4149 | MNS1 |
Chirag Patel gene: MNS1 was added gene: MNS1 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: MNS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MNS1 were set to PMID: 31534215; 30148830 Phenotypes for gene: MNS1 were set to Heterotaxy; male infertility; Heterotaxy, visceral, 9, autosomal, with male infertility 618948 Review for gene: MNS1 was set to GREEN Added comment: Eight families reported altogether. However, four are Amish and share same homozygous founder variant, and some of the other reported families are consanguineous and share another founder. A reported female with a third variant, also had a homozygous variant in DNAH5 with a blended phenotype postulated. Sources: Expert list |
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| Fetal anomalies v0.4145 | CFAP45 |
Chirag Patel gene: CFAP45 was added gene: CFAP45 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: CFAP45 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CFAP45 were set to PMID: 33139725 Phenotypes for gene: CFAP45 were set to Heterotaxy, visceral, 11, autosomal, with male infertility, MIM#619608 Review for gene: CFAP45 was set to GREEN Added comment: Three unrelated individuals reported with bi-alleic LOF variants, mouse model recapitulated phenotype. Sources: Expert list |
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| Fetal anomalies v0.4143 | EDN3 |
Chirag Patel gene: EDN3 was added gene: EDN3 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: EDN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: EDN3 were set to PMID: 8630502; 11303518; 9359047; 10231870; 30171849; 27370713 Phenotypes for gene: EDN3 were set to Central hypoventilation syndrome, congenital, MIM# 209880; Waardenburg syndrome, type 4B, MIM# 613265; {Hirschsprung disease, susceptibility to, 4}, MIM# 613712 Review for gene: EDN3 was set to GREEN Added comment: Variants in this gene have been reported in both isolated HD and syndromic HD, variable penetrance. However, the variants reported in PMID 9359047 with isolated HD are present at high frequencies in gnomad: p.Ala17Thr >800 hets in gnomad, p.Ala224Thr >100 hets. Association with syndromic neural crest disorders is more definitive, and HD is reported in a proportion of individuals. Sources: Expert list |
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| Fetal anomalies v0.4132 | RASGRP2 |
Krithika Murali gene: RASGRP2 was added gene: RASGRP2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: RASGRP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RASGRP2 were set to 28637664; 28726538; 28762304; 30046681; 34066320; 33711653; 33376940; 32609603; 30849270; 30046681 Phenotypes for gene: RASGRP2 were set to ?Bleeding disorder, platelet-type, 18 - MIM#615888 Review for gene: RASGRP2 was set to RED Added comment: Postnatal presentation only with no antenatal features reported. Sources: Literature |
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| 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 v0.4132 | PLEKHM1 |
Krithika Murali gene: PLEKHM1 was added gene: PLEKHM1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PLEKHM1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: PLEKHM1 were set to 17404618; 17997709; 27291868; 27777970; 28290981 Phenotypes for gene: PLEKHM1 were set to ?Osteopetrosis, autosomal recessive 6 - MIM#611497; Osteopetrosis, autosomal dominant 3 - MIM#618107 Review for gene: PLEKHM1 was set to RED Added comment: No antenatal features reported. -- PMID: 17997709 Del Fattore et al 2008 - female proband with monoallelic variant, no antenatal features reported. PMID: 27291868 Bo et al 2016 - male proband with osteopetrosis and heterozygous de novo variant. No antenatal features reported. PMID: 28290981 Moore et al 2017 - compound het variants, osteopetrosis diagnosis in a 19 year old. No antenatal features reported. PMID: 21054159 Almarzooqi et al 2010 - heterozygous variant, infantile osteopetrosis and xanthogranuloma, uncomplicated pregnancy. Sources: Literature |
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| Fetal anomalies v0.4132 | FERMT3 |
Krithika Murali gene: FERMT3 was added gene: FERMT3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FERMT3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FERMT3 were set to 31068971; 34485203; 33391282; 31724816; 30412664; 25854317; 28095295; 26359933; 25072369; 22134107; 20216991; 19234463; 19234460; 18779414 Phenotypes for gene: FERMT3 were set to Leukocyte adhesion deficiency, type III - MIM#612840 Review for gene: FERMT3 was set to RED Added comment: Biallelic variants associated with LAD3 syndrome (primary immunodeficiency and platelet function defects). Symptom onset reported from birth, no antenatal features reported. --- PMID: 34485203 Yahya et al 2021 - no antenatal issues reported PMID: 33391282 Kambli et al 2020 - no antenatal features reported for 5 individuals with LAD3 PMID 31068971 Shahid et al 2019 - no antenatal features PMID: 31724816 Manukjan et al 2019 - no antenatal issues reported in 1 affected individual PMID: 28095295 Palagano et al 2017 - report female proband with infantile-onset osteopetrosis and symptomatic haematological anomalies at birth requiring bone marrow transplant. Authors postulate in utero onset but no antenatal features reported. PMID: 26359933 Suratannon et al 2016 - report a female Thai proband with a milder/atypical phenotype, no antenatal features reported PMID: 25854317 Crazzolara et al 2015 - presented D7 of life with infection, bleeeding issues and noted radiologically to have dense bones. No antenatal features. PMID: 25072369 Stepensky et al 2015 - report 3 individuals with bleeding tendency from birth and onset of recurrent infections as an infant, normal antenatal history. PMID: 20357244 McDowall et al 2010 - symptom onset from birth, no antenatal features PMID: 20216991 Jurk et al 2010 - 2 affected siblings, no antenatal features reported. PMID: 19234463 Svensson et al 2009 - no antenatal features reported PMID: 19234460 Malinin et al 2009 - no antenatal features reported PMID: 19064721 Kuijpers et al 2009 - 9 individuals from 7 unrelated families, no antenatal features reported. Sources: Literature |
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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 v0.4122 | SPRED1 |
Zornitza Stark changed review comment from: Multiple affected individuals reported, deletions account for ~10% of causative variants. Legius syndrome is characterised by multiple cafe-au-lait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism or macrocephaly, lipomas, and mild learning disabilities or attention problems. It is not associated with neurofibromas, optic gliomas, Lisch nodules, or tumor predisposition. The SPRED1 gene encodes a negative regulator of the RAS-MAPK pathway, similar to neurofibromin.; to: Multiple affected individuals reported, deletions account for ~10% of causative variants. Legius syndrome is characterised by multiple cafe-au-lait spots, sometimes associated with skin fold freckling, variable dysmorphic features such as hypertelorism or macrocephaly, lipomas, and mild learning disabilities or attention problems. It is not associated with neurofibromas, optic gliomas, Lisch nodules, or tumor predisposition. The SPRED1 gene encodes a negative regulator of the RAS-MAPK pathway, similar to neurofibromin. Clinical presentation is typically post-natal. |
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| Fetal anomalies v0.4109 | SUMF1 |
Zornitza Stark changed review comment from: Single case report found of hydrops in this metabolic condition. Sources: Expert list; to: Single case report found of hydrops in this metabolic condition. Hydrocephalus and structural brain abnormalities reported. Sources: Expert list |
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| Fetal anomalies v0.4106 | SUZ12 | Zornitza Stark changed review comment from: Thirteen individuals from 12 families.; to: Thirteen individuals from 12 families. Overgrowth of prenatal onset, brain abnormalities reported in some. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4074 | TFAP2B |
Zornitza Stark changed review comment from: PDA, facial dysmorphism and clinodactyly unlikely to be detectable antenatally.; to: Char syndrome: PDA, facial dysmorphism and clinodactyly unlikely to be detectable antenatally. Craniosynostosis: Four individuals reported in PMID: 31292255 (Correction in PMID: 31405973) as part of a craniosynostosis cohort: 2 de novo and 2 inherited. There is evidence for reduced penetrance as in one case the variant was inherited from an unaffected parent (affected parent for the other inherited variant). |
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| Fetal anomalies v0.4039 | TRAPPC9 | Zornitza Stark changed review comment from: Note multiple intragenic CNVs reported for this gene.; to: Note multiple intragenic CNVs reported for this gene. Cleft lip and brain abnormalities reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4010 | UBE3B | Zornitza Stark changed review comment from: Intellectual disability, microcephaly, dysmorphic features, including blepharophimosis and ptosis. Over 20 families reported.; to: Intellectual disability, microcephaly, dysmorphic features, including blepharophimosis and ptosis. Congenital heart disease. Over 20 families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3994 | WDR19 | Zornitza Stark changed review comment from: Variants in this gene are associated with a range of ciliopathies. Two families reported with a predominantly skeletal phenotype.; to: Variants in this gene are associated with a range of ciliopathies. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3984 | XPA | Zornitza Stark changed review comment from: Multiple families reported where ID is part of the phenotype, though some share haplotype and are likely distantly related.; to: Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3970 | UPF3B | Zornitza Stark changed review comment from: Well established gene-disease association, more than 7 families reported, mouse model and other functional data.; to: Well established gene-disease association, more than 7 families reported, mouse model and other functional data. Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3958 | TUSC3 | Zornitza Stark changed review comment from: More than 5 unrelated families reported, note homozygous deletions in at least two.; to: More than 5 unrelated families reported, note homozygous deletions in at least two. Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3951 | TGFB1 |
Zornitza Stark changed review comment from: Three individuals from two unrelated families reported. DD/ID and seizures in addition to IBD/immunodeficiency. Sources: Expert list; to: Three individuals from two unrelated families reported. DD/ID and seizures in addition to IBD/immunodeficiency, clinical presentation is typically post-natal. |
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| Fetal anomalies v0.3938 | SLC9A6 | Zornitza Stark changed review comment from: Angelman-like disorder. ID, seizures, microcephaly. More than 20 unrelated families reported, functional data including mouse model.; to: Angelman-like disorder. ID, seizures, microcephaly. More than 20 unrelated families reported, functional data including mouse model. Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3934 | SLC37A4 |
Zornitza Stark changed review comment from: Bi-allelic LOF variants in this gene cause glycogen storage disorder. Single individual reported with heterozygous de novo variant in this gene. Clinical features included dysmorphic features (low set ears, a broad nose, mandibular micrognathia and facial asymmetry) and hepatopathy. The variant abolishes the ER retention signal of the transporter and generates a weak Golgi retention signal. Intracellular mislocalization of the transporter is postulated to lead to a congenital disorder of glycosylation instead of glycogen storage disease. Sources: Literature; to: Bi-allelic LOF variants in this gene cause glycogen storage disorder. Clinical presentation is typically post-natal. Single individual reported with heterozygous de novo variant in this gene. Clinical features included dysmorphic features (low set ears, a broad nose, mandibular micrognathia and facial asymmetry) and hepatopathy. The variant abolishes the ER retention signal of the transporter and generates a weak Golgi retention signal. Intracellular mislocalization of the transporter is postulated to lead to a congenital disorder of glycosylation instead of glycogen storage disease. Sources: Literature |
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| Fetal anomalies v0.3923 | SDHAF1 | Zornitza Stark changed review comment from: More than 5 families reported, functional data. Presentation is typically with leukoencephalopathy.; to: More than 5 families reported, functional data. Presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3916 | PURA |
Zornitza Stark changed review comment from: Multiple individuals reported with de novo variants in this gene and severe ID, hypotonia, apnoea, seizures.; to: Multiple individuals reported with de novo variants in this gene and severe ID, hypotonia, apnoea, seizures. Typically presents post-natally, but congenital heart disease reported in some. |
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| Fetal anomalies v0.3915 | ALB |
Krithika Murali gene: ALB was added gene: ALB was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ALB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ALB were set to 23730173; 15300429; 31057599 Phenotypes for gene: ALB were set to Analbuminemia- MIM#616000 Review for gene: ALB was set to GREEN Added comment: Biallelic variants associated with congenital analbuminaemia. Prenatal features include IUGR and oligohydramnios. Allelic condition OMIM# 615999 Mono-allelic disease and dysalbuminemic hyperthyroxinemia: gain-of-function mechanism, missense variants of ALB with increased affinity for thyroid hormones. Immunoassay methods may show variably elevated free thyroid hormone levels. Individuals are euthyroid and identification is important to avoid unnecessary medical or surgical treatment. Sources: Literature |
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| Fetal anomalies v0.3908 | MAPK1 |
Krithika Murali gene: MAPK1 was added gene: MAPK1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAPK1 were set to 32721402 Phenotypes for gene: MAPK1 were set to Noonan syndrome 13 - MIM#619087 Review for gene: MAPK1 was set to GREEN Added comment: Associated with Noonan syndrome including congenital heart defects. No new publications since last PanelApp review Aug 2020 -- Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants. The phenotype corresponded to a neurodevelopmental disorder and - as the authors comment - consistently included DD, ID , behavioral problems. Postnatal growth delay was observed in approximately half. Hypertelorism, ptosis, downslant of palpebral fissures, wide nasal bridge as low-set/posteriorly rotated ears were among the facial features observed (each in 3 or more subjects within this cohort). Together with short/webbed neck and abnormalities of skin (lentigines / CAL spots) and growth delay these led to clinical suspicion of Noonan s. or disorder of the same pathway in some. Congenital heart defects (ASD, mitral valve insufficiency, though not cardiomyopathy) occurred in 4/7. Bleeding diathesis and lymphedema were reported only once. MAPK1 encodes the mitogen-activated protein kinase 1 (also known as ERK2) a serine/threonine kinase of the RAS-RAF-MEK-(MAPK/)ERK pathway. MAPK1 de novo variants were identified in all individuals following trio exome sequencing (and extensive previous genetic investigations which were non-diagnostic). The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome). Sources: Literature |
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| 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 v0.3908 | PDIA6 |
Krithika Murali gene: PDIA6 was added gene: PDIA6 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PDIA6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDIA6 were set to 33495992 Phenotypes for gene: PDIA6 were set to Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes Review for gene: PDIA6 was set to AMBER Added comment: No new publications since last PanelApp review. Single case upgraded to Amber on the basis of functional data --- 1 case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage‐dependent manner, supporting a loss‐of‐function effect of this variant. Phenotypic correlation with the previously reported mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. The phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans. Sources: Literature |
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| Fetal anomalies v0.3908 | GRK2 |
Krithika Murali gene: GRK2 was added gene: GRK2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: GRK2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GRK2 were set to 33200460 Phenotypes for gene: GRK2 were set to Jeune asphyxiating thoracic dystrophy (ATD) Review for gene: GRK2 was set to AMBER Added comment: 2 unrelated families from a single study reported with supportive functional evidence. Sources: Literature |
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| Fetal anomalies v0.3906 | SCN1A | Zornitza Stark changed review comment from: Arthrogryposis reported.; to: Arthrogryposis and malformations of cortical development reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3905 | SCN1A | Zornitza Stark edited their review of gene: SCN1A: Added comment: Arthrogryposis reported.; Changed publications: 33820833 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3898 | PTEN | Zornitza Stark changed review comment from: More than 10 individuals reported with PMG.; to: More than 10 individuals reported with PMG, otherwise clinical presentation is generally post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3860 | POLG |
Zornitza Stark changed review comment from: Cataracts are described in individuals with bi-allelic and mono-allelic POLG variants. Fetal presentation with cerebellar abnormalities reported PMID 29574624.; to: Cataracts are described in individuals with bi-allelic and mono-allelic POLG variants, though onset may be later. Fetal presentation with cerebellar abnormalities reported PMID 29574624. |
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| Fetal anomalies v0.3860 | POLG |
Zornitza Stark changed review comment from: Cataracts are described in individuals with bi-allelic and mono-allelic POLG variants.; to: Cataracts are described in individuals with bi-allelic and mono-allelic POLG variants. Fetal presentation with cerebellar abnormalities reported PMID 29574624. |
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| Fetal anomalies v0.3856 | POLD1 | Zornitza Stark edited their review of gene: POLD1: Added comment: Four unrelated individuals with deletion of ser605 residue reported. Mandibular hypoplasia would be identifiable antenatally.; Changed rating: GREEN; Changed publications: 23770608; Changed phenotypes: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome 615381; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3853 | PDHB | Zornitza Stark edited their review of gene: PDHB: Added comment: Fetal presentation at 22 weeks reported with intrauterine growth retardation, short corpus callosum, ventricular dilation, and cerebellar hypoplasia, PMID 26865159.; Changed publications: 15138885, 26014431, 26865159 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3850 | NT5C2 | Zornitza Stark changed review comment from: ID and CC abnormalities are associated variable features. Nine unrelated families reported, ID reported in >3.; to: ID and CC abnormalities are associated variable features. Nine unrelated families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3845 | NGLY1 |
Zornitza Stark changed review comment from: Over 20 affected individuals reported with bi-allelic variants in this gene. Rat model.; to: Over 20 affected individuals reported with bi-allelic variants in this gene. Rat model. Clinical presentation is typically post-natal with predominantly neurological features. |
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| Fetal anomalies v0.3834 | MYT1L | Zornitza Stark changed review comment from: Over 50 individuals reported with deletions and SNVs affecting MYT1L, and variable phenotype comprising intellectual disability, obesity, and behavioral problems.; to: Over 50 individuals reported with deletions and SNVs affecting MYT1L, and variable phenotype comprising intellectual disability, obesity, and behavioral problems. Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3825 | 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 v0.3756 | TPO |
Krithika Murali gene: TPO was added gene: TPO was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TPO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TPO were set to 34220711; 30662777 Phenotypes for gene: TPO were set to Thyroid dyshormonogenesis 2A - MIM#274500 Review for gene: TPO was set to GREEN Added comment: Well-established association with thyroid dyshormonogenesis. 3 affected individuals from 2 unrelated families reported with fetal goitre. 34220711 Rodrigues et al 2021 - report 2 siblings who were diagnosed with fetal goitre on antenatal ultrasound at 26 and 32 weeks gestation. Pathogenic compound het TPO variants identified inherited from unaffected carrier parents. 30662777 - report a proband diagnosed with fetal goitre at 29 weeks gestation. Compound heterozygous TPO variants identified. Sources: Literature |
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| Fetal anomalies v0.3726 | THRB |
Krithika Murali gene: THRB was added gene: THRB was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: THRB was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: THRB were set to 35130567; 30430796; 30074255; 28938413; 4163616 Phenotypes for gene: THRB were set to Thyroid hormone resistance, autosomal recessive - MIM#274300; Thyroid hormone resistance - MIM#188570; Thyroid hormone resistance, selective pituitary - MIM#145650 Review for gene: THRB was set to GREEN Added comment: Biallelic variants associated with thyroid hormone resistance. PMID 4163616 first reported this condition in a consanguineous Mexican family with congenital deafness, goitre and stippled epiphyses. Diagnosis was made incidentally at a later age but possibility of goitre being detected antenatally. SGA also reported but this is generally in the context of having a mother also affected by thyroid hormone resistance secondary to biallelic or monoallelic variants. Sources: Literature |
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| Fetal anomalies v0.3722 | TBL1X |
Krithika Murali gene: TBL1X was added gene: TBL1X was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TBL1X 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: TBL1X were set to 30591955; 27603907 Phenotypes for gene: TBL1X were set to Hypothyroidism, congenital, nongoitrous, 8 - MIM#301033 Review for gene: TBL1X was set to AMBER Added comment: Associated with central congenital hypothyroidism. Antenatal phenotype not reported. Thyroid hypoplasia has been noted in affected individuals. Generally diagnosed after newborn screening or later in childhood. Sources: Literature |
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| Fetal anomalies v0.3722 | SLC5A5 |
Krithika Murali gene: SLC5A5 was added gene: SLC5A5 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SLC5A5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC5A5 were set to 34806438; 34726525; 33815280; 32805706; 31115276 Phenotypes for gene: SLC5A5 were set to Thyroid dyshormonogenesis 1 - MIM#274400 Review for gene: SLC5A5 was set to GREEN Added comment: Biallelic variants associated with congenital hypothyroidism. PMID 32805706 Stoupa et al 2020 report an affected male with antenatal goitre diagnosed at 25 weeks gestation and treated with intraamniotic levothyroxine injections. Sources: Literature |
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| Fetal anomalies v0.3721 | SLC26A7 |
Krithika Murali gene: SLC26A7 was added gene: SLC26A7 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SLC26A7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC26A7 were set to 34780050; 32486989; 31372509; 30333321; 29546359 Phenotypes for gene: SLC26A7 were set to Thyroid dyshormogenesis - no OMIM gene disease association Review for gene: SLC26A7 was set to GREEN Added comment: Biallelic variants associated with congenital hypothyroidism secondary to thyroid dyshormogenesis. PMID 32486989 report an affected female diagnosed with goitre D4 of life. Sources: Literature |
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| Fetal anomalies v0.3721 | SLC26A4 |
Krithika Murali gene: SLC26A4 was added gene: SLC26A4 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SLC26A4 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SLC26A4 were set to Pendred syndrome - MIM#274600 Review for gene: SLC26A4 was set to AMBER Added comment: Known association with congenital hypothyroidism and bilateral sensorineural hearing loss. If goitre present, manifests later in childhood. No antenatal phenotype reported. Sources: Literature |
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| Fetal anomalies v0.3721 | PROP1 |
Krithika Murali gene: PROP1 was added gene: PROP1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PROP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PROP1 were set to 15941866; 11549703; 20301521; 32415500 Phenotypes for gene: PROP1 were set to Pituitary hormone deficiency, combined, 2- #262600 Review for gene: PROP1 was set to AMBER Added comment: Biallelic variants associated with panhypopituitarism. Features include central congenital hypothyroidism and hypogonadotrophic hypogonadism including micropenis. Diagnosed postnatally in infancy or early childhood due to growth failure and failure to thrive. Antenatal diagnosis not reported, although severe micropenis due to other disorders has been detected antenatally. Sources: Literature |
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| Fetal anomalies v0.3718 | KMT2E |
Zornitza Stark changed review comment from: 38 individuals from 36 families reported. Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. Additional common features include autism, macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. The four individuals with missense variants presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E postulated to explain this divergence in phenotype.; to: Micro/macrocephaly reported, see below, age of onset uncertain. Non-specific brain abnormalities also. 38 individuals from 36 families reported. Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. Additional common features include autism, macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. The four individuals with missense variants presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E postulated to explain this divergence in phenotype. |
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| Fetal anomalies v0.3715 | KCNQ3 | Zornitza Stark changed review comment from: Intellectual disability has been reported as a feature.; to: Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3709 | NKX2-1 |
Krithika Murali gene: NKX2-1 was added gene: NKX2-1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: NKX2-1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NKX2-1 were set to 23911641; 11854319; 24714694 Phenotypes for gene: NKX2-1 were set to Choreoathetosis, hypothyroidism, and neonatal respiratory distress - MIM#610978 Review for gene: NKX2-1 was set to GREEN Added comment: Heterozygous variants associated with congenital hypothyroidism, choreathetosis with or without pulmonary dysfunction. Allelic disorder to benign hereditary chorea (118700), which is less severe. Hypoplasia of the thyroid reported in some individuals. OMIM also reports septal heart defects noted in some patients. Sources: Literature |
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| Fetal anomalies v0.3709 | IYD |
Krithika Murali gene: IYD was added gene: IYD was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: IYD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IYD were set to 18434651; 18765512; 838849; 14169503 Phenotypes for gene: IYD were set to Thyroid dyshormonogenesis 4 - MIM#274800 Review for gene: IYD was set to GREEN Added comment: Known association with congenital hypothyroidism secondary to thyroid dyshormonogenesis. Although antenatal diagnosis not reported, goitre known phenotypic feature. Sources: Literature |
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| Fetal anomalies v0.3709 | IRS4 | Krithika Murali edited their review of gene: IRS4: Added comment: Associated with isolated central congenital hypothyroidism (insufficient pituitary TSH production). Postnatal diagnosis with no prenatal features reported. Small thyroid gland is a late postnatal phenotypic feature.; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3709 | IRS4 |
Krithika Murali gene: IRS4 was added gene: IRS4 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: IRS4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: IRS4 were set to 34566885; 34225927; 34093435; 33107432; 30061370 Phenotypes for gene: IRS4 were set to Hypothyroidism, congenital, nongoitrous, 9- MIM#301035 Review for gene: IRS4 was set to RED Added comment: Associated with isolated central congenital hypothyroidism (insufficient pituitary TSH production). Postnatal diagnosis with no prenatal features reported. Sources: Literature |
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| Fetal anomalies v0.3709 | DUOX1 |
Krithika Murali gene: DUOX1 was added gene: DUOX1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: DUOX1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: DUOX1 were set to 29650690; 34019632 Phenotypes for gene: DUOX1 were set to congenital hypothyroidism, No OMIM # Review for gene: DUOX1 was set to AMBER Added comment: Gene reviewed for PanelApp in Feb 2021 - "11 cases, but digenic model, with variants in other genes". No further case reports published since. PMID 34019632 provide evidence of recapitulation of congenital hypothyroidism phenotype in duox mutant zebrafish. Sources: Literature |
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| Fetal anomalies v0.3709 | NPRL3 |
Krithika Murali gene: NPRL3 was added gene: NPRL3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: NPRL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NPRL3 were set to 27173016; 26285051; 33461085 Phenotypes for gene: NPRL3 were set to Epilepsy, familial focal, with variable foci 3- MIM#617118 Review for gene: NPRL3 was set to GREEN Added comment: Known association with focal epilepsy (variable penetrance) with focal cortical dysplasia being a reported feature. FCD has the potential to be detected prenatally. Sources: Literature |
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| Fetal anomalies v0.3708 | ITGA7 | Zornitza Stark changed review comment from: Primarily a muscle phenotype, accompanied by gross motor delay as expected. One out of 3 reported individuals had intellectual disability.; to: Primarily a muscle phenotype, typically presents post-natally. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3706 | IQSEC2 | Zornitza Stark changed review comment from: More than 20 unrelated families reported.; to: More than 20 unrelated families reported. Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3697 | HECW2 |
Zornitza Stark changed review comment from: Typically denovo missense variants in the HECT domain. PMID: 29807643 - R1191Q single case with severe D/ID, EE and regression PMID: 29395664 - single case with regression, loss of swallowing, increased abnormal movements/hand stereotypies, Rett like, cortical visual impairment and EE PMID: 27334371 - propose GOF or dominant negative; 1 case plus references 5 previous cases PMID: 27389779 - four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. p. Arg1330Trp, p.Glu1445Gly reported >1 case. Regression reported in the context of refractory EE; to: Clinical presentation is typically post-natal. Typically denovo missense variants in the HECT domain. PMID: 29807643 - R1191Q single case with severe D/ID, EE and regression PMID: 29395664 - single case with regression, loss of swallowing, increased abnormal movements/hand stereotypies, Rett like, cortical visual impairment and EE PMID: 27334371 - propose GOF or dominant negative; 1 case plus references 5 previous cases PMID: 27389779 - four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. p. Arg1330Trp, p.Glu1445Gly reported >1 case. Regression reported in the context of refractory EE |
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| Fetal anomalies v0.3693 | HDAC4 |
Zornitza Stark changed review comment from: Contradictory evidence: deletions linked to brachydactyly-MR but note some individuals reported without MR. Only two reports of intragenic variants (still structural rather than SNVs).; to: Contradictory evidence: deletions linked to brachydactyly-MR but note some individuals reported without MR. Only two reports of intragenic variants (still structural rather than SNVs). Subtle brain abnormalities, hip dislocation reported in PMID 33537682. |
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| Fetal anomalies v0.3685 | H3F3A | Zornitza Stark changed review comment from: 33 unrelated individuals reported with missense variants in H3F3A. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.; to: 33 unrelated individuals reported with missense variants in H3F3A. Phenotype primarily comprised intellectual disability and minor congenital anomalies, including micro/macrocephaly, craniosynostosis, contractures, congenital heart disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3681 | GRIN2A |
Zornitza Stark changed review comment from: Large cohort of 248 individuals reported in PMID: 30544257: The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. Pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes. Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function.; to: Large cohort of 248 individuals reported in PMID: 30544257: The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. Pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes. Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. Clinical presentation is typically postnatal. |
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| Fetal anomalies v0.3660 | GATM |
Zornitza Stark changed review comment from: Bi-allelic variants cause a disorder characterized by developmental delay/regression, intellectual disability, severe disturbance of expressive and cognitive speech, and severe depletion of creatine/phosphocreatine in the brain. At least four unrelated families reported.; to: Bi-allelic variants cause a disorder characterized by developmental delay/regression, intellectual disability, severe disturbance of expressive and cognitive speech, and severe depletion of creatine/phosphocreatine in the brain. At least four unrelated families reported. Clinical presentation is typically post-natal. |
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| Fetal anomalies v0.3643 | FOXP1 |
Zornitza Stark changed review comment from: Single individual reported as part of a CDH cohort. Sources: Literature; to: Single individual reported as part of a CDH cohort. Otherwise clinical presentation is typically post-natal. Sources: Literature |
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| Fetal anomalies v0.3619 | DLG3 | Zornitza Stark changed review comment from: At least 6 unrelated families reported. Some females have mild symptoms.; to: At least 6 unrelated families reported. Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3617 | DLAT | Zornitza Stark changed review comment from: Only two families with ID reported; third individual had paroxysmal dyskinesia.; to: Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3610 | ST3GAL5 |
Zornitza Stark changed review comment from: Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterised by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss. Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood. Although initially reported in the Amish (founder variant p.Arg288Ter), families from other ethnicities have also been reported.; to: Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterised by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss. Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood. Although initially reported in the Amish (founder variant p.Arg288Ter), families from other ethnicities have also been reported. Clinical presentation is typically post-natal. |
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| Fetal anomalies v0.3608 | RSPRY1 |
Zornitza Stark changed review comment from: Two unrelated individuals reported, some functional evidence. Dev delay/autism part of the phenotype. Sources: Expert list; to: Two unrelated individuals reported, some functional evidence. Multiple skeletal anomalies. Sources: Expert list |
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| Fetal anomalies v0.3580 | RPL10 |
Zornitza Stark changed review comment from: At least three families reported. Progressive microcephaly, up to -9.6 SD described. Sources: Expert list; to: At least three families reported. Progressive microcephaly, up to -9.6 SD described. IUGR, congenital heart disease. Sources: Expert list |
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| Fetal anomalies v0.3575 | RORA |
Zornitza Stark changed review comment from: Eleven unrelated individuals with de novo variants in this gene; postulated that some variants exert dominant-negative effect resulting in a more severe phenotype than the LoF variants. Sources: Expert list; to: Eleven unrelated individuals with de novo variants in this gene; postulated that some variants exert dominant-negative effect resulting in a more severe phenotype than the LoF variants. Clinical presentation is generally post-natal, but pontocerebellar hypoplasia rarely reported. Sources: Expert list |
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| Fetal anomalies v0.3564 | RIN2 | Zornitza Stark changed review comment from: Macrocephaly, subcortical cysts and other brain abnormalities are a feature.; to: Macrocephaly, subcortical cysts and other brain abnormalities are a feature. More than 5 unrelated families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3563 | RFT1 |
Zornitza Stark changed review comment from: Bi-allelic variants are associated with DD/ID, seizures, deafness. More than 10 unrelated families reported.; to: Bi-allelic variants are associated with DD/ID, seizures, deafness. More than 10 unrelated families reported. Clinical presentation is typically post-natal, though age of onset of microcephaly is uncertain. |
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| Fetal anomalies v0.3551 | RAD51 |
Zornitza Stark changed review comment from: Three unrelated individuals reported with de novo variants in this gene and FA phenotype. However, only one had radial ray abnormalities. Sources: Expert Review; to: Three unrelated individuals reported with de novo variants in this gene and FA phenotype. Sources: Expert Review |
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| Fetal anomalies v0.3544 | RAB11A |
Zornitza Stark changed review comment from: Five individuals reported with DNMs and neurodevelopmental phenotypes as part of this paper; however, clinical details are sparse. Emerging gene, phenotype not yet clearly delineated. Sources: Literature; to: Five individuals reported with DNMs and neurodevelopmental phenotypes as part of this paper; however, clinical details are sparse. Emerging gene, phenotype not yet clearly delineated. Clinical presentation is post-natal. Sources: Literature |
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| Fetal anomalies v0.3541 | WNT9B |
Krithika Murali gene: WNT9B was added gene: WNT9B was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: WNT9B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WNT9B were set to 34145744 Phenotypes for gene: WNT9B were set to Renal agenesis/hypoplasia/dysplasia, no OMIM # Review for gene: WNT9B was set to AMBER Added comment: Now new publications since last PanelApp review Sept 2021 --- WNT9B plays a key role in the development of the mammalian urogenital system. It is essential for the induction of mesonephric and metanephric tubules, the regulation of renal tubule morphogenesis, and the regulation of renal progenitor cell expansion and differentiation. WNT9B−/− mice have renal agenesis/hypoplasia and reproductive tract abnormalities. Lemire et al. (2021) report 4 individuals from 2 unrelated consanguineous families with bilateral renal agenesis/hypoplasia/dysplasia and homozygous variants in WNT9B. The proband from Family 1 had bilateral renal cystic dysplasia and chronic kidney disease, with 2 deceased siblings with bilateral renal hypoplasia/agenesis. The 3 affected family members were homozygous for a Gly317Arg missense variant in WNT9B. Proband from Family 2 had renal hypoplasia/dysplasia, chronic kidney disease, and was homozygous for a Pro5Alafs*52 nonsense variant in WNT9B. The proband's unaffected brother is also homozygous for the nonsense variant in WNT9B, suggesting nonpenetrance. Sources: Literature |
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| Fetal anomalies v0.3508 | SRGAP1 |
Krithika Murali gene: SRGAP1 was added gene: SRGAP1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SRGAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SRGAP1 were set to 26026792 Phenotypes for gene: SRGAP1 were set to congenital anomalies of the kidney and urinary tract Review for gene: SRGAP1 was set to AMBER Added comment: PMID 26026792 Hwang et al report 2 unrelated families with heterozygous SRGAP1 variants. - Family 1 - proband with prenatally diagnosed multicystic dysplastic kidney, affected mother with right duplex kidney - Family 2 - proband with horseshoe kidney with a multicystic dysplastic right upper pole. Variant paternally inherited, father not available for renal ultrasound Supportive mouse models Sources: Literature |
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| Fetal anomalies v0.3505 | TMCO1 |
Zornitza Stark changed review comment from: Multiple families reported. Although some have the same recurrent founder variants, sufficient number of families from different ethnicities and with different variants reported for Green rating.; to: Multiple families reported. Although some have the same recurrent founder variants, sufficient number of families from different ethnicities and with different variants reported for Green rating. Skeletal abnormalities are pertinent to this panel. |
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| Fetal anomalies v0.3505 | TPM3 | Zornitza Stark Phenotypes for gene: TPM3 were changed from Congenital fiber-type disproportion myopathy 255310 to Myopathy, congenital, with fiber-type disproportion, MIM# 255310 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3504 | TPM3 | Zornitza Stark reviewed gene: TPM3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Myopathy, congenital, with fiber-type disproportion, MIM# 255310; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3502 | SLIT2 |
Krithika Murali gene: SLIT2 was added gene: SLIT2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SLIT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLIT2 were set to 26026792; 15130495 Phenotypes for gene: SLIT2 were set to CAKUT; vesicoureteric reflux Review for gene: SLIT2 was set to AMBER Added comment: PMID 26026792 Hwang et al 2019 - identified three unrelated individuals with CAKUT and different heterozygous SLIT2 missense mutations. - 1 patient presented with multiple bilateral subcortical renal cysts - 1 patient presented with multicystic dysplastic kidneys - 1 patient had right renal agenesis Authors provide supportive variant-specific mouse models. PMID: 34059960 Liu et al 2021 - 3 unrelated children from a Chinese Kidney Disease Database with vesicoureteric reflux had SLIT3 VUS identified PMID 19350278 Zu et al 2009 - x2 unrelated individuals with SLIT2 variants - not segregating with disease in either family Sources: Literature |
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| 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 v0.3491 | NDUFA10 | Zornitza Stark changed review comment from: Two families, functional data, but phenotypic description only available for one, IUGR reported.; to: Two families, functional data, IUGR reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3491 | NDUFA10 | Zornitza Stark changed review comment from: Two families, functional data, but phenotypic description only available for one (DD/ID part of the phenotype).; to: Two families, functional data, but phenotypic description only available for one, IUGR reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3484 | SEMA3A |
Krithika Murali gene: SEMA3A was added gene: SEMA3A was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SEMA3A was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: SEMA3A were set to 28075028; 33369061; 20301509; 21059704; 24124006; 22927827 Phenotypes for gene: SEMA3A were set to {Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897; congenital heart disease Review for gene: SEMA3A was set to GREEN Added comment: Heterozygous variants associated with isolated GnRH deficiency with or without anosmia (Kallman syndrome like). Anomalies such as unilateral renal aplasia which can be detected antenatally reported with Kallman syndrome but not published with heterozygous SEMA3A variants. More severe phenotype with biallelic SEMA3A variants reported with features detectable antenatally. PMID 33369061 Gileta et al 2021 - report x1 patient. Female proband was compound heterozygote for a nonsense variant and a multiexonic deletion of SEMA3A. Presents with postnatal short stature, congenital cardiac anomalies, dysmorphic features, hypogonadotrophic hypogonadism and anosmia. PMID 28075028 Baumann et al 2017 - report x1 patient. Homozygous LoF variants identified in a proband from a consanguineous Turkish family. Noted at birth to have a high-positioned scapulae, deformed ribs and a lateral clavicular hook. The patient also had upper/lower limb contractures and aberrant right subclavian artery. Mild facial dysmorphism, micropenis and hypogonadotrophic hypogonadism also noted in the first week of life. Postnatal short stature (length 50cm at term birth) PMID 24124006 Hofmann et al 2013 - first reported biallelic variants in a proband with postnatal short stature, skeletal anomalies of the thorax, congenital heart defect and camptodactyly Sources: Literature |
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| Fetal anomalies v0.3464 | HOXB6 |
Krithika Murali gene: HOXB6 was added gene: HOXB6 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: HOXB6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HOXB6 were set to 17003840; 22371315 Phenotypes for gene: HOXB6 were set to Hypospadias Review for gene: HOXB6 was set to RED Added comment: PMID 17003840 Chen et al 2007 report 2 babies with hypospadias and heterozygous HOXB6 variants. Cohort of 90 unrelated Chinese patients with hypospadias and 380 controls. x1 patient - heterozygous, maternally inherited HOXB6 c.124C>A p.P42T in a child with scrotal, micropenis, bifid scrotum, cryptorchidism. Baby also has maternally inherited SRD5A2 and de novo MID1 variant. The HOXB6 variant is absent from gnomad v2, v3, not previously reported in ClinVar, minor GS change (38), moderately conserved (change in non-placental mammals), not in a region of missense constraint. x1 patient - penile hypospadias, heterozygous HOXB6 c.367T>C p.C123R. No segregation information. 5 hets (East Asian, gnomad v2), 2 hets (East Asian, gnomad v3). GS 180, conserved in mammals (changed in birds), not in a region of missense constraint, not previously reported in ClinVar, predicted to escape NMD. x2 patients with hypospadias from a single study, variants of uncertain significance. Sources: Literature |
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| Fetal anomalies v0.3413 | COQ7 |
Krithika Murali gene: COQ7 was added gene: COQ7 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: COQ7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COQ7 were set to 33215859; 28125198; 31240163; 28409910; 26084283 Phenotypes for gene: COQ7 were set to Coenzyme Q10 deficiency, primary, 8 - MIM#616733 Review for gene: COQ7 was set to GREEN Added comment: Biallelic variants associated with primary coenzyme Q10 (CoQ10) deficiency, a heterogeneous multi-system disorder including early-postnatal features such as neonatal encephalopathy, contractures. Antenatal features reported include IUGR, oligohydramnios, feetal lung hypoplasia, dysplastic kidneys. Specifically for COQ7-related CoQ10 deficiency: PMID 33215859 Hashemi et al 2020 - report two affected individuals from a consanguineous Iranian family with homozygous COQ7 variants progressive spastic paraparesis diagnosed at age 1.5-2 with normal antenatal history. PMID 31240163 Kwong et al 2019 - report a patient with compound hetereozygous COQ7 variants, encephalo‐myo‐nephro‐cardiopathy, persistent lactic acidosis, and basal ganglia lesions resulting in early infantile death. Skin fibroblast studies showed decreased combined complex II + III activity and reduction in CoQ10 level. The proband was a DCDA twin, noted to have IUGR, oligohydramnios, cardiomegaly and tricuspid regurgitation antenatally. PMID 28409910 Wang et al 2017 - no antenatal features reported in their proband PMID 26084283 Freyer et al 2015 - report x1 patient with homozygous COQ7 variant. The pregnancy was complicated by oligohydramniosis, fetal lung hypoplasia and growth retardation. Sources: Literature |
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| Fetal anomalies v0.3400 | TLK2 |
Krithika Murali gene: TLK2 was added gene: TLK2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TLK2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: TLK2 were set to 29861108; 31558842; 34821460 Phenotypes for gene: TLK2 were set to Intellectual developmental disorder, autosomal dominant 57 - MIM#618050 Review for gene: TLK2 was set to GREEN Added comment: Associated with syndromic ID. Potential to detect reported phenotypic features of microcephaly, IUGR, craniosynostosis (rare) antenatally. Sources: Literature |
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| Fetal anomalies v0.3400 | STAT3 |
Krithika Murali gene: STAT3 was added gene: STAT3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: STAT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: STAT3 were set to 30617622; 31771449; 34366294 Phenotypes for gene: STAT3 were set to Hyper-IgE recurrent infection syndrome - MIM#147060; Autoimmune disease, multisystem, infantile-onset, 1 - MIM#615952 Added comment: Well known association with Hyper IgE syndrome and multisystem autoimmune disease. Early post-natal diagnosis reported. Prenatally detectable features include craniosynostosis and IUGR. 31771449 Terry et al 2020 report a baby with a de novo heterozygous likely pathogenic STAT3 variant. Severe IUGR and oligohydramnios was noted on USS at 21 weeks gestation. Sources: Literature |
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| Fetal anomalies v0.3400 | PJA1 |
Krithika Murali gene: PJA1 was added gene: PJA1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PJA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: PJA1 were set to 32530565 Phenotypes for gene: PJA1 were set to Trigonocephaly, intellectual disability Review for gene: PJA1 was set to AMBER Added comment: No new publications since last PanelApp review August 2020 -- Recurrent variant, p.Arg376Cys, reported in 7 Japanese individuals, supportive mouse model. Individuals shared a common haplotype, suggestive of founder effect. Sources: Literature |
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| Fetal anomalies v0.3400 | LTBP1 |
Krithika Murali gene: LTBP1 was added gene: LTBP1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LTBP1 were set to 33991472 Phenotypes for gene: LTBP1 were set to Cutis laxa, autosomal recessive, type IIE - MIM#619451 Review for gene: LTBP1 was set to GREEN Added comment: Homozygous premature truncating LTBP1 variants in eight affected individuals from four unrelated consanguineous families reported associated with autosomal recessive cutis laxa type IIE. Phenotypic features relevant in the prenatal setting include: - Congenital diaphragmatic hernia (1 individual) - Cleft palate (2 individuals) - Congenital heart defects - Renal anomalies (1 individual) - Microretrognathia (1 individual) - Hydrocephalus (1 individual) - Skeletal anomalies (craniosynostosis, short stature, brachydactyly, and syndactyly). Supportive patient-derived fibroblast and zebrafish studies. Sources: Literature |
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| Fetal anomalies v0.3400 | EFNA4 |
Krithika Murali gene: EFNA4 was added gene: EFNA4 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: EFNA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: EFNA4 were set to 29215649; 29168297; 16540516 Phenotypes for gene: EFNA4 were set to Craniosynostosis Review for gene: EFNA4 was set to AMBER Added comment: PMID 29215649 Lee et al 2018 - Cohort of 309 individuals with craniosynostosis tested with a 20-gene panel. Report 1 individual with unicoronal CS with a likely pathogenic EFNA4 variant. PMID 29168297 Clarke et al 2018 - Study enrolled 397 probands with single suture CS. Report one maternally inherited EFNA4 VUS NM_005227.2:c.550C>T; p.(Leu184Phe) with metopic CS, x1 het in gnomad (v2), variant predicted to escape NMD, not reported in ClinVar/Decipher. PMID 16540516 Merrill et al 2006 - Tested 81 patients with non-syndromic coronal CS. 3 heterozygous EFNA4 variants detected - x2 missense variants: - c.178C>T p.H60Y -- 361 hets gnomad - c.349 C>A p.P117T - 337 hets - novel frameshift delin 471_472delCCinsA. All 3 variants inherited from unaffected parent. Functional studies on fibroblast cells from the proband with the frameshift delin variant demonstrated an alternatively spliced minor isoform of EFNA4. Sources: Literature |
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| Fetal anomalies v0.3380 | MN1 |
Zornitza Stark changed review comment from: Over 20 individuals described with de novo truncating variants in this gene; these cluster in the C-terminal and the authors postulate that that syndrome is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Sources: Literature; to: Over 20 individuals described with de novo truncating variants in this gene; these cluster in the C-terminal and the authors postulate that that syndrome is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Diaphragmatic hernia, craniosynostosis and brain abnormalities reported. Sources: Literature |
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| Fetal anomalies v0.3372 | SMARCAL1 |
Daniel Flanagan changed review comment from: Well-established gene-disease association; over 40 patients with biallelic mutations in SMARCAL1; Zebrafish and mouse models that recapitulates phenotype have been reported. This disorder combines abnormality of the immune and skeletal systems. Primary features include growth retardation (IUGR in 50%), renal failure, cerebral infarcts, skin pigmentation and CID (lymphocytopaenia, recurrent infections and/or T-cell immunodeficiency) beginning in childhood. GeneReviews: Short stature (99% of individuals) that typically manifests as a short neck and trunk with lumbar lordosis and a protruding abdomen.; to: Well-established gene-disease association; over 40 patients with biallelic mutations in SMARCAL1; Zebrafish and mouse models that recapitulates phenotype have been reported. This disorder combines abnormality of the immune and skeletal systems. Primary features include growth retardation (IUGR in 50%), renal failure, cerebral infarcts, skin pigmentation and CID (lymphocytopaenia, recurrent infections and/or T-cell immunodeficiency) beginning in childhood. GeneReviews: Short stature (99% of individuals) that typically manifests as a short neck and trunk with lumbar lordosis and a protruding abdomen. Most affected children have prenatal and postnatal disproportionate growth failure. A few have normal intrauterine growth followed by postnatal growth failure. |
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| Fetal anomalies v0.3359 | LIPT2 |
Zornitza Stark changed review comment from: Three individuals from two unrelated families; profound ID. Sources: Expert list; to: Three individuals from two unrelated families; onset is typically post-natal, though brain abnormalities reported in some. Sources: Expert list |
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| Fetal anomalies v0.3353 | LIAS | Zornitza Stark changed review comment from: At least three families reported, severe ID is part of the phenotype.; to: At least three families reported, clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3349 | KPTN | Zornitza Stark changed review comment from: 15 patients (9 from Amish families) reported with macrocephaly and intellectual disability with hom or chet variants in KPTN (PMID: 32808430).; to: 15 patients (9 from Amish families) reported with macrocephaly and intellectual disability with hom or chet variants in KPTN (PMID: 32808430). Age of onset of macrocephaly uncertain. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3342 | KLHL7 | Zornitza Stark changed review comment from: IUGR and contractures.; to: IUGR and contractures. More than 10 families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3342 | KLHL7 | Zornitza Stark changed review comment from: Overall IUGR rather than microcephaly, head sizes when reported appear to be in the -1-2SD range.; to: IUGR and contractures. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3330 | NEXMIF |
Zornitza Stark changed review comment from: Females have been described as both asymptomatic carriers or affected. Given only PTCs have been reported, there is no genotype-phenotype correlation. OMIM describes that a phenotype manifests depending on X-inactivation skewing No reported pathogenic missense to date except for the one LP hemizygous in DDD that is maternally inherited (Decipher) Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy.; to: Females have been described as both asymptomatic carriers or affected. Given only PTCs have been reported, there is no genotype-phenotype correlation. OMIM describes that a phenotype manifests depending on X-inactivation skewing No reported pathogenic missense to date except for the one LP hemizygous in DDD that is maternally inherited (Decipher) Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy. Typically presents post-natally. |
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| Fetal anomalies v0.3327 | NHP2 | Zornitza Stark changed review comment from: Three individuals reported altogether, of those two had DD/ID.; to: Three individuals reported altogether, one of whom had the more severe HH phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3317 | KDM1A |
Zornitza Stark changed review comment from: Three unrelated individuals with de novo missense variants in this gene and a neurodevelopmental phenotype. Note one of the individuals also had a de novo indel in ANKRD11. Some data published subsequently demonstrating functional impact of all three variants.; to: Three unrelated individuals with de novo missense variants in this gene and a neurodevelopmental phenotype. Note one of the individuals also had a de novo indel in ANKRD11. Some data published subsequently demonstrating functional impact of all three variants. LGA, cleft palate, brain abnormalities reported. |
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| Fetal anomalies v0.3313 | KCNQ5 |
Zornitza Stark changed review comment from: Four unrelated individuals reported with de novo missense variants in this gene and a neurodevelopmental disorder, including epileptic encephalopathy in some. Three of the variants demonstrated to be LoF and one GoF. Further individual reported in PMID 30359776 with mild ID and absence epilepsy and an intragenic duplication causing likely LoF.; to: Four unrelated individuals reported with de novo missense variants in this gene and a neurodevelopmental disorder, including epileptic encephalopathy in some. Three of the variants demonstrated to be LoF and one GoF. Further individual reported in PMID 30359776 with mild ID and absence epilepsy and an intragenic duplication causing likely LoF. Clinical presentation is typically post-natal. |
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| Fetal anomalies v0.3309 | KCNJ6 |
Zornitza Stark changed review comment from: Keppen-Lubinsky syndrome characterised by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth. Four unrelated individuals reported with de novo variants in this gene (one recurred in 2), mouse model. One of the individuals did not have lipodystrophy but had a prominent hyperkinetic movement disorder.; to: Keppen-Lubinsky syndrome characterised by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth. Four unrelated individuals reported with de novo variants in this gene (one recurred in 2), mouse model. One of the individuals did not have lipodystrophy but had a prominent hyperkinetic movement disorder. Clinical presentation is typically post-natal, with normal growth parameters at birth. |
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| Fetal anomalies v0.3302 | KCNC3 | Zornitza Stark changed review comment from: Mild ID reported only in some individuals with this progressive neurological disorder.; to: Progressive neurological disorder, childhood onset. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3298 | JAM3 |
Zornitza Stark changed review comment from: Autosomal recessive disorder with a distinctive phenotype comprising haemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Affected individuals have a catastrophic neurologic clinical course resulting in death in infancy. Four unrelated families reported.; to: Autosomal recessive disorder with a distinctive phenotype comprising haemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Affected individuals have a catastrophic neurologic clinical course resulting in death in infancy. Four unrelated families reported. Perinatal presentation. |
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| Fetal anomalies v0.3295 | ITCH | Zornitza Stark changed review comment from: Multiple affected individuals reported from Amish community, however, single variant, founder effect.; to: Multiple affected individuals reported from Amish community, however, single variant, founder effect. Short stature but age of onset uncertain. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3293 | IRX5 | Zornitza Stark changed review comment from: Two families reported with Hamamy syndrome, some functional data. ID was borderline.; to: Two families reported with Hamamy syndrome, some functional data. Multiple congenital anomalies reported: CHD, craniosynostosis, syndactyly. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.3279 | ZBTB24 |
Krithika Murali gene: ZBTB24 was added gene: ZBTB24 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ZBTB24 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZBTB24 were set to 32865561; 21596365; 29023266; 32061411; 21906047; 28128455; 23739126; 22786748 Phenotypes for gene: ZBTB24 were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 2 - MIM#614069 Review for gene: ZBTB24 was set to GREEN Added comment: Well reported association with ICF2 (immunodeficiency-centromeric instability facial anomalies syndrome 2). Patients have immunodeficiency (mainly hypo/agammaglobulinemia in the presence of B cells), recurrent infections (namely respiratory and gastrointestinal) and dysmorphic facies. Although antenatal features not thoroughly described for published cases, low birth weight has been a reported feature as well as hypertelorism and micrognathia/retrognathia - these have the potential to be detected prenatally. PMID 32865561 Helfricht et al 2020 - "loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance". PMID 32061411 Banday. et al 2020 - report a patient with this condition and granulomatous hepatitis. Review phenotype of previously reported patients, low birth weight and facial dysmorphism including micrognathia noted in other cases. PMID 29023266 Conrad et al 2017 - describe a 17 month old boy with recurrent infections, growth failure, facial anomalies (including hyperterlorism/low set ears), and inflammatory bowel disease. No antenatal information. PMID 28128455 van den Boogaard 2017 - 5 new patients described PMID 23739126 Nitta et al 2013 - report 3 unrelated patients, x1 patient - lower birth weight and head circumference. At age 5 had macrocephaly, hyperterlorism. Noted to have bilateral hydronephrosis. x1 patient BW 2660g, micrognathia, hyperterlorism. PMID 21906047 Chouery et al 2012 - 3 siblings from a Lebanese family with novel homozygous LoF variant. Apparently normal pregnancies, at time of diagnostic assessment HC between the 5th and 15th centiles, height below the 5th percentile. Dysmorphic features including high arched palate, small chin, retrognathism and everted lower lips. PMID 22786748 Cerbone et al 2012 - report an 8 year old M of consanguineous Moroccan ancestry with ID, dysmorphic features, cafe au last macules and a large arachnoid cyst in the right temporal region, causing compression of the temporal lobe and lateral ventricle PMID 21596365 de Greef et al 2011 - report 4 new unrelated patients, no antenatal information Sources: Literature |
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| Fetal anomalies v0.3254 | HESX1 | Zornitza Stark changed review comment from: Variants in this gene are associated with a spectrum of abnormalities: isolated pituitary deficiency through to septo-optic dysplasia. Optic nerve hypoplasia reported as part of this rather than AMC.; to: Variants in this gene are associated with a spectrum of abnormalities including corpus callosum abnormalities and hand abnormalities. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3253 | HADHB | Zornitza Stark changed review comment from: ID is part of the phenotype.; to: SGA and cardiomyopathy reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3250 | GTF2E2 | Zornitza Stark commented on gene: GTF2E2: Microcephaly reported but onset uncertain. Craniosynostosis in one individual. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3243 | GRIN2D |
Zornitza Stark changed review comment from: Five unrelated individuals reported, two with recurrent variant (NM_000836.2:c.1999G>A or p.Val667Ile). GoF postulated as mechanism. Sources: Expert list; to: Five unrelated individuals reported, two with recurrent variant (NM_000836.2:c.1999G>A or p.Val667Ile). GoF postulated as mechanism. Clinical presentation is typically post-natal. Sources: Expert list |
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| 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 v0.3235 | UQCC2 |
Krithika Murali gene: UQCC2 was added gene: UQCC2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: UQCC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UQCC2 were set to 24385928; 28804536 Phenotypes for gene: UQCC2 were set to Mitochondrial complex III deficiency, nuclear type 7 - MIM#615824 Review for gene: UQCC2 was set to GREEN Added comment: Biallelic variants associated with mitochondrial complex III deficiency. 2 unrelated families and variant-specific functional evidence/segregation information provided. PMID 24385928 Tucker et al 2013 - report a patient with homozygous splice site UQCC2 variants. Presented with severe intrauterine growth retardation, neonatal lactic acidosis and renal tubular dysfunction of consanguineous Lebanese ancestry. Supportive functional studies including using patient fibroblasts. PMID: 28804536 Feichtinger et al 2017 - report a second unrelated patient of consanguineous Turkish ancestry with UQCC2 deficiency, a female infant born at 32 weeks gestation after a a pregnancy complicated by IUGR and oligohydramnios. Followed by a fulminant postnatal course including respiratory distress syndrome, developed epileptic seizures progressing to status epilepticus, profound lactic acidosis with elevated urinary pyruvate and death at day 33 of life. Homozygous missense UQCC2 variants identified leading to a severe reduction of UQCC2 protein in patient's muscle and fibroblast cells. Sources: Literature |
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| Fetal anomalies v0.3232 | GNB5 |
Zornitza Stark changed review comment from: Multiple affected individuals reported. Sources: Expert list; to: Presentation is typically post-natal. Sources: Expert list |
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| Fetal anomalies v0.3225 | GNAI1 | Zornitza Stark changed review comment from: 7 de novo missense and 1 PTV variants reported in the DDD paper Table 1.; to: 7 de novo missense and 1 PTV variants reported in the DDD paper Table 1. Typically presents post-natally. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3221 | GMNN |
Zornitza Stark changed review comment from: Two of the three reported individuals had ID. Sources: Expert list; to: IUGR is a key feature. Sources: Expert list |
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| Fetal anomalies v0.3217 | GFPT1 |
Zornitza Stark changed review comment from: 15 unrelated families reported with bi-allelic variants and a congenital myasthenic syndrome. Two families with leukoencephalopathy as well as CMS. The GFPT1 gene encodes an isoform of glutamine:fructose-6-phosphate amidotransferase (GFAT), which catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine 6-phosphate and glutamate. It is the first and rate-limiting enzyme of the hexosamine biosynthetic pathway. Hexosamine is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans. Muscle samples from several patients showed decreased protein glycosylation, suggesting this is a disorder of glycosylation. However, there is also some data put forward in PMID 30635494 that this may be a mitochondrial condition.; to: 15 unrelated families reported with bi-allelic variants and a congenital myasthenic syndrome. Two families with leukoencephalopathy as well as CMS. Presentation typically in childhood/adolescence. |
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| Fetal anomalies v0.3217 | GALNT2 |
Zornitza Stark changed review comment from: Seven individuals from four families reported with bi-allelic LOF variants and global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. Sources: Literature; to: Seven individuals from four families reported with bi-allelic LOF variants and global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. Microcephaly and poor growth but age of onset of these features is uncertain. Sources: Literature |
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| Fetal anomalies v0.3213 | GABRG2 | Zornitza Stark changed review comment from: Multiple unrelated families reported, variable severity of both seizures and ID.; to: Multiple unrelated families reported, variable severity of both seizures and ID. Typically presents post-natally. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3207 | FZD5 |
Zornitza Stark changed review comment from: Four unrelated families reported. Sources: Literature; to: Four unrelated families reported. Coloboma tends to be isolated, which would be difficult to detect antenatally. Sources: Literature |
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| Fetal anomalies v0.3205 | FUT8 |
Zornitza Stark changed review comment from: Three unrelated individuals reported with bi-allelic variants in this gene. Sources: Expert list; to: Three unrelated individuals reported with bi-allelic variants in this gene. IUGR and congenital anomalies reported. Sources: Expert list |
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| Fetal anomalies v0.3200 | FRRS1L |
Zornitza Stark changed review comment from: Five unrelated individuals reported. Sources: Expert list; to: Five unrelated individuals reported. Presentation is typically post-natal. Sources: Expert list |
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| Fetal anomalies v0.3197 | FRMPD4 | Zornitza Stark changed review comment from: Multiple affected individuals from unrelated families.; to: Multiple affected individuals from unrelated families. Corpus callosum abnormalities, retrognathia reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3192 | FIG4 | Zornitza Stark Phenotypes for gene: FIG4 were changed from Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Charcot-Marie-Tooth disease type 4J, MONDO:0012640; Yunis-Varon syndrome, OMIM:216340; Yunis-Varon syndrome, MONDO:0008995; ?Polymicrogyria, bilateral temporooccipital, OMIM:612691; Bilateral parasagittal parieto-occipital polymicrogyria, MONDO:0012986 to Yunis-Varon syndrome, OMIM:216340; Yunis-Varon syndrome, MONDO:0008995; ?Polymicrogyria, bilateral temporooccipital, OMIM:612691; Bilateral parasagittal parieto-occipital polymicrogyria, MONDO:0012986 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3163 | PPP3CA |
Zornitza Stark changed review comment from: The mono-allelic condition is relevant antenatally. However, only 2 individuals reported. DEE tends to present post-natally.; to: Condition causing multiple congenital anomalies is postulated to be due to GoF variants. However, only 2 individuals reported. DEE postulated to be due to LoF variants, and presents post-natally. |
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| Fetal anomalies v0.3151 | SF3B2 |
Krithika Murali gene: SF3B2 was added gene: SF3B2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SF3B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SF3B2 were set to 34344887 Phenotypes for gene: SF3B2 were set to Craniofacial microsomia Review for gene: SF3B2 was set to GREEN Added comment: No new relevant published evidence since PanelApp review Aug 2021 -- Twenty individuals from seven families reported with de novo or transmitted haploinsufficient variants in SF3B2. Affected individuals had mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus resulted in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The families were ascertained from a cohort and the authors suggest that haploinsufficient variants in SF3B2 are the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases. Sources: Literature |
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| Fetal anomalies v0.3151 | SEPT9 |
Krithika Murali gene: SEPT9 was added gene: SEPT9 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SEPT9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SEPT9 were set to 16186812; 19451530; 19939853; 19139049; 18492087 Phenotypes for gene: SEPT9 were set to Amyotrophy, hereditary neuralgic, MIM# 162100 Review for gene: SEPT9 was set to AMBER Added comment: No new relevant published evidence since last PanelApp review May 2021 -- Only one report identified from 2008 of dysmorphic features including cleft palate co-occurring with HNA. New gene name is SEPTIN9, also note founder variants as well as 5'UTR variants and intragenic duplications reported. Sources: Literature |
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| Fetal anomalies v0.3151 | PLEKHA5 |
Krithika Murali gene: PLEKHA5 was added gene: PLEKHA5 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: PLEKHA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PLEKHA5 were set to 29805042 Phenotypes for gene: PLEKHA5 were set to cleft lip; cleft palate Review for gene: PLEKHA5 was set to AMBER Added comment: No new published evidence since last PanelApp review April 2020 --- One de novo variant reported, another 5 '3C' rare variants reported in 6 families in this cohort; unclear if monogenic or polygenic contribution to CL/P. Sources: Literature, Expert list |
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| Fetal anomalies v0.3151 | PLEKHA7 |
Krithika Murali gene: PLEKHA7 was added gene: PLEKHA7 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PLEKHA7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PLEKHA7 were set to 29805042 Phenotypes for gene: PLEKHA7 were set to Cleft palate Review for gene: PLEKHA7 was set to AMBER Added comment: No new evidence since last PanelApp review in Jan 2021 -- Six rare variants identified in 4 individuals in a CL/P cohort, however, only one of these classified as likely pathogenic. One individual had bi-allelic variants. Some supportive functional data Sources: Literature |
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| Fetal anomalies v0.3151 | PPP1R13L |
Krithika Murali gene: PPP1R13L was added gene: PPP1R13L was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PPP1R13L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPP1R13L were set to 32666529; 28864777 Phenotypes for gene: PPP1R13L were set to Dilated cardiomyopathy, onset in infancy; Cleft lip and palate Review for gene: PPP1R13L was set to GREEN Added comment: No new information since last PanelApp review June 2021 -- At least 6 unrelated families. NMD-predicted, missense and stop-loss (extension) variants have been reported in individuals with autosomal recessive PPP1R13L-related syndrome. Patients described with biallelic pathogenic variants in PPP1R13L all had severe infantile-onset dilated cardiomyopathy, with additional features including cleft lip and palate, wedge-shaped teeth, and sparse, dry, woolly hair described in several individuals. Death due to HF progression before 5yo reported in cases that didn't receive a heart transplant. Cognitive delay also reported in two unrelated individuals (PMID: 28069640, PMID: 32666529). Sources: Literature |
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| Fetal anomalies v0.3151 | METTL23 |
Krithika Murali gene: METTL23 was added gene: METTL23 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: METTL23 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: METTL23 were set to 32878022; 32439618; 32067349; 24626631; 24501276 Phenotypes for gene: METTL23 were set to Mental retardation, autosomal recessive 44 - #615942 Review for gene: METTL23 was set to RED Added comment: Biallelic variants associated with syndromic ID. Published studies provide no or limited antenatal information with no consistent prenatal phenotype described. -- PMID: 32878022 – Khan et al 2020 - homozygous missense variants identified in consanguineous Pakistani family with 3 affected siblings having ID, epilepsy, behavioural issues, hypotonia and dysmorphic features (prominent large-size eyes, eyebrows, ears, short upturned nose with flat nasal bridge, and thin upper lip). Authors report that prenatal, perinatal and neonatal medical records of all patients were normal. PMID 32439618 – Smaili et al 2020 report two Moroccan siblings presenting with mild intellectual disability and dysmorphic features. WES identified homozygous METTL23 gene variants. Describe uneventful pregnancies and postnatal course. Macrocephaly reported in both siblings (HC 52cm in a 7 year old M and 50cm in 6 yo F) - no information regarding HC of parents provided, macrocephaly not a consistently reported feature of this condition. PMID: 32067349 – Almannai et al 2020 - 6 individuals from 4 families - 2 families unrelated, 2 families come from same Saudi tribe and are therefore likely to be distantly related with same homozygous METTL23 variant identified in both. No prenatal features or immediate postnatal issues described related to this condtion. One subject reported to have an MRI-B showing mild ventriculomegaly at a later age which may reflect mild white matter volume loss. This subject also had a 618 Kilobases duplication at 7p11.2 (57,261,112-57,878,853) identified on CGH array. PMID: 24626631 – Bernkopf 2014 - describe 2 unrelated families. Provide no antenatal information or report no issues antenatally/at birth apart from one baby being large and cyanosed postnatally PMID: 24501276 – Reiff et al 2014 - report 7 affected members of a large, consanguineous Arab family with ID and mild dysmorphic features. X1 patient had cleft uvula and submucosal cleft palate. Sources: Literature |
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| Fetal anomalies v0.3151 | LRP6 |
Krithika Murali gene: LRP6 was added gene: LRP6 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: LRP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LRP6 were set to 16126904; 30950205; 26387593; 26963285; 28813618; 29500247; 33164649; 34306029 Phenotypes for gene: LRP6 were set to Tooth agenesis, selective, 7 - MIM#616724; cleft lip/palate Review for gene: LRP6 was set to AMBER Added comment: LoF variants known to be associated with tooth agenesis. In addition, x2 unrelated families from 2 different studies with heterozygous LRP6 variant had tooth agenesis and cleft lip/palate (PMID 29500247; 26963285). Growth failure reported in some individuals but unclear if prenatal in onset (PMID 26963285). Minor finger/ear anomalies reported in x2 patients (PMID 26387593; 30950205)- unlikely to be detected antenatally and one of the reported patients (30950205) had x2 chromosome deletions, one of which involved LRP6 and multiple other genes. --- PMID: 34306029 Huang et al 2021 - Heterozygous LRP6: c.2570G > A (p.R857H), harbored by six members of a Chinese family, including 4 with tooth agenesis. Sparse hair another phenotypic feature. PMID: 33164649 Yu et al 2021 - identified 4 novel LRP6 heterozygous mutations in 4 of 77 oligodontia patients. One patient with a nonsense paternally inherited variant had a hypohidrotic ectodermal dysplasia phenotype - no antenatal features, father had oligodontia. Supportive functional evidence PMID: 29500247 Basha et al 2018 - Nonsense LRP6 variant identified in a family with cleft lip/palate. Proband had bilateral cleft lip and palate with missing upper lateral incisors, mother had bilateral cleft lip. x1 unaffected brother but family members not reassessed for oligodontia after variant identified. PMID: 28813618 Dinckan et al 2018 - heterozygous splice site LRP6 variant identified in 1 family with isolated tooth agenesis. Affected family members also had mild periocular hyperpigmentation and hypoplastic alae nasi - thought to be unrelated to phenotype PMID: 26963285 Ockeloen et al 2016 - frameshift variant identified in patient with tooth agenesis and orofacial clefting - boy born with bilateral cleft lip, L) sided cleft of the alveolus and complete cleft of the hard and soft palate. Also noted to have growth retardation, hypermetropia and small median alveolar manibular cleft. Maternal relatives with variant had severe tooth agenesis but no clefting. Canonical splice site variant identified in a patient with isolated severe tooth agenesis. Targeted resequencing showed statistically significant enrichment of unique LRP6 variants in tooth agenesis patients (7/67 versus 13/706 controls), not orofacial clefting cohort. 4/7 of these patients required growth hormone therapy and 3/7 had clinodactyly in addition to dental anomalies. PMID: 26387593 – Massink et al 2015 - x4 LoF heterozygous LRP6 variants identified in 4 unrelated families with isolated severe tooth agenesis. All affected members of one family showed minor anatomical variation of the ear and underdevelopment of the thumb PMID: 30950205 Ross et al 2019 - Proband with oligodontia and thrombocytopenia, also had mild finger and ear anomalies. Array revealed an interstitial loss of 150 kb in 8p23.1 encompassing MCPH1 and ANGPT2 and an interstitial loss of 290 kb in 12p13.2 encompassing ETV6, BCL2L14 and LRP6. Sources: Literature |
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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 v0.3140 | HOXA2 |
Krithika Murali gene: HOXA2 was added gene: HOXA2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: HOXA2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: HOXA2 were set to 18394579; 23775976; 27503514; 28109504; 31567444; 32649979 Phenotypes for gene: HOXA2 were set to Microtia with or without hearing impairment (AD) - MIM#612290 Review for gene: HOXA2 was set to GREEN Added comment: Heterozygous variants associated with non-syndromic microtia and hearing loss reported in over 5 families Homozygous variant associated with severe microtia, hearing loss and partial cleft palate reported in 3 affected individuals in 1 family. Supportive mouse models --- PMID: 18394579 Alasti et al 2008 - first identified 3 affected individuals from one consanguineous Persian family also had partial cleft palate with homozygous HOXA2 variant. Only family with AR inheritance reported so far. PMID: 23775976 Brown et al 2013 – multiple affected individuals from one family with non-syndromic bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing identified heterozygous protein truncating HOXA2 nonsense change (c.703C>T, p.Q235*). PMID: 27503514 Piceci et al 2017 – reported one family with isolated bilateral microtia segregating as an autosomal dominant trait. Heterozygous protein truncating nonsense variant identified [c.670G>T, p.(Glu224*)] segregating in all affected individuals PMID: 28109504 Hao et al 2017 - 2 novel variants in the 5’ UTR of HOXA2 identified in a screen of patients with microtia, limited phenotypic information PMID: 31567444 Meddaugh et al 2020 - reported heterozygous variant in 4-year-old Caucasian male with bilateral dysplastic ears and conductive hearing loss. PMID: 32649979 Si et al 2020 – reported two Chinese families with non-syndromic bilateral microtia identifying two separate heterozygous nonsense HOXA2 variants Sources: Literature |
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| Fetal anomalies v0.3140 | FTO |
Krithika Murali gene: FTO was added gene: FTO was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FTO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FTO were set to 19559399; 26378117 Phenotypes for gene: FTO were set to Growth retardation, developmental delay, facial dysmorphism - MIM#612938; multiple congenital malformations Review for gene: FTO was set to AMBER Added comment: Biallelic variants associated with syndromic ID reported in 2 unrelated families. PMID: 26378117 Daoud et al 2016 - homozygous missense variant identified in a female proband. 3rd child to consanguineous Tunisian parents. Proband also carried a paternally inherited balanced translocation. Antenatal USS identified IUGR. Postnatal Echo showed PDA and hypertrabeculation of LV apex. PMID 19559399 Boissel et al 2009 - homozygous missense variant identified in 9 affected individuals from a consanguineous Palestinian Arab family. Phenotypic features identified most pertinent to the prenatal setting include: 3/7 IUGR, 7/7 retrognathia, congenital heart disease 6/8, lissencephaly 3/8, hypertrophic cardiomyopathy 4/8, hydrocephalus 4/8, cleft palate/bifid uvula 3/6. Sources: Literature |
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| Fetal anomalies v0.3140 | EIF3F |
Krithika Murali gene: EIF3F was added gene: EIF3F was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: EIF3F was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EIF3F were set to 33736665 Phenotypes for gene: EIF3F were set to ntellectual developmental disorder, autosomal recessive 67- MIM#618295 Review for gene: EIF3F was set to GREEN Added comment: No new publications since PanelApp review Oct 2021 Hüffmeier et al (2021) reported 21 patients who were homozygous/compound heterozygous for Phe232Val variant in EIF3F. All affected individuals had developmental delay and speech delay. About half had behavioural problems, altered muscular tone, hearing loss, and short stature (3/7 from birth). The study suggests that microcephaly (4/10 from birth), reduced sensitivity to pain, cleft lip/palate (1/21), congenital heart defect (1/21), gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Sources: Literature |
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| 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 v0.3140 | ANKRD17 |
Krithika Murali gene: ANKRD17 was added gene: ANKRD17 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ANKRD17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ANKRD17 were set to 33909992 Phenotypes for gene: ANKRD17 were set to Chopra-Amiel-Gordon syndrome - MIM#619504; multiple congenital malformations Review for gene: ANKRD17 was set to GREEN Added comment: 33909992 - Chopra et al 2021 reported 34 individuals from 33 families with a syndromic ID Multiple cases with antenatal anomalies or features detectable antenatally reported - 3/34 with cleft lip and/or palate (including 2 with Pierre Robin sequence) - 1/34 retrognathia - 5/34 renal anomalies including 3 with unilateral renal agenesis and 1 with antenatal diagnosis of horseshoe kidney - 2/34 microcephaly - 4/34 macrocephaly (1 noted on 37/40 antenatal USS to have macrocephaly and enlarged cisterna magna, 1 also had NSD1 variant) - 5/34 IUGR/fetal growth concerns -1/34 with VSD Sources: Literature |
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| Fetal anomalies v0.3140 | ACBD5 |
Krithika Murali gene: ACBD5 was added gene: ACBD5 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ACBD5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ACBD5 were set to 27799409; 23105016; 33427402; 34668366 Phenotypes for gene: ACBD5 were set to Retinal dystrophy with leukodystrophy - MIM#618863 Review for gene: ACBD5 was set to RED Added comment: Biallelic ACBD5 variants cause impairment of very long-chain fatty acid metabolism. Patients have retinal dystrophy and leukodystrophy. Other features include ataxia, spastic paraparesis, developmental delay and facial dysmorphism. One patient with cleft palate reported but this may be an incidental finding and not related to this condition. No other antenatal features reported. -- PMID 27799409 Ferdinandusse et al 2017 - patient born full-term with cleft palate, progressive leukodystrophy, ataxia, retinal dystrophy and facial dysmorphism PMID 23105016 Abu-Safieh et al 2013 - limited phenotypic information, reported 3 siblings with homozygous splice site ACBD5 variants with spastic paraparesis and leukodystrophy. PMID: 33427402 Bartlett et al 2020 - 36 year old F proband born at term after an uncomplicated pregnancy, normal growth parameters. PMID: 34668366 Gorukmez et al 2021 - x2 siblings with homozygous variant – no antenatal features reported Sources: Literature |
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| Fetal anomalies v0.3123 | POP1 |
Zornitza Stark changed review comment from: Anauxetic dysplasia is a spondyloepimetaphyseal dysplasia characterized by severe short stature of prenatal onset, very short adult height (less than 1 meter), hypodontia, midface hypoplasia, and mild intellectual disability.; to: Anauxetic dysplasia is a spondyloepimetaphyseal dysplasia characterized by severe short stature of prenatal onset, very short adult height (less than 1 meter), hypodontia, midface hypoplasia, and mild intellectual disability. At least 4 unrelated families reported. |
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| Fetal anomalies v0.3117 | PLPBP |
Zornitza Stark changed review comment from: Over 20 individuals reported. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding.; to: Over 20 individuals reported. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. Abnormal fetal movements reported. |
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| Fetal anomalies v0.3113 | TOPORS | Zornitza Stark Marked gene: TOPORS as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3113 | TOPORS | Zornitza Stark Gene: topors has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3113 | TOPORS | Zornitza Stark Classified gene: TOPORS as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3113 | TOPORS | Zornitza Stark Gene: topors has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3106 | TOPORS |
Krithika Murali gene: TOPORS was added gene: TOPORS was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TOPORS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TOPORS were set to 34132027 Phenotypes for gene: TOPORS were set to MONDO:0005308; ciliopathy; postaxial polydactyly; multiple lingual hamartomas; dysmorphic features Review for gene: TOPORS was set to AMBER Added comment: Gene recently reviewed, no new publications since -- PMID:34132027 - Two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for the same missense variant (p.Pro10Gln). Suggested possible founder allele. Further search did not identify any additional publications. Note mono-allelic variants associated with RP. Sources: Literature |
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| Fetal anomalies v0.3106 | RPS29 |
Krithika Murali gene: RPS29 was added gene: RPS29 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: RPS29 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RPS29 were set to 24829207 Phenotypes for gene: RPS29 were set to Diamond-Blackfan anemia 13 - MIM#615909 Review for gene: RPS29 was set to AMBER Added comment: 2 unrelated families reported with Diamond Blackfan anaemia. DBA known to be associated with congenital malformations. 1 affected individual reported in this publication to have congenital aortic stenosis and Sprengel deformity. Sources: Literature |
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| Fetal anomalies v0.3106 | RPS28 |
Krithika Murali gene: RPS28 was added gene: RPS28 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: RPS28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RPS28 were set to 24942156 Phenotypes for gene: RPS28 were set to Diamond Blackfan anemia 15 with mandibulofacial dysostosis - MIM#606164 Review for gene: RPS28 was set to AMBER Added comment: 2 unrelated families reported in 2014. Antenatally detectable phenotypic features included cleft palate, micrognathia, cardiac, auricular and renal anomalies Sources: Literature |
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| 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 v0.3022 | 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 v0.3016 | PIGY |
Zornitza Stark changed review comment from: Two unrelated families only; variable phenotype described. One family had a promoter region homozygous variant.; to: Two unrelated families only; variable phenotype described. One family had a promoter region homozygous variant. Joint contractures, microcephaly, cataracts and other ultrasound-detectable abnormalities reported. |
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| Fetal anomalies v0.3006 | PGM3 |
Zornitza Stark changed review comment from: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity. More than 10 unrelated families reported. Typically presents post-natally.; to: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity. More than 10 unrelated families reported. Typically presents post-natally. However, more severe presentations with skeletal abnormalities and congenital malformations reported in PMID 28543917 and 24931394. |
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| Fetal anomalies v0.3003 | PGM3 |
Zornitza Stark changed review comment from: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity. More than 10 unrelated families reported.; to: Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Bi-allelic variants in this gene are associated with a primary immunodeficiency syndrome characterised by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity. More than 10 unrelated families reported. Typically presents post-natally. |
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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 v0.2987 | PET100 |
Zornitza Stark changed review comment from: Founder effect in 6 Australian families of Lebanese origin (M1?) reported originally; functional data. Second family with different variants also reported; and another 2 Lebanese families with same founder variant.; to: Founder effect in 6 Australian families of Lebanese origin (M1?) reported originally; functional data. Second family with different variants also reported; and another 2 Lebanese families with same founder variant. IUGR is a feature. |
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| Fetal anomalies v0.2975 | KIAA0825 |
Krithika Murali gene: KIAA0825 was added gene: KIAA0825 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: KIAA0825 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIAA0825 were set to 33776623; 32147526; 30982135 Phenotypes for gene: KIAA0825 were set to Polydactyly, postaxial, type A10 - MIM#618498 Review for gene: KIAA0825 was set to GREEN Added comment: 4 families of Pakistani/Sindhi origin reported with post-axial polydactyly Sources: Literature |
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| Fetal anomalies v0.2974 | PACS1 |
Zornitza Stark changed review comment from: Multiple individuals reported with recurrent p.Arg203Trp variant; in vitro assays is suggestive of dominant-negative disease mechanism; to: Multiple individuals reported with recurrent p.Arg203Trp variant; in vitro assays is suggestive of dominant-negative disease mechanism Brain, cardiac and renal abnormalities reported. |
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| Fetal anomalies v0.2970 | IFT27 |
Krithika Murali gene: IFT27 was added gene: IFT27 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: IFT27 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IFT27 were set to 24488770; 30761183; 26763875; 25443296 Phenotypes for gene: IFT27 were set to Bardet-Biedl syndrome 19-MIM#615996 Review for gene: IFT27 was set to GREEN Added comment: Biallelic variants associated with Bardet-Biedl syndrome. Phenotypic features detectable antenatally include polydactyly, cardiac and brain anomalies also reported. Sources: Literature |
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| Fetal anomalies v0.2970 | HMGB1 |
Krithika Murali gene: HMGB1 was added gene: HMGB1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HMGB1 were set to 34164801 Phenotypes for gene: HMGB1 were set to microcephaly; intellectual disability Review for gene: HMGB1 was set to GREEN Added comment: 34164801 Uguen et al 2021 report 6 unrelated individuals with LoF HMGB1 variants associated with syndromic ID. 4 individuals reported to have microcephaly - majority noted to have microcephaly at birth +/- growth restriction. Sources: Literature |
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| Fetal anomalies v0.2970 | FAM92A |
Krithika Murali gene: FAM92A was added gene: FAM92A was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FAM92A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAM92A were set to 30395363 Phenotypes for gene: FAM92A were set to Polydactyly, postaxial, type A9 - MIM#618219 Review for gene: FAM92A was set to AMBER Added comment: 30395363 - homozygous nonsense variants in FAM92A segregated with postaxial polydactyly in x1 consanguineous Parkistani family. Supportive mouse model reported. Sources: Literature |
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| Fetal anomalies v0.2968 | OSGEP |
Zornitza Stark changed review comment from: 25 families reported. Sources: Expert list; to: 25 families reported. IUGR and oligohydramnios are a feature. Sources: Expert list |
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| Fetal anomalies v0.2964 | NUS1 |
Zornitza Stark edited their review of gene: NUS1: Added comment: The CDG disorder caused by bi-allelic variants in this gene has iUGR as a feature. Note limited reports (one published, one ClinVar). The DEE disorder associated with mono-allelic variants typically presents post-natally.; Changed rating: AMBER; Changed phenotypes: Congenital disorder of glycosylation, type 1aa; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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| Fetal anomalies v0.2957 | NTRK2 |
Zornitza Stark changed review comment from: Three unrelated individuals reported with this phenotype. Note recurrent missense in this gene also causes EE. Sources: Expert list; to: Clinical presentation for both disorders is typically post-natal. Sources: Expert list |
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| Fetal anomalies v0.2955 | NSUN2 | Zornitza Stark edited their review of gene: NSUN2: Added comment: Low birth weight reported. Microcephaly also reported, age of onset unclear.; Changed rating: AMBER; Changed publications: 22541559, 22541562, 22577224 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2951 | TRRAP |
Krithika Murali gene: TRRAP was added gene: TRRAP was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TRRAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TRRAP were set to 30827496 Phenotypes for gene: TRRAP were set to Developmental delay with or without dysmorphic facies and autism- #618454; multiple congenital anomalies Review for gene: TRRAP was set to GREEN Added comment: 13 unrelated individuals reported with a complex syndromic neurodevelopmental disorder associated with malformations that can be detected antenatally. This includes, brain, heart, kidney, urogenital anomalies, abdominal wall hernias, cleft lip/palate Sources: Literature |
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| Fetal anomalies v0.2951 | G6PD |
Krithika Murali gene: G6PD was added gene: G6PD was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: G6PD was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: G6PD were set to 1316704; 26279483; 18177777; 17825683; 1127504; 7472841 Phenotypes for gene: G6PD were set to Haemolytic anaemia, G6PD deficient (300908) Review for gene: G6PD was set to AMBER Added comment: Well-known association with G6PD deficiency. Borderline red-amber gene for fetal anomalies. However, as features of anaemia can sometimes be detected in fetus antenatally and therapeutic/maternal trigger avoidance options available, I have favoured amber rating. PMID: 26279483 Keller et al 2015 - report a mother who is a carrier for a G6PD variant (Guadalajara variant) with a family history of a brother and paternal uncle who died as neonates from severe hydrops. She was counselled to avoid substances that could precipitate oxidative stress from 22 weeks gestation onwards. During her first pregnancy, a male fetus was found to have mild cardiomegaly at 31 weeks with elevated MCAPSV - suggestive of anaemia. Intrauterine transfusion instituted. Presence of maternally inherited G6PD variant confirmed in the fetus. There are other case reports of hydrops fetalis presumed secondary to G6PD deficiency but evidence is limited.. 4999390; 1127504 - older studies, no genomic confirmation available. 4999390 Perkins et al 1971 - Mother presumed to be a carrier for G6PD deficiency and all 3 babies presumed to have the same - 1st child neonatal jaundice with abnormal G6PD test result and death at 59 days of life from undetermined cause - 2nd pregnancy - mother given sulfizoxazole for UTI during pregnancy, delivered stillborn infant at 36 weeks with hydrops fetalis and severe anaemia - 3rd child - well, neonatal jaundice and abnormal G6PD test. Mother O neg blood group, all three babies +ve blood group, DAT -ve and RhoGam given each pregnancy. 1127504 - Mentzer and Collier et al 1975 Male infant died at 2 hours of life with evidence of haemolysis and autopsy findings of hydrops. G6PD screening test in baby abnormal. Mother had low-normal G6PD activity, abnormal ascorbate cyanide test, abnormal MTT cytochemical however no abnormal migrating band of G6PD activity was present on electrophoresis. URTI episode during pregnancy, ascorbic acid consumption and fava bean consumption noted. G6PD deficiency presumed in mother and infant but not genomically confirmed. 23719252; 24999569 - Two case reports identified. However, a second diagnosis was present in both and the G6PD deficiency may have contributed to severity rather than being the primary factor. Sources: Literature |
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| Fetal anomalies v0.2933 | ST3GAL3 | Zornitza Stark changed review comment from: PMID: 31584066 reports on two di-chorionic infant twins p.Y220*, presenting with epileptic encephalopathy with impaired neuromotor development.; to: Clinical presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2921 | SOX5 |
Zornitza Stark changed review comment from: Comment when marking as ready: Note many cases reported of intragenic deletion.; to: Comment when marking as ready: Note many cases reported of intragenic deletion. Presentation is typically post-natal. |
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| Fetal anomalies v0.2907 | SMG9 |
Zornitza Stark changed review comment from: Three unrelated families reported, severe congenital malformation syndrome, ID is part of the phenotype in survivors. Sources: Expert list; to: Three unrelated families reported, severe congenital malformation syndrome. Sources: Expert list |
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| Fetal anomalies v0.2898 | SLC25A4 | Zornitza Stark changed review comment from: Variants in this gene cause both dominant and recessive disease. MIM#617184 reported as causing profound hypotonia and frequent need for respiratory support; the other two conditions, one AR and the other AD, appear less severe. Not convinced ID is an intrinsic part of the phenotype.; to: Variants in this gene cause both dominant and recessive disease. MIM#617184 reported as causing profound hypotonia and frequent need for respiratory support; the other two conditions, one AR and the other AD, appear less severe. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2893 | SLC1A2 |
Zornitza Stark changed review comment from: Four unrelated individuals reported. Sources: Expert list; to: Four unrelated individuals reported. Post-natal presentation. Sources: Expert list |
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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 v0.2892 | MVK |
Krithika Murali gene: MVK was added gene: MVK was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MVK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MVK were set to 27012807; 16722536 Phenotypes for gene: MVK were set to Mevalonic aciduria-#610377; Hyper-IgD syndrome - #260920 Review for gene: MVK was set to GREEN Added comment: Biallelic MVK variants associated with mevalonate kinate deficiencies - an overlapping spectrum of phenotypes includes mevalonic aciduria (MVA) on the severe end and hyper-IgD syndrome (HIDS) generally having a less severe clinical course and later diagnosis. Fetal manifestations of MVA reported include microcephaly and hydrops fetalis. Sources: Literature |
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| Fetal anomalies v0.2892 | LAMB2 |
Krithika Murali gene: LAMB2 was added gene: LAMB2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: LAMB2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LAMB2 were set to 16450351 Phenotypes for gene: LAMB2 were set to Pierson syndrome-MIM#609049; Nephrotic syndrome, type 5, with or without ocular abnormalities-MIM#614199 Review for gene: LAMB2 was set to AMBER Added comment: Biallelic variants associated with Pierson syndrome. Phenotypic features include congenital nephrotic syndrome, ocular anomalies including microcoria. Most affected individuals die early from renal disease with survivors tending to have ID/visual loss. Prenatal features reported in 1 consanguineous Turkish family with 4 pregnancies affected by Pierson syndrome. Antenatal ultrasound features noted include: - 2/4 homogenous hyperechogenicity of the kidneys similar to bone tissue - 2/4 enlargement of fetal kidneys - 2/4 bilateral pyelectasis - 1/4 oligohydramnios --> anhydramnios - 1/4 hydrops - 1/4 ancencephaly All 4 fetuses had ultrasound anomalies. Anencephaly seen in the 4th pregnancy noted at 11 weeks resulting in MTOP. Homozygosity for LAMB2 variant confirmed. PM showed that kidneys were appropriate for gestational age. I could not find another case report of anencephaly with Pierson syndrome, this may be an incidental finding. Sources: Literature |
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| Fetal anomalies v0.2869 | SETD2 |
Zornitza Stark changed review comment from: Multiple affected individuals with macrocephaly, intellectual disability, speech delay, low sociability, and behavioral problems. More variable features include postnatal overgrowth, obesity, advanced carpal ossification, developmental delay, and seizures; to: Multiple affected individuals with macrocephaly, intellectual disability, speech delay, low sociability, and behavioral problems. More variable features include postnatal overgrowth, obesity, advanced carpal ossification, developmental delay, and seizures. Chiari malformation and ventriculomegaly reported. |
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| Fetal anomalies v0.2865 | SETD1A |
Zornitza Stark changed review comment from: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism. In addition, there are 4 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; to: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism. In addition, there are 4 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders. Presentation of both disorders is typically post-natal. |
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| Fetal anomalies v0.2849 | HS2ST1 |
Krithika Murali gene: HS2ST1 was added gene: HS2ST1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HS2ST1 were set to 33159882 Phenotypes for gene: HS2ST1 were set to Neurofacioskeletal syndrome with or without renal agenesis-MIM#619194; multiple congenital anomalies; arthrogryposis Review for gene: HS2ST1 was set to GREEN Added comment: PMID 33159882 - Scheenberger et al 2020 Biallelic HS2ST1 variants associated with disease reported in 4 affected individuals from 3 unrelated families, including one affected fetus with arthrogryposis, skeletal anomalies, bilateral renal agenesis. Other congenital anomalies reported include agenesis or hypoplasia of the corpus callosum. Sources: Literature |
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| Fetal anomalies v0.2846 | SACS | Zornitza Stark changed review comment from: ID has only been reported in a minority of individuals; predominantly a motor phenotype.; to: Progressive condition, onset in infancy/childhood. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2846 | FLNC |
Krithika Murali changed review comment from: ClinGen definitive gene-disease validation for myofibrillar myopathy type 5 and dilated cardiomyopathy. Predominantly adult onset phenotype, AD inheritance. 4 unrelated cases with likely de novo FLNC variants presenting with congenital myopathy and arthrogryposis have also been reported which are features amenable to antenatal detection. PMID 29858533 Kiselev et al reported 4 unrelated patients with early onset myopathy and restrictive cardiomyopathy. 3/4 also presented with arthrogryposis. x1 patient required delivery via CS due to breech presentation and at birth was noted to have arthrogryposis and hip dysplasia - de novo FLNC variant confirmed. RCM diagnosed age 2 x1 patient noted to have IUGR in a pregnancy complicated by pre-eclampsia. At birth was noted to have arthrogryposis, hip subluxation and abdominal wall weakness with herniation. RCM diagnosed age 6 months. Variant not present in unaffected mother, paternal DNA unavailable. x1 patient required CS delivery due to insufficient rotation in birth canal. Noted to have arthrogryposis at birth. Variant confirmed to be de novo x1 patient presented with muscle weakness first year of life, RCM age 3. Parents declined genetic testing. --- Other cases of interest PMID 30260051 Schubert et al 2018 - report two restrictive cardiomyopathy families with childhood onset disease with age 1 being the earliest age of diagnosis in a DCDA monozygotic twin who was also diagnosed with a small VSD perinatally. Both twins were also noted to have extra-cardiac manifestations at the time of diagnosis including developmental delay, hypotonia, dysmorphic facial features, and clasped thumbs with onset of kidney dysfunction age 3 post-cardiac transplant. PMID: 32516863 – Kolbel et al 2020 report one neonate with homozygous FLNC variant c.1325C>G (p.Pro442Arg). Absent from gnomad. Presented with weak suck first month of life with subsequent motor development delay, generalised muscular hypotonia, contractures. Variant confirmed in both unaffected parents. Authors postulate this is a novel case of homozygous FLNC variants associated with congenital presentation. This is a single case report, only heterozygous variants reported so far including in congenital presentations, both parents with het variants unaffected. Possibility of an alternative genetic explanation for this patient's presentation not excluded. Sources: Literature; to: ClinGen definitive gene-disease validation for myofibrillar myopathy type 5 and dilated cardiomyopathy. Predominantly adult onset phenotype, AD inheritance. 4 unrelated cases with likely de novo FLNC variants presenting with congenital myopathy and arthrogryposis have also been reported. These features/complications of these features are amenable to antenatal detection. PMID 29858533 Kiselev et al reported 4 unrelated patients with early onset myopathy and restrictive cardiomyopathy. 3/4 also presented with arthrogryposis. x1 patient required delivery via CS due to breech presentation and at birth was noted to have arthrogryposis and hip dysplasia - de novo FLNC variant confirmed. RCM diagnosed age 2 x1 patient noted to have IUGR in a pregnancy complicated by pre-eclampsia. At birth was noted to have arthrogryposis, hip subluxation and abdominal wall weakness with herniation. RCM diagnosed age 6 months. Variant not present in unaffected mother, paternal DNA unavailable. x1 patient required CS delivery due to insufficient rotation in birth canal. Noted to have arthrogryposis at birth. Variant confirmed to be de novo x1 patient presented with muscle weakness first year of life, RCM age 3. Parents declined genetic testing. --- Other cases of interest PMID 30260051 Schubert et al 2018 - report two restrictive cardiomyopathy families with childhood onset disease with age 1 being the earliest age of diagnosis in a DCDA monozygotic twin who was also diagnosed with a small VSD perinatally. Both twins were also noted to have extra-cardiac manifestations at the time of diagnosis including developmental delay, hypotonia, dysmorphic facial features, and clasped thumbs with onset of kidney dysfunction age 3 post-cardiac transplant. PMID: 32516863 – Kolbel et al 2020 report one neonate with homozygous FLNC variant c.1325C>G (p.Pro442Arg). Absent from gnomad. Presented with weak suck first month of life with subsequent motor development delay, generalised muscular hypotonia, contractures. Variant confirmed in both unaffected parents. Authors postulate this is a novel case of homozygous FLNC variants associated with congenital presentation. This is a single case report, only heterozygous variants reported so far including in congenital presentations, both parents with het variants unaffected. Possibility of an alternative genetic explanation for this patient's presentation not excluded. Sources: Literature |
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| Fetal anomalies v0.2846 | FLNC |
Krithika Murali gene: FLNC was added gene: FLNC was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FLNC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FLNC were set to 29858533; 30260051; 32516863 Phenotypes for gene: FLNC were set to Arthrogryposis; congenital myopathy; Cardiomyopathy, familial restrictive 5 - MIM #617047; Cardiomyopathy, familial hypertrophic, 26 -MIM# 617047; Myopathy, distal, 4 - #614065; Myopathy, myofibrillar, 5 - MIM#609524 Review for gene: FLNC was set to GREEN Added comment: ClinGen definitive gene-disease validation for myofibrillar myopathy type 5 and dilated cardiomyopathy. Predominantly adult onset phenotype, AD inheritance. 4 unrelated cases with likely de novo FLNC variants presenting with congenital myopathy and arthrogryposis have also been reported which are features amenable to antenatal detection. PMID 29858533 Kiselev et al reported 4 unrelated patients with early onset myopathy and restrictive cardiomyopathy. 3/4 also presented with arthrogryposis. x1 patient required delivery via CS due to breech presentation and at birth was noted to have arthrogryposis and hip dysplasia - de novo FLNC variant confirmed. RCM diagnosed age 2 x1 patient noted to have IUGR in a pregnancy complicated by pre-eclampsia. At birth was noted to have arthrogryposis, hip subluxation and abdominal wall weakness with herniation. RCM diagnosed age 6 months. Variant not present in unaffected mother, paternal DNA unavailable. x1 patient required CS delivery due to insufficient rotation in birth canal. Noted to have arthrogryposis at birth. Variant confirmed to be de novo x1 patient presented with muscle weakness first year of life, RCM age 3. Parents declined genetic testing. --- Other cases of interest PMID 30260051 Schubert et al 2018 - report two restrictive cardiomyopathy families with childhood onset disease with age 1 being the earliest age of diagnosis in a DCDA monozygotic twin who was also diagnosed with a small VSD perinatally. Both twins were also noted to have extra-cardiac manifestations at the time of diagnosis including developmental delay, hypotonia, dysmorphic facial features, and clasped thumbs with onset of kidney dysfunction age 3 post-cardiac transplant. PMID: 32516863 – Kolbel et al 2020 report one neonate with homozygous FLNC variant c.1325C>G (p.Pro442Arg). Absent from gnomad. Presented with weak suck first month of life with subsequent motor development delay, generalised muscular hypotonia, contractures. Variant confirmed in both unaffected parents. Authors postulate this is a novel case of homozygous FLNC variants associated with congenital presentation. This is a single case report, only heterozygous variants reported so far including in congenital presentations, both parents with het variants unaffected. Possibility of an alternative genetic explanation for this patient's presentation not excluded. Sources: Literature |
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| Fetal anomalies v0.2841 | MFRP | Alison Yeung Added comment: Comment on list classification: Ocular anomalies not detectable on US. No extra-ocular fetal anomalies reported. Marked as Red for fetal anomalies gene panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2825 | NOVA2 |
Zornitza Stark changed review comment from: Six individuals with de novo frameshift variants resulting in C-terminal extension suggesting partial LoF as mechanism. Sources: Literature; to: Six individuals with de novo frameshift variants resulting in C-terminal extension suggesting partial LoF as mechanism. Structural brain abnormalities reported. Sources: Literature |
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| Fetal anomalies v0.2825 | KIF26B |
Zornitza Stark gene: KIF26B was added gene: KIF26B was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: KIF26B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KIF26B were set to 30151950 Phenotypes for gene: KIF26B were set to Progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis Review for gene: KIF26B was set to RED Added comment: 1 report only of infant with progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis secondary to the involvement of anterior horn cells and ventral (motor) nerves. Whole exome sequencing on the trio identified a de novo KIF26B missense variant (p.Gly546Ser). Functional analysis of the variant protein in cultured cells revealed a reduction in the KIF26B protein's ability to promote cell adhesion, a defect that potentially contributes to its pathogenicity. Sources: Expert Review |
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| 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 v0.2818 | SLC35A1 | Zornitza Stark changed review comment from: Three unrelated families reported.; to: Three unrelated families reported, variable severity, including onset. Microcephaly reported, but onset uncertain. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2801 | MCPH1 |
Zornitza Stark changed review comment from: Single individual reported as part of a CDH cohort. Sources: Literature; to: Well established primary micorcephaly gene. Sources: Literature |
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| Fetal anomalies v0.2799 | MCOLN1 | Zornitza Stark edited their review of gene: MCOLN1: Added comment: Prenatal presentations with brain abnormalities reported.; Changed rating: GREEN; Changed publications: 33963976 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2793 | MAPRE2 |
Zornitza Stark changed review comment from: ID is part of the phenotype, more severe in those with bi-allelic variants. Sources: Expert list; to: Cleft palate and microcephaly reported. Sources: Expert list |
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| Fetal anomalies v0.2772 | LRRC6 | Zornitza Stark changed review comment from: More than 10 unrelated families reported.; to: More than 10 unrelated families reported. Situs inversus is a feature. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2772 | LRP5 | Zornitza Stark Phenotypes for gene: LRP5 were changed from HIGH BONE MASS TRAIT; ENDOSTEAL HYPEROSTOSIS WORTH TYPE; VITREORETINOPATHY EXUDATIVE TYPE 4; OSTEOPETROSIS AUTOSOMAL DOMINANT TYPE 1; OSTEOPOROSIS-PSEUDOGLIOMA SYNDROME to Osteoporosis-pseudoglioma syndrome, MIM# 259770; Polycystic liver disease 4 with or without kidney cysts, MIM# 617875 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2770 | LRP5 | Zornitza Stark edited their review of gene: LRP5: Changed rating: GREEN; Changed phenotypes: Osteoporosis-pseudoglioma syndrome, MIM# 259770, Polycystic liver disease 4 with or without kidney cysts, MIM# 617875 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2766 | LMX1B |
Zornitza Stark changed review comment from: Nail-patella syndrome (NPS) is an autosomal-dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Varying degrees of proteinuria or hematuria are present, and can occasionally progress to chronic renal failure. >300 families reported.; to: Nail-patella syndrome (NPS) is an autosomal-dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Varying degrees of proteinuria or hematuria are present, and can occasionally progress to chronic renal failure. >300 families reported. Prenatal presentations with abnormal limb movement reported. |
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| Fetal anomalies v0.2761 | LMBRD1 | Zornitza Stark changed review comment from: DD/ID reported in many affected individuals.; to: Onset in infancy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2760 | LMBR1 |
Zornitza Stark changed review comment from: Radial aplasia but with ulnar dimelia. Reported microduplications in LMBR1 associated with Laurin-Sandrow syndrome are in the SHH regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene. Duplications are >10kb. Sources: Expert list; to: Variants are associated with multiple types of limb anomalies. Note that the reported microduplications in LMBR1 associated with Laurin-Sandrow syndrome are in the SHH regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene. Duplications are >10kb. Sources: Expert list |
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| Fetal anomalies v0.2756 | ERGIC1 |
Krithika Murali gene: ERGIC1 was added gene: ERGIC1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ERGIC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ERGIC1 were set to 28317099; 34037256; 31230720 Phenotypes for gene: ERGIC1 were set to Arthrogryposis multiplex congenita 2, neurogenic type; OMIM # 208100 Review for gene: ERGIC1 was set to GREEN Added comment: Recent Panelapp review by Z. Stark Oct 2021 - no new publications since --- Pehlivan et al. 2019 (PMID:31230720) identified the third case of arthrogryposis in a child who harboured a previously unreported homozygous variant (c.782G>A; p.Gly261Asp) in this gene. Parents were heterozygous carriers. Functional studies were not performed. Created: 14 Oct 2021, 7:23 a.m. | Last Modified: 14 Oct 2021, 7:23 a.m. Panel Version: 0.9373 Reinstein et al. (2018) used WES in a large consanguineous Israeli Arab kindred consisting of 16 patients affected with the neurogenic type of arthrogryposis multiplex congenita. They identified a homozygous missense (V98E) mutation in ERGIC1 gene, which segregated with the disorder in the kindred, and was not found in the ExAC database or in 212 ethnically matched controls. Functional studies of the variant and studies of patient cells were not performed. ERGIC1 encodes a cycling membrane protein which has a possible role in transport between endoplasmic reticulum and Golgi. Marconi et al (2021) used genome sequencing in a consanguineous family with 2 affected siblings presenting congenital arthrogryposis and some facial dysmorphism. They identified a homozygous 22.6 Kb deletion encompassing the promoter and first exon of ERGIC1. mRNA quantification showed the complete absence of ERGIC1 expression in the two affected siblings and a decrease in heterozygous parents. Sources: Literature Sources: Literature |
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| Fetal anomalies v0.2756 | ERBB3 |
Krithika Murali gene: ERBB3 was added gene: ERBB3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ERBB3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ERBB3 were set to 31752936; 17701904; 33720042 Phenotypes for gene: ERBB3 were set to Lethal congenital contractural syndrome 2, MIM# 607598; Hirschsprung disease (HSCR, aganglionic megacolon) MIM#142623 Review for gene: ERBB3 was set to GREEN Added comment: Biallelic variants associated with multi-system disorder, including gut dysmotility/Hirschsprung disease; with or without contractures. -- PMID 33497358: 6 individuals from 4 unrelated families reported with severe gut dysmotility and other features of neurocristinopathy including short-segment HSCR, progressive axonal peripheral neuropathy, dysautonomia, hypopigmentation, deafness. Note variants in this gene have also recently been linked to Hirschsprung's disease. PMID 17701904: Lethal congenital contractual syndrome: Two families reported with contractures, positional approach used in gene discovery (2007). PMID 33720042 - Seven variants (missense and frameshfit) from four independent families with Hirschsprung disease (HSCR) reported. All reported individuals variably associated with conditions such as HSCR, chronic intestinal pseudo-obstruction, peripheral neuropathy, and arthrogryposis. Functional study revealed mutant proteins reduced protein expression or altered phosphorylation of the mutant receptors. Sources: Literature |
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| Fetal anomalies v0.2729 | MED25 |
Krithika Murali gene: MED25 was added gene: MED25 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MED25 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MED25 were set to 25792360; 32816121; 32816121; 32324310 Phenotypes for gene: MED25 were set to multiple congenital anomalies; congenital heart defects; hypospadias, thin corpus callosum, cerebral ventricular dilatation; Basel-Vanagait-Smirin-Yosef syndrome - #616449; Congenital cataract-microcephaly-naevus flammeus syndrome MONDO:0014643 Review for gene: MED25 was set to GREEN Added comment: Multiple individuals reported - biallelic variants associated with severe syndromic neurodevelopmental disorder diagnosed from infancy. PMID 32324310 - report one patient with antenatal ultrasound demonstrating cleft lip and clenched hands. Additional features associated wtih this condition that may be diagnosed antenatally include cleft palate, cardiac septal defects, hypospadias, polymicrogyria, thin corpus callosum, microcephaly and cerebral ventricular dilatation. Sources: Literature |
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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 | 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 v0.2728 | 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 v0.2712 | FMN1 |
Krithika Murali gene: FMN1 was added gene: FMN1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FMN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FMN1 were set to 20610440; 19383632; 15202026 Phenotypes for gene: FMN1 were set to oligosyndactyly; radioulnar synostosis; hearing loss; renal defects Review for gene: FMN1 was set to AMBER Added comment: No OMIM gene-disease association. No additional evidence since last review of this gene in Sep 2021. PMID 20610440 - a 263 Kb homozygous deletion of FMN1 reported in an individual with oligosyndactyly, radioulnar synostosis, hearing loss and renal defects. Supporting null mouse model with oligosyndactyly. A large duplication including FMN1 and GREM1 reported in another individual with Cenani–Lenz syndrome. Sources: Literature |
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| Fetal anomalies v0.2712 | FAT1 |
Krithika Murali gene: FAT1 was added gene: FAT1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FAT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAT1 were set to 30862798; 26905694; 34202629; 34013115; 33418956; 32902815 Phenotypes for gene: FAT1 were set to multiple congenital anomalies; nephropathy; ocular anomalies; hand and foot anomalies Review for gene: FAT1 was set to GREEN Added comment: No OMIM gene-disease association, but multiple affected individuals from unrelated families reported with biallelic FAT1 variants and syndromic features consisting of ocular anomalies, hand/foot malformations and nephropathy. Although diagnosis antenatally not yet reported, some phenotypic features are detectable antenatally. PMID: 30862798 Larouchi et al 2019 - homozygous frameshift FAT1 variants identified in 10 affected individuals from 5 unrelated consanguineous families. The patients presented with syndromic features including ocular anomalies (ptosis, microphthalmia, coloboma, amblyopia), nephropathy (FSGS, proteinuria, haematuria), toe syndactyly and facial dysmorphism. Animal models showing that deletion of Fat1 leads to coloboma in mouse and zebrafish. PMID 26905694 Gee et al 2016 – report recessive mutations in FAT1 in four unrelated consanguineous families with a combination of steroid-resistant nephrotic syndrome, tubular ectasia, haematuria and variable neurodevelopmental findings such ID, polymicrogyria and hydrocephalus. X1 child with pulmonary stenosis. PMID: 34202629 Peluso et al 2021 – Homozygous FAT1 frameshift variant NM_005245.4:c.9729del identified in a child of consanguineous parents with bilateral anophthalmia and hand/foot malformations including - right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. Patient also had congenital heart defects including VSD, ASD and bicuspid aortic valve. Proband also had a microarray which detected a maternally inherited 350 kb 15q26.3 duplication including OMIM morbid gene CERS3 (AR condition) and part of the OMIM morbid gene ADAMTS17 (AR condition). Mother healthy, CNV unrelated to patient’s phenotype. PMID: 34013115 Fabretti et al 2021 – report 4 patients with biallelic FAT1 variants from 3 unrelated families with syndactyly, ophthalmologic and renal phenotype consistent with previously reported cases. PMID: 33418956 Haug et al 2021 - Genetic analysis showed that proband with phenotypic features consistent with other reported cases was compound heterozygous for a frameshift FAT1 variant and 1.8Mb 4q35.2 del including FAT1. PMID: 32902815 Rossanti et al 2021 – Biallelic FAT1 variants reported in a child with isolated mild proteinuria and no syndromic features Sources: Literature |
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| Fetal anomalies v0.2711 | ANGPT2 |
Zornitza Stark gene: ANGPT2 was added gene: ANGPT2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: ANGPT2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: ANGPT2 were set to 34876502; 32908006 Phenotypes for gene: ANGPT2 were set to Hydrops; Lymphatic malformation-10, MIM#619369 Review for gene: ANGPT2 was set to GREEN Added comment: Mono-allelic disease: association with lymphoedema in 5 unrelated individuals PMID 32908006 Bi-allelic disease PMID 34876502: single family reported with four fetuses with hydrops fetalis homozygous for ANGPT2 NM_001147.2:c.557A>G. The consanguineous parents and surviving sibblings (a girl and a boy), were heterozygous for this variant. This variant is predicted to create a cryptic exonic splice site, resulting in a r.557_566del and nonsense-mediated mRNA decay. This prediction was supported by the lack of a transcript from this allele in the parents. Sources: Literature |
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| Fetal anomalies v0.2687 | PAX8 |
Zornitza Stark changed review comment from: Typically presents post-natally.; to: Isolated congenital hypothyroidism typically presents post-natally. However note PMID 33434492 reports 5 individuals identified in large cohorts with MRKHS and likely deleterious variants in PAX8. At least one of the individuals had congenital hypothyroidism together with features of MRKHS. |
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| Fetal anomalies v0.2676 | PAK3 |
Zornitza Stark changed review comment from: Well established gene-disease association, over 20 families reported. PMID: 31943058 (2020) - Animal mouse model with a hemizygous variant (p.R67C) in the Pak3 gene, recapitulated some features of the human ID phenotype. Mutant male mice exhibited impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. Analysing critical periods of hippocampal neurogenesis revealed dysfunctional maturation and learning-associated recruitment, as well as accelerated death of selective populations of adult-born hippocampal neurons - offering a possible mechanism to the observed cognitive impairments.; to: Well established gene-disease association, over 20 families reported. Prenatal presentation with agenesis of corpus callosum reported, PMID 31843706. PMID: 31943058 (2020) - Animal mouse model with a hemizygous variant (p.R67C) in the Pak3 gene, recapitulated some features of the human ID phenotype. Mutant male mice exhibited impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. Analysing critical periods of hippocampal neurogenesis revealed dysfunctional maturation and learning-associated recruitment, as well as accelerated death of selective populations of adult-born hippocampal neurons - offering a possible mechanism to the observed cognitive impairments. |
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| Fetal anomalies v0.2665 | WNT5A | Zornitza Stark changed review comment from: LD/ID reported in ~20% according to this cohort/literature review.; to: Robinow syndrome is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2597 | MAP3K20 | Zornitza Stark reviewed gene: MAP3K20: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Centronuclear myopathy 6 with fiber-type disproportion MIM#617760, Split-foot malformation with mesoaxial polydactyly MIM#616890; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2597 | HAND2 |
Krithika Murali edited their review of gene: HAND2: Added comment: No OMIM gene disease association. Borderline red-amber gene. PMID: 26676105 Lu et al 2016 - 145 unrelated patients with CHD, Han Chinese descent versus 200 unrelated controls had HAND2 gene sequencing. In x1 patient with ToF hetrozygous HAND2 c.140T>C p.L47P variant identified, parents unaffected, variant reported to be de novo but paternity not confirmed. Absent from gnomad, x1 het synonymous variant in this position only. Functional analysis showed reduced transcriptional activity PMID: 32134193 Cohen et al 2020 - 31-month-old male with unicommissural unicuspid aortic valve, moderate aortic stenosis, and mild pulmonic stenosis. CMA identified 546kb deletion on chr 4q34.1 (174364195-174910239[GRCh37/hg19]). Deletion encompasses exons 1 and 2 of SCRG1, HAND2, and HAND2-AS1. Deletion paternally inherited - proband's father had history of ToF. Novel deletion - no similar deletions in Decipher or DGV. Proband also had CHD7 VUS (c.2830C>T, p.Arg944Cys) – but no features of CHARGE syndrome and CHD7 variant present in 7 hets in gnomad PMID: 30217752 Liu et al 2019 - screened 206 unrelated Han Chinese patients with adult-onset idiopathic DCM and 300 unrelated controls. Identified HAND2 variant c.199G>T; p.(Glu67*). Authors report segregation of the variant with other affected individuals in the family including x2 with VSD/PDA PMID: 26865696 Sun et al 2016 - HAND2 sequenced in 192 unrelated Han Chinese patient. Het p.S65I variant identified in a patient with VSD and present in all 7 family members with CHD and absent from 13 unaffected members. Variant present in gnomad – 3 hets (x1 East Asian, x1 South Asian, x1 Latin American) PMID 20819618 - Shen et al 2010 131 unrelated Han Chinese patients with ToF had HAND2 gene sequencing. Het c.32C>G p.Pro11Arg identified in x2 unrelated patients – no seg, not in gnomad but in area of low coverage. c.42C>T – present in x1 patient with ToF + VSD – no segregation data, not in gnomad but in area of low coverage; Changed rating: AMBER; Changed publications: 26865696, 32134193, 26676105, 30217752, 20819618 |
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| Fetal anomalies v0.2539 | TRPM7 |
Zornitza Stark changed review comment from: 4 variants identified in a stillbirth cohort. Some supportive evidence that these variants alter channel function.; to: 4 variants identified in a stillbirth cohort. Ion channel expressed in the nervous and cardiac systems. The variant associated with ALS/dementia in the Guam population, p.Thr1482Ile is present in >23,000 hets in gnomad, which is out of keeping for a rare Mendelian disorder. Note recent publication associating missense variants with cardiac arrhythmia and stillbirth, with some functional data provided to substantiate effect of variant on protein function but not necessarily establish gene-disease association. |
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| Fetal anomalies v0.2494 | STIL | Zornitza Stark changed review comment from: More than 10 unrelated families reported.; to: More than 10 unrelated families reported. Brain abnormalities in one. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2479 | ZMYND11 |
Zornitza Stark changed review comment from: New case series of additional 16 individuals reported, including four individuals from the same family. Common phenotypic features: developmental delay, particularly affecting speech, mild‐moderate intellectual disability, significant behavioral abnormalities, seizures, and hypotonia. There are subtle shared dysmorphic features, including prominent eyelashes and eyebrows, a depressed nasal bridge with bulbous nasal tip, anteverted nares, thin vermilion of the upper lip, and wide mouth. Novel features include brachydactyly and tooth enamel hypoplasia. Most identified variants are likely to result in premature truncation and/or nonsense‐mediated decay. Two ZMYND11 variants located in the final exon reported —p.(Gln586*) (likely escaping nonsense‐mediated decay) and p.(Cys574Arg)—are predicted to disrupt the MYND‐type zinc‐finger motif and likely interfere with binding to its interaction partners.; to: New case series of additional 16 individuals reported, including four individuals from the same family. Common phenotypic features: developmental delay, particularly affecting speech, mild‐moderate intellectual disability, significant behavioral abnormalities, seizures, and hypotonia. There are subtle shared dysmorphic features, including prominent eyelashes and eyebrows, a depressed nasal bridge with bulbous nasal tip, anteverted nares, thin vermilion of the upper lip, and wide mouth. Novel features include brachydactyly and tooth enamel hypoplasia. Most identified variants are likely to result in premature truncation and/or nonsense‐mediated decay. Two ZMYND11 variants located in the final exon reported —p.(Gln586*) (likely escaping nonsense‐mediated decay) and p.(Cys574Arg)—are predicted to disrupt the MYND‐type zinc‐finger motif and likely interfere with binding to its interaction partners. Presentation is post-natal. |
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| Fetal anomalies v0.2476 | ZMYND10 | Zornitza Stark changed review comment from: More than 10 families reported.; to: More than 10 families reported. Situs inversus is a feature. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2448 | USP27X |
Zornitza Stark changed review comment from: Four individuals from two unrelated families reported. Sources: Expert list; to: Four individuals from two unrelated families reported. Post-natal presentation. Sources: Expert list |
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| Fetal anomalies v0.2427 | TUFM | Zornitza Stark changed review comment from: IUGR is a feature.; to: IUGR is a feature. Micropolymicrogyria also reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2422 | TTC25 |
Zornitza Stark changed review comment from: 2 families reported with PCD. Mouse model showed immotile nodal cilia. Gene ncodes a component of the outer dynein arm required to develop the main mechanical force to generate ciliary beats. (Gene is non coding in gnomad v2 and coding in v3); to: 2 families reported with PCD. Some individuals had situs inversus. Mouse model showed immotile nodal cilia. Gene ncodes a component of the outer dynein arm required to develop the main mechanical force to generate ciliary beats. (Gene is non coding in gnomad v2 and coding in v3) |
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| Fetal anomalies v0.2408 | TRMT10A | Zornitza Stark changed review comment from: More than 5 unrelated families reported. ID is a feature.; to: More than 5 unrelated families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2403 | TRIM32 |
Zornitza Stark changed review comment from: Single family reported in 2006.; to: BBS: Single family reported in 2006. Muscular dystrophy: onset is typically in childhood. |
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| Fetal anomalies v0.2392 | TRAF3IP1 |
Zornitza Stark changed review comment from: 5 unrelated families, zebrafish and mouse models.; to: 5 unrelated families, zebrafish and mouse models. Nephronophthisis is a key feature, polydactyly reported in some. |
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| Fetal anomalies v0.2366 | TELO2 |
Zornitza Stark changed review comment from: Five unrelated families reported. Sources: Expert list; to: Five unrelated families reported. Microcephaly, congenital heart disease, renal malformations reported. Sources: Expert list |
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| Fetal anomalies v0.2366 | HAND1 |
Krithika Murali edited their review of gene: HAND1: Added comment: No OMIM gene disease association PMID: 28112363 Li et al 2017 - HAND1 gene sequenced in 158 unrelated patients with CHDs and 600 controls. A de novo heterozygous truncating variant was identified (c.394A>T p.K132X) in a 5 month old body with double outlet right ventricle and VSD. Absent from gnomad, not present in unaffected parents or in controls. Functional analysis supported loss of HAND1 transcriptional activity. PMID: 29317578 Wang et al 2017 – article in Chinese, abstract in English. A total of 125 patients with congenital VSD and 210 controls. HAND1 truncating variant identified in an individual with VSD( c.355G>T E119X ). Absent from population database, x1 missense variant at same position 28 hets and x1 synonymous variant with 1 het present in gnomad. No segregation data PMID: 29179274 Zhi et al 2017 - A novel heterozygous mutation, a substitution of thymine for guanine at nucleotide 346 (c.346G>T), predicting the conversion of a glutamic acid-encoding codon into a stop codon at codon 116 (p.E116X), was detected in a patient with sporadic DCM out of a cohort of 120 Chinese patients with DCM versus 200 healthy controls. Absent from gnomad. No segregation data. Article in Chinese, abstract in English, unlikely to be congenital onset. PMID: 27942761 Wang et al 2017 - 165 unrelated patients with CHD and 600 unrelated controls. Heterozygous missense HAND1 variant identified in a patient with TOF (c.352C>T p.R118C) . Functional studies supporting significantly reduced transcriptional activity, absent from gnomad, damaging in silicos, no parental testing. PMID: 26581070 Zhou et al 2016 - heterozygous truncating HAND1 variant, c.313A > T p.R105X identified in a DCM family, absent in controls, reduced transcrptional activities, x1 het inframe deletion at the same position in gnomad and x1 synonymous variant. Segregated with family members with DCM and VSD. PMID: 31286141 Firulli et al 2020 – mouse models showing that myocardial deletion of Hand1 resulted in morphological defects including interventricular septal defects, abnormal LV papillary muscles and cardiac conduction system defects PMID: 29016838 Firulli et al 2017 - Hand1A126FS mutation does exhibit embryonic lethal cardiac defects in mouse models; Changed rating: AMBER; Changed publications: 31286141, 29016838, 29317578, 29179274, 28112363, 27942761, 26581070 |
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| Fetal anomalies v0.2366 | DYNC1I1 |
Krithika Murali gene: DYNC1I1 was added gene: DYNC1I1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: DYNC1I1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DYNC1I1 were set to 22914741; 25231166; 32219838 Phenotypes for gene: DYNC1I1 were set to Split-hand/split-foot malformation (SHFM) Review for gene: DYNC1I1 was set to GREEN Added comment: Gene disease association reviewed Sept 2021 - no new publications At least 6 unrelated families with overlapping deletions that included exons 15 and 17 of DYNC1I1. Exons 15 and 17 have previously been shown to act as tissue-specific enhancers of Dlx5/6 in mouse and zebrafish. No SNVs reported in association with disease. Sources: Literature |
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| 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 v0.2364 | TECPR2 |
Zornitza Stark changed review comment from: SPG49 is an autosomal recessive complicated form of spastic paraplegia. PMID 23176824 reported 4 Jewish Bukharian individuals homozygous for same founder variant and delayed psychomotor development, intellectual disability, and onset of spastic paraplegia in the first decade. Affected individuals also had dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, some of which were fatal. Three additional patients from unrelated non-Bukharian families reported in PMID 26542466, harboring two novel variants (c.1319delT, c.C566T) in this gene. In addition to intellectual disability and evolving spasticity, autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events were prominent. Included due to mild CC abnormalities.; to: SPG49 is an autosomal recessive complicated form of spastic paraplegia. PMID 23176824 reported 4 Jewish Bukharian individuals homozygous for same founder variant and delayed psychomotor development, intellectual disability, and onset of spastic paraplegia in the first decade. Affected individuals also had dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, some of which were fatal. Three additional patients from unrelated non-Bukharian families reported in PMID 26542466, harboring two novel variants (c.1319delT, c.C566T) in this gene. In addition to intellectual disability and evolving spasticity, autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events were prominent. Included due to mild CC abnormalities, though clinical presentation is predominantly post-natal. |
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| Fetal anomalies v0.2364 | TECPR2 |
Zornitza Stark changed review comment from: SPG49 is an autosomal recessive complicated form of spastic paraplegia. PMID 23176824 reported 4 Jewish Bukharian individuals homozygous for same founder variant and delayed psychomotor development, intellectual disability, and onset of spastic paraplegia in the first decade. Affected individuals also had dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, some of which were fatal. Three additional patients from unrelated non-Bukharian families reported in PMID 26542466, harboring two novel variants (c.1319delT, c.C566T) in this gene. In addition to intellectual disability and evolving spasticity, autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events were prominent; to: SPG49 is an autosomal recessive complicated form of spastic paraplegia. PMID 23176824 reported 4 Jewish Bukharian individuals homozygous for same founder variant and delayed psychomotor development, intellectual disability, and onset of spastic paraplegia in the first decade. Affected individuals also had dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, some of which were fatal. Three additional patients from unrelated non-Bukharian families reported in PMID 26542466, harboring two novel variants (c.1319delT, c.C566T) in this gene. In addition to intellectual disability and evolving spasticity, autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events were prominent. Included due to mild CC abnormalities. |
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| Fetal anomalies v0.2360 | TCF20 |
Zornitza Stark changed review comment from: Many unrelated patients reported, including 24 families reported in Torti 2019 (PMID:30739909). Most variants are protein-truncating.; to: Many unrelated patients reported, including 24 families reported in Torti 2019 (PMID:30739909). Most variants are protein-truncating. Typically presents post-natally. |
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| 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 v0.2354 | TBR1 |
Zornitza Stark changed review comment from: Heterozygous de novo PTC and missense variants reported in at least 7 unrelated patients with impaired intellectual development with autism and speech delay (PMID: 25232744, 30250039).; to: Heterozygous de novo PTC and missense variants reported in at least 7 unrelated patients with impaired intellectual development with autism and speech delay (PMID: 25232744, 30250039). Pachygyria in some individuals. |
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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 v0.2339 | EMC1 |
Zornitza Stark changed review comment from: Four unrelated families with bi-allelic variants in this gene reported. Single individual with heterozygous variant: insufficient evidence at present for mono allelic variants causing disease. Sources: Expert list; to: Four unrelated families with bi-allelic variants in this gene reported. Microcephaly is acquired; CC abnormalities reported. Single individual with heterozygous variant: insufficient evidence at present for mono allelic variants causing disease. Sources: Expert list |
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| Fetal anomalies v0.2337 | EIF2S3 |
Zornitza Stark changed review comment from: 9 families reported (3 had the same variant) with MEHMO syndrome (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity).; to: 9 families reported (3 had the same variant) with MEHMO syndrome (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity). Cleft palate also reported. |
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| Fetal anomalies v0.2331 | EEF1A2 |
Zornitza Stark changed review comment from: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1A2 null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.; to: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1A2 null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function. However, presentation is typically post-natal. |
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| Fetal anomalies v0.2322 | DPM3 | Zornitza Stark changed review comment from: Most affected individuals reported to date have not had ID.; to: Most affected individuals reported to date have not had ID. Predominantly limb-girdle weakness with onset in later childhood or adulthood. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2320 | DPM2 |
Zornitza Stark changed review comment from: 3 patients from 2 families reported.; to: 3 patients from 2 families reported. Congenital contractures. |
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| Fetal anomalies v0.2320 | FOXH1 |
Krithika Murali edited their review of gene: FOXH1: Added comment: No OMIM gene disease association. Overall, evidence for this gene and its association with congenital heart disease is conflicting. Roessler et al 2008 PMID 18538293 Pilot consortium study of 375 unrelated individuals prospectively ascertained with cardiovascular malformations. Patients not seen at NIH and parents/siblings not consented. Therefore only samples from proband collected. Also screened 300-500 patients with holoprosencephaly and 125 unrelated controls. Over 60 heterozygous FOXH1 variants reported in patients with congenital heart disease or holoprosencephaly. The majority of reported variants were of questionable pathogenicity as they were present in gnomad, had variants present in gnomad with alternative amino acid changes at the same position, had limited evidence of effect on FOXH1 functional activity or were synonymous variants. Furthermore, no variant segregation data available. De Luca et al 2009 PMID 19933292 FOXH1 (Pro21Ser) missense variant identified. Not present in gnomad but in area of low coverage, alternative aa change reported in the same location in x1 het. Identified in proband with TGA and x2 other unaffected family members. Proband who was also heterozogous for an amino acid substitution (Gly17Cys) in the ZIC3 gene Wei et al 2020 Clinical Genetics PMID 32003456 Exome sequencing performed in 605 patients with sporadic conotruncal defects and 300 controls in patients of Chinese descent with ages ranging from 6 days to 12 years old, majority <2 years old. 14 gene panel used. Identified 7 FOXH1 missense variants in 10 unrelated patients with congenital heart disease. All reported variants associated with reduced protein expression of FOXH1 protein on Western blot to varying degrees. No segregation data provided. • FOXH1 c.104C>G p.P35R identified in a 9 month old with double outlet right ventricle. Absent from gnomad but is in an area of low exome coverage. Variant with alternative amino acid change at same position (FOXH1 c.104C>T p.P35L) previously identified in a patient with congenital heart disease (Roessler et al 2008) • X2 patients - FOXH1 c.205T>C p.Phe69Leu. Also present in gnomad – x1 het non-Finnish European. X1 patient with alternative amino acid change at same position also identified (FOXH1 c.206T>C p.Phe69Ser) – absent from gnomad. • X2 patients with FOXH1 c.209T>C p.Phe70Ser - absent from gnomad • X2 patients with FOXH1 c.232A>G p.Lys78Glu – x2 hets gnomad (European non-Finnish, South Asian) • X1 patient with FOXH1 c.277A>G p.Lys93Glu – x1 het gnomad (European Finnish) • X1 patients FOXH1 c.277A>G p.Glu165Gln – absent from gnomad, benign in silicos PMID 12094232, PMID 16304598 - Previous mouse models have demonstrated a role for Foxh1 in heart morphogenesis.; Changed rating: AMBER; Changed publications: 18538293, 19933292, 32003456, 12094232, 16304598; Changed phenotypes: Congenital heart disease |
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| Fetal anomalies v0.2316 | MBOAT7 |
Ain Roesley changed review comment from: 20 families with ID and seizures as main features microcephaly reported though OFC at birth are largely unknown low birth weight (>-3SD) reported in 1 family; to: > 20 families with ID and seizures as main features microcephaly reported though OFC at birth are largely unknown low birth weight (>-3SD) reported in 1 family |
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| Fetal anomalies v0.2310 | DNM2 |
Zornitza Stark changed review comment from: Single family reported with lethal congenital contractures, 3 sibs, postulated hypomorphic missense. Monoallelic variants in this gene is associated with neuropathy/myopathy/mitochondrial disease. Sources: Expert Review; to: Single family reported with lethal congenital contractures, 3 sibs, postulated hypomorphic missense. Monoallelic variants in this gene is associated with neuropathy/myopathy/mitochondrial disease and generally have onset in childhood or later. Sources: Expert Review |
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| Fetal anomalies v0.2307 | DNM1L |
Zornitza Stark changed review comment from: Dominant and recessive disease described depending on domain affected; dominant negative effect of heterozygous missense variants. LoF/LoF or LoF/missense for AR variants.; to: Dominant and recessive disease described depending on domain affected; dominant negative effect of heterozygous missense variants. LoF/LoF or LoF/missense for AR variants. Decreased fetal movements reported. |
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| Fetal anomalies v0.2307 | MAP3K20 | Ain Roesley reviewed gene: MAP3K20: Rating: GREEN; Mode of pathogenicity: None; Publications: 27816943, 26755636; Phenotypes: Centronuclear myopathy 6 with fiber-type disproportion MIM#617760, Split-foot malformation with mesoaxial polydactyly MIM#616890; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2300 | DNM1 |
Zornitza Stark changed review comment from: Well-established link between heterozygous variants in DNM1 and developmental and epileptic encephalopathy. Yigit et al. 2021 (PMID: 34172529) recently reported two unrelated patients with DEE and homozygous truncating variants (c.97C>T; p.(Gln33*) and c.850C>T; p.(Gln284*), respectively) in the DNM1 gene. All parents were heterozygous carriers but did not show any clinical symptoms indicating a recessive inheritance pattern. No function studies were performed.; to: Well-established link between heterozygous variants in DNM1 and developmental and epileptic encephalopathy. Yigit et al. 2021 (PMID: 34172529) recently reported two unrelated patients with DEE and homozygous truncating variants (c.97C>T; p.(Gln33*) and c.850C>T; p.(Gln284*), respectively) in the DNM1 gene. All parents were heterozygous carriers but did not show any clinical symptoms indicating a recessive inheritance pattern. No function studies were performed. Clinical presentation is typically post-natal. |
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| Fetal anomalies v0.2271 | DHX30 |
Zornitza Stark changed review comment from: Twelve unrelated individuals reported with de novo missense variants, some recurrent. Missense cluster within nucleic acid binding motifs (~p.457-p.787). Post-natal onset.; to: Twelve unrelated individuals reported with de novo missense variants, some recurrent. Missense cluster within nucleic acid binding motifs (~p.457-p.787). Post-natal presentation. |
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| Fetal anomalies v0.2271 | DHX30 |
Zornitza Stark changed review comment from: Twelve unrelated individuals reported with de novo missense variants, some recurrent. Missense cluster within nucleic acid binding motifs (~p.457-p.787).; to: Twelve unrelated individuals reported with de novo missense variants, some recurrent. Missense cluster within nucleic acid binding motifs (~p.457-p.787). Post-natal onset. |
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| Fetal anomalies v0.2267 | DHDDS |
Zornitza Stark changed review comment from: Five unrelated individuals reported with mono-allelic variants and a neurodevelopmental phenotype. Sources: Expert list; to: Five unrelated individuals reported with mono-allelic variants and a neurodevelopmental phenotype. However, presentation is post-natal. Sources: Expert list |
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| Fetal anomalies v0.2261 | DDX6 |
Zornitza Stark changed review comment from: Five unrelated individuals reported with 5 different de novo heterozygous missense mutations in exon 11 of the DDX6 gene. All variants occurred at conserved residues in either the QxxR or V motifs within the second RecA-2 domain of the helicase core; this region is involved in RNA and/or ATP binding, suggesting functional consequences. Sources: Literature; to: Five unrelated individuals reported with 5 different de novo heterozygous missense mutations in exon 11 of the DDX6 gene. All variants occurred at conserved residues in either the QxxR or V motifs within the second RecA-2 domain of the helicase core; this region is involved in RNA and/or ATP binding, suggesting functional consequences. Multiple congenital anomalies. Sources: Literature |
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| Fetal anomalies v0.2259 | DDX59 | Zornitza Stark changed review comment from: 5 unrelated families reported, renal involvement is not prominent.; to: 5 unrelated families reported, multiple congenital anomalies. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2257 | HYLS1 |
Zornitza Stark changed review comment from: A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human and patient cells have shown mislocalisation of the protein to the nucleus (PMID: 15843405, PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774). 2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932). No other variants have been reported as pathogenic in this gene. Amber rating given only single founder variant reported with a hydrocephalus phenotype with supporting functional data from multiple animal models indicative of ciliopathy.; to: A recurring homozygous missense variant p.Asp211Gly has been identified in at least 64 cases of hydrolethalus syndrome, described as a Finnish founder mutation (PMID: 15843405, PMID: 18648327). Functional studies in human and patient cells have shown mislocalisation of the protein to the nucleus (PMID: 15843405, PMID: 19400947). Functional studies in c. elegans showed that this variant impaired ciliogenesis (PMID: 19656802). Functional studies in drosophila showed that deletion of HYLS1 led to cilia dysfunction (PMID: 32509774). 2 homozygous living siblings (stop-loss, extension variant p.Ter300TyrextTer11) both diagnosed with Joubert syndrome. Patients had molar tooth signs and dysplasia of cerebellar vermis (PMID: 26830932). No other variants have been reported as pathogenic in this gene. Overall, sufficient evidence that variants in this gene cause a ciliopathy. |
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| Fetal anomalies v0.2255 | HSPG2 | Zornitza Stark changed review comment from: ID reported in ~25% of affected individuals.; to: Multiple congenital anomalies are a feature of both conditions. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2253 | HSD17B4 |
Zornitza Stark changed review comment from: DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. Less severe presentations have been termed type IV deficiency or Perrault syndrome.; to: DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. Less severe presentations have been termed type IV deficiency or Perrault syndrome. Cortical dysplasia, renal cysts are reported features. |
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| Fetal anomalies v0.2249 | HRAS | Zornitza Stark changed review comment from: Well established gene-disease association, over 100 affected individuals reported with a characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and developmental disability. Facial warts, particularly nasolabial, are often present in childhood.; to: Well established gene-disease association, over 100 affected individuals reported with a characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and developmental disability. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2244 | HIVEP2 |
Zornitza Stark changed review comment from: More than 10 unrelated individuals reported, most variants are LOF, supportive mouse model.; to: More than 10 unrelated individuals reported, most variants are LOF, supportive mouse model. Microcephaly and CC abnormalities reported in some. |
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| 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 v0.2205 | GORAB | Zornitza Stark changed review comment from: Reviewed against assessment by GEL curation team: agree ID is not a predominant feature of this condition.; to: Joint laxity including hip dislocation; microcephaly reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2201 | GNPTG |
Zornitza Stark changed review comment from: Mucolipidosis type III gamma is characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates. More than 20 unrelated families reported, mouse model.; to: Mucolipidosis type III gamma is characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates. More than 20 unrelated families reported, mouse model. Progressive metabolic disorder with childhood onset. |
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| Fetal anomalies v0.2195 | SOX11 | Chirag Patel edited their review of gene: SOX11: Added comment: Coffin-Siris syndrome is characterized by mild intellectual disability, dysmorphic facial features, hypertrichosis, microcephaly, growth deficiency, and hypoplastic fifth toenails. sox11a/b knockdown in zebrafish causes brain abnormalities, potentially explaining the brain phenotype of CSS. Numerous cases reported with heterozygous mutations. Can present with IUGR antenatally. Suitable for fetal anomalies panel.; Changed publications: PubMed: 24886874, 33785884, 33430815, 33086258, 31530938 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2052 | LAMA1 | Zornitza Stark Phenotypes for gene: LAMA1 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; CEREBELLAR DYSPLASIA WITH CYSTS WITH OR WITHOUT RETINAL DYSTROPHY to Poretti-Boltshauser syndrome, MIM# 615960 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2050 | LAMA1 |
Zornitza Stark changed review comment from: Four families with Poretti-Bolthauser syndrome identified in a cohort of 'unsolved' Joubert syndrome patients -- included due to phenotypic overlap. Sources: Literature; to: Cerebellar abnormalities. Four families with Poretti-Bolthauser syndrome identified in a cohort of 'unsolved' Joubert syndrome patients. Sources: Literature |
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| Fetal anomalies v0.2048 | L1CAM | Zornitza Stark changed review comment from: L1CAM conditions are typically associated with adducted thumb/lower limb spasticity. Single report identified of arthrogryposis.; to: Well established gene-disease association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2041 | KMT2D |
Zornitza Stark changed review comment from: Rare reports of CDH in Kabuki syndrome, not a characteristic or common feature; however, 4 identified in this CDH cohort.; to: Multiple congenital anomalies syndrome. |
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| Fetal anomalies v0.2039 | KMT2C |
Zornitza Stark changed review comment from: Mostly PTCs, 2 missense reported in ClinVar but in silicos evidence only; to: Mostly PTCs, 2 missense reported in ClinVar but in silicos evidence only. Multiple congenital anomalies syndrome. |
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| Fetal anomalies v0.2024 | KIF1A | Zornitza Stark edited their review of gene: KIF1A: Added comment: Brain abnormalities reported with the mono-allelic disorder.; Changed rating: GREEN; Changed phenotypes: NESCAV syndrome, MIM# 614255; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2000 | ZNF462 |
Chirag Patel changed review comment from: Dysgenesis of corpus callosum and structural heart defects reported as part of syndrome.; to: Dysgenesis of corpus callosum and structural heart defects reported as part of syndrome. Suitable for fetal anomalies panel. |
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| Fetal anomalies v0.1999 | ZNF462 | Chirag Patel commented on gene: ZNF462: Dysgenesis of corpus callosum and structural heart defects reported as part of syndrome. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1998 | KDM6A | Zornitza Stark changed review comment from: Cannot find specific reports of CDH in association with variants in this gene.; to: Multiple congenital anomalies syndrome. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1995 | KDM5C |
Zornitza Stark changed review comment from: Intellectual disability, progressive lower limb spasticity, epilepsy and a number of other more variable features. Affected females reported PMID 32279304.; to: Intellectual disability, progressive lower limb spasticity, epilepsy and a number of other more variable features. Affected females reported PMID 32279304. Micro and macrocephaly reported. |
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| Fetal anomalies v0.1991 | KANSL1 | Zornitza Stark changed review comment from: Well established gene-disease association, CNVs common.; to: Well established gene-disease association, CNVs common. Cardiac and GU abnormalities reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1985 | MAMLD1 | Zornitza Stark commented on gene: MAMLD1: Multiple individuals reported with hypospadias PMID: 26815876: 3’UTR is associated with increased risk of isolated hypospadias in Indian children | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1971 | NSD2 |
Zornitza Stark gene: NSD2 was added gene: NSD2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: NSD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NSD2 were set to 30345613; 31171569 Phenotypes for gene: NSD2 were set to Rauch-Steindl syndrome, MIM# 619695 Review for gene: NSD2 was set to GREEN Added comment: 7 unrelated individuals reported with LOF variants. Gene thought to be responsible for many of the features of Wolf-Hirschorn syndrome. Prenatal growth retardation is a feature. Sources: Literature |
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| Fetal anomalies v0.1938 | NAA10 |
Zornitza Stark edited their review of gene: NAA10: Added comment: For Ogden association, PMID 34075687: lethal X-linked. 9 males from 3 families with recurrent Ser37Pro All presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias For non-lethal syndromic ID: reported in 10 males and (mostly de novo) in 37 females variants causing this are missense located along the protein and 1 truncating; Changed publications: 30842225, 24431331, 34075687; Changed phenotypes: Microphthalmia, syndromic 1, MIM# 309800 Ogden syndrome MIM#300855 |
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| Fetal anomalies v0.1933 | KCTD7 |
Daniel Flanagan changed review comment from: Biallelic KCTD7 variants reported in multile families with myoclonic epilepsy. No antenatally relevant features.; to: Biallelic KCTD7 variants reported in multile families with myoclonic epilepsy. Two affected siblings had microcephaly by the age of 12 years and 10 years, but were normal at infancy. |
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| Fetal anomalies v0.1930 | PI4KA |
Zornitza Stark gene: PI4KA was added gene: PI4KA was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PI4KA were set to 34415310 Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis MIM#616531; Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis MONDO:0014679 Review for gene: PI4KA was set to GREEN Added comment: 8 families reported with CNS abnormalities. Sources: Expert Review |
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| Fetal anomalies v0.1923 | GNAO1 |
Zornitza Stark changed review comment from: Loss of function mutations (PTCs and missense) cause EEIE, and gain of function mutations (missense, inframe deletion) cause NDIM. Almost all reports are de novo, rare parental mosaicism also reported (PMID: 30682224); to: Loss of function mutations (PTCs and missense) cause EEIE, and gain of function mutations (missense, inframe deletion) cause NDIM. Almost all reports are de novo, rare parental mosaicism also reported (PMID: 30682224) Microcephaly reported in some individuals. |
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| Fetal anomalies v0.1920 | GLIS3 | Zornitza Stark changed review comment from: Significant proportion of affected children described as having developmental delay.; to: Renal cystic dysplasia is a feature. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1871 | UROS | Zornitza Stark Phenotypes for gene: UROS were changed from CONGENITAL ERYTHROPOIETIC PORPHYRIA to Porphyria, congenital erythropoietic, MIM# 263700 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1865 | UROS | Alison Yeung reviewed gene: UROS: Rating: RED; Mode of pathogenicity: None; Publications: 24027798, 12533808; Phenotypes: PORPHYRIA, CONGENITAL ERYTHROPOIETIC (MIM #263700); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1837 | GBE1 | Zornitza Stark edited their review of gene: GBE1: Added comment: Three unrelated families reported with severe prenatal presentation of this muscle disorder causing fetal akinesia.; Changed rating: GREEN; Changed publications: 30303820; Changed phenotypes: Glycogen storage disease IV, MIM#232500, Fetal akinesia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1833 | GBA | Zornitza Stark edited their review of gene: GBA: Added comment: Multiple reports of perinatal lethal cases. IUGR, hydrops, polyhydramnios, decreased fetal movements.; Changed rating: GREEN; Changed phenotypes: Gaucher disease, perinatal lethal, MIM# 608013 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1825 | GALC |
Zornitza Stark changed review comment from: Cannot find reports of hydrops with this specific lysosomal storage disorder. Sources: Expert list; to: Cannot find reports of hydrops with this specific lysosomal storage disorder. Progressive post-natal course. Sources: Expert list |
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| Fetal anomalies v0.1813 | FREM1 |
Zornitza Stark changed review comment from: Single individual reported with compound het variants in this gene, supportive mouse model. Individual did not have features of BNAR/MOTA syndromes. Sources: Literature; to: Single individual reported with compound het variants in this gene and CDH, supportive mouse model. Individual did not have features of BNAR/MOTA syndromes. Sources: Literature |
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| Fetal anomalies v0.1813 | FREM1 |
Zornitza Stark edited their review of gene: FREM1: Added comment: Bi-allelic variants are associated with multiple congenital anomaly syndromes (MOTA and BNAR), which likely represent a spectrum. Three families reported with trigonocephaly and single missense variants.; Changed rating: GREEN; Changed publications: 32016392, 21931569, 21507892, 19732862, 20301721, 28111185; Changed phenotypes: Manitoba oculotrichoanal syndrome 248450, Bifid nose with or without anorectal and renal anomalies, MIM# 608980, Trigonocephaly 2, MIM# 614485 |
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| Fetal anomalies v0.1800 | FOXP3 | Zornitza Stark edited their review of gene: FOXP3: Added comment: Multiple reports of hydrops (over 10 individuals).; Changed rating: GREEN; Changed publications: 33637067, 30813833, 33330291 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1765 | FOXC2 |
Zornitza Stark changed review comment from: Single individual reported with CDH, some supportive functional data. Sources: Literature; to: Lymphoedema-distichiasis is an autosomal dominant disorder that classically presents as lymphoedema of the limbs and double rows of eyelashes (distichiasis). Other features that may present antenatally include cardiac defects, cleft palate, spinal extradural cysts, and CDH. Well established gene-disease association, multiple families reported. Sources: Literature |
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| Fetal anomalies v0.1762 | FOLR1 | Zornitza Stark Phenotypes for gene: FOLR1 were changed from NEURODEGENERATION DUE TO CEREBRAL FOLATE TRANSPORT DEFICIENCY to Neurodegeneration due to cerebral folate transport deficiency, MIM# 613068 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1713 | COX10 |
Zornitza Stark changed review comment from: More than 5 unrelated families reported, mitochondrial encephalopathy including developmental delay in some, though early severe multi-system disease or regression are the typical patterns of neurological involvement.; to: More than 5 unrelated families reported, mitochondrial encephalopathy including developmental delay in some, though early severe multi-system disease or regression are the typical patterns of neurological involvement. At least one individual reported with severe HCM in neonatal period. |
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| Fetal anomalies v0.1700 | CLTC | Zornitza Stark edited their review of gene: CLTC: Added comment: PMID 34230591: review of previously reported cases and report of 3 new cases, including one with prenatally ascertained brain and renal abnormalities.; Changed rating: GREEN; Changed publications: 29100083, 26822784, 34230591 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1689 | CHRNA4 | Zornitza Stark changed review comment from: ID only reported in one family with this condition.; to: Post-natal onset. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1682 | CCDC65 |
Zornitza Stark changed review comment from: Same homozygous PTC (p.I293Pfs*2) reported in 3 Ashkenzi Jewish families. PMID: 24094744 performs functional assay on null zebrafish model - replicates human phenotype supporting LOF. Three different LoF reported in context of primary ciliary dyskinesia by diagnostic laboratories in ClinVar.; to: Same homozygous PTC (p.I293Pfs*2) reported in 3 Ashkenzi Jewish families. PMID: 24094744 performs functional assay on null zebrafish model - replicates human phenotype supporting LOF. Three different LoF reported in context of primary ciliary dyskinesia by diagnostic laboratories in ClinVar. Situs inversus not reported. |
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| Fetal anomalies v0.1666 | SCO2 | Zornitza Stark changed review comment from: Typically manifests post-natally though rare fetal presentations reported, PMID 15210538.; to: Severe neonatal presentations, and at least two reports of fetal presentations. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1642 | AUTS2 | Zornitza Stark changed review comment from: Mental retardation, autosomal dominant 26, MIM#615834; to: Low birth weight and microcephaly reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1635 | ATP1A3 | Zornitza Stark edited their review of gene: ATP1A3: Added comment: Individuals with PMG reported.; Changed publications: 33762331, 33880529; Changed phenotypes: Developmental and epileptic encephalopathy 99, MIM# 619606, Polymicrogyria | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1623 | APOPT1 |
Zornitza Stark changed review comment from: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time. Clinical presentation is typically in childhood.; to: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time. Clinical presentation is typically in early childhood. |
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| Fetal anomalies v0.1623 | APOPT1 |
Zornitza Stark changed review comment from: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time.; to: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time. Clinical presentation is typically in childhood. |
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| Fetal anomalies v0.1618 | ALDOB | Zornitza Stark changed review comment from: ID is not an intrinsic feature of this condition; most reported individuals have had normal cognition; to: Presentation is typically post-natal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1616 | ALDH5A1 | Zornitza Stark changed review comment from: Over 50 unrelated families reported. Intellectual disability is part of the phenotype, which also includes developmental delay, hypotonia, ataxia, seizures, hyperkinetic behaviour, aggression, and sleep disturbances.; to: Over 50 unrelated families reported. Typically presents post-natally with intellectual disability, hypotonia, ataxia, seizures, hyperkinetic behaviour, aggression, and sleep disturbances. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1611 | ALAD | Zornitza Stark Phenotypes for gene: ALAD were changed from ACUTE HEPATIC PORPHYRIA to Porphyria, acute hepatic , MIM#612740 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1610 | ALAD | Zornitza Stark reviewed gene: ALAD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Porphyria, acute hepatic , MIM#612740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1608 | FLVCR2 |
Zornitza Stark edited their review of gene: FLVCR2: Added comment: The proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome is a (usually) prenatally lethal disorder characterized by hydranencephaly, a distinctive glomerular vasculopathy in the central nervous system and retina, and diffuse ischemic lesions of the brain stem, basal ganglia, and spinal cord with calcifications. It is usually diagnosed by ultrasound between 26 and 33 weeks' gestation. At least 5 unrelated families reported.; Changed rating: GREEN; Changed publications: 30712878, 20206334, 20518025, 20690116, 25677735; Changed phenotypes: Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome, MIM# 225790 |
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| 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 v0.1596 | FH |
Zornitza Stark changed review comment from: Listed as a cause of non-immune hydrops in a review, but cannot find reported cases. Sources: Expert list; to: Listed as a cause of non-immune hydrops in a review, but cannot find reported cases. Polymicrogyria and CC abnormalities reported. Sources: Expert list |
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| Fetal anomalies v0.1587 | FGF3 |
Zornitza Stark changed review comment from: Most features would not be detectable antenatally, but micrognathia may be evident.; to: Most features would not be detectable antenatally, but micrognathia may be evident. Over 50 affected individuals reported, functional data including animal models, expression studies and in vitro functional assays. |
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| Fetal anomalies v0.1582 | FGD1 |
Zornitza Stark changed review comment from: Aarskog-Scott syndrome is characterised by short stature, hypertelorism, shawl scrotum, brachydactyly, joint hyperextensibility, short nose, widow's peak, and inguinal hernia. Most patients do not have intellectual disability, but some may have neurobehavioral features. Carrier females may present with subtle features, such as widow's peak or short stature. Numerous cases reported with variants in FGD1 gene with replication over time.; to: Aarskog-Scott syndrome is characterised by short stature, hypertelorism, shawl scrotum, brachydactyly, joint hyperextensibility, short nose, widow's peak, and inguinal hernia. Most patients do not have intellectual disability, but some may have neurobehavioral features. Carrier females may present with subtle features, such as widow's peak or short stature. Cleft lip/palate reported. Numerous cases reported with variants in FGD1 gene with replication over time. |
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| Fetal anomalies v0.1576 | FBLN5 | Zornitza Stark changed review comment from: ID is not typically a feature.; to: Fetal overgrowth, CDH and joint dislocations/bone fractures reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.1469 | 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 | TBX2 |
Krithika Murali gene: TBX2 was added gene: TBX2 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: TBX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TBX2 were set to 29726930 Phenotypes for gene: TBX2 were set to Vertebral anomalies and variable endocrine and T-cell dysfunction - MIM#618223; Congenital heart disease; skeletal abnormalities; thymus aplasia Review for gene: TBX2 was set to GREEN Added comment: Liu et al. (2018) reported 4 affected individuals from 2 unrelated families with congenital cardiac defects (ASD, PDA, double outlet right ventricle, pulmonary stenosis), skeletal abnormalities (camptodactyly, congenital fusion thoracic spine, hemivertebrae ).Thymus aplasia/hypoplasia, cleft palate also noted. Other associated features include - facial dysmorphisms, variable developmental delay, and endocrine system disorders (e.g. autoimmune hypothyroidism, hypoparathyroidism). Sources: Literature, Expert list |
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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 | SMAD6 |
Krithika Murali gene: SMAD6 was added gene: SMAD6 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: SMAD6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMAD6 were set to 22275001; 31138930; 27606499; 32499606 Phenotypes for gene: SMAD6 were set to Aortic valve disease 2 - MIM#614823; {Craniosynostosis 7, susceptibility to} - MIM#617439; {Radioulnar synostosis, nonsyndromic} - #179300 Review for gene: SMAD6 was set to GREEN Added comment: Heterozygous SMAD6 variants have been reported with: congenital cardiovascular malformations including valvular disease radioulnar synostosis craniosynostosis (penetrance is 57%. A common polymorphism near BMP2 (rs1884302) was initially proposed to influence penetrance, but follow-up study did not corroborate this. In vitro luciferase assays suggest loss of SMAD6 inhibitory function) Sources: Literature, Expert list |
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| Fetal anomalies v0.1469 | ROBO4 |
Krithika Murali gene: ROBO4 was added gene: ROBO4 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: ROBO4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ROBO4 were set to 30455415 Phenotypes for gene: ROBO4 were set to Aortic valve disease 3- MIM#618496 Review for gene: ROBO4 was set to GREEN Added comment: Heterozygous variants identified in individuals from 2 unrelated families with bicuspid aortic valve and aortic dilatation. Supportive functional data. Incomplete penetrance also a feature. Sources: Literature, Expert list |
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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 v0.1469 | MYBPC3 |
Krithika Murali gene: MYBPC3 was added gene: MYBPC3 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: MYBPC3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYBPC3 were set to 16679492; 17937428; 19858127 Phenotypes for gene: MYBPC3 were set to Neonatal hypertrophic cardiomyopathy; Cardiomyopathy, hypertrophic, 4 - MIM#115197 Review for gene: MYBPC3 was set to GREEN Added comment: 16679492 - two unrelated neonates with severe hypertrophic cardiomyopathy caused by compound heterozygous truncating mutations in the MYBPC3 gene (no antenatal findings reported) 17937428 - 20 Old Order Amish children with severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site mutation in the MYBPC3 gene, diagnosed in the first 3 weeks of life, surviving individuals required cardiac transplant before age 1 19858127 - infant with fatal cardiomyopathy and skeletal myopathy due to a homozygous mutation, p.R943X Sources: Literature, Expert list |
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| Fetal anomalies v0.1469 | MESP1 |
Krithika Murali gene: MESP1 was added gene: MESP1 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: MESP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MESP1 were set to 28677747; 28050627; 27185833; 26694203 Phenotypes for gene: MESP1 were set to Congenital heart disease Review for gene: MESP1 was set to AMBER Added comment: Gene last reviewed April 2021 - Rare/novel variants reported in at least 7 unrelated individuals with congenital heart disease, in-silicos conflicting, familial segregation only available for some (one de novo, three inherited, others unresolved). Functional data implicates gene in cardiac development. No additional published evidence. Sources: Literature, Expert list |
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| Fetal anomalies v0.1469 | HAND2 |
Krithika Murali gene: HAND2 was added gene: HAND2 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: HAND2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HAND2 were set to 26865696; 32134193; 26676105 Phenotypes for gene: HAND2 were set to Congenital heart defects Review for gene: HAND2 was set to GREEN Added comment: Heterozygous LoF variants associated with congenital heart defects reported in at least 3 unrelated families. Sources: Literature, Expert list |
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| Fetal anomalies v0.1469 | GATA5 |
Krithika Murali gene: GATA5 was added gene: GATA5 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: GATA5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: GATA5 were set to 27066509; 23289003; 22961344; 23031282 Phenotypes for gene: GATA5 were set to Congenital heart defects, multiple types, 5 - #617912 Review for gene: GATA5 was set to GREEN Added comment: Heterozygous variants asociated with multiple types of congenital heart defects (septal defects, ToF). Autosomal recessive inheritance also reported in a patient with double outflow right ventricle in a consanguineous Lebanese family Sources: Literature, Expert list |
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| Fetal anomalies v0.1469 | FOXH1 |
Krithika Murali gene: FOXH1 was added gene: FOXH1 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: FOXH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FOXH1 were set to 19933292; 18538293; 19525021 Phenotypes for gene: FOXH1 were set to Congenital heart disease; holoprosencephaly Review for gene: FOXH1 was set to GREEN Added comment: Associated with congenital heart defects (including septal defects, tetralogy of fallot and transposition of the great arteries) as well as holoprosencephaly with supportive functional studies. Sources: Expert list, Literature |
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| Fetal anomalies v0.1469 | FBRSL1 |
Krithika Murali gene: FBRSL1 was added gene: FBRSL1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FBRSL1 were set to 32424618; 34805182 Phenotypes for gene: FBRSL1 were set to Congenital malformations; congenital heart defect Review for gene: FBRSL1 was set to GREEN Added comment: Associated with novel malformation and intellectual disability syndrome. Three unrelated children with de novo PTCs that escape NMD, with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations - 2/3 had heart defects (ASD, VSD), cleft palate and hearing impairement. Supported by Xenopus oocyte functional studies Sources: Literature |
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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 v0.1464 | BMPR2 |
Krithika Murali gene: BMPR2 was added gene: BMPR2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: BMPR2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BMPR2 were set to 31382961 Phenotypes for gene: BMPR2 were set to Persistent pulmonary hypertension of the neonate; Pulmonary hypertension, familial primary, 1, with or without HHT - MIM#178600; Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated- MIM#178600; Pulmonary venoocclusive disease 1-#265450 Penetrance for gene: BMPR2 were set to Incomplete Review for gene: BMPR2 was set to AMBER Added comment: BMPR2 gene variants known to be associated with sporadic/familial pulmonary hypertension and pulmonary venoocclusive disease. Fetal phenotype not reported but known to be associated with persistent pulmonary hypertension of the neonate - critical condition diagnosed in the early postnatal period. Sources: Literature |
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| Fetal anomalies v0.1451 | AFF2 |
Zornitza Stark changed review comment from: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar. Missense variants found to be over-represented in an autism cohort.; to: This is classically a triplet expansion disorder. Note one report of an intragenic deletion which segregated with ID in a family, and two truncating variants classified as pathogenic by laboratories in ClinVar. Missense variants found to be over-represented in an autism cohort. Congenital anomalies are not a prominent feature of this disorder. |
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| Fetal anomalies v0.1446 | ACVRL1 | Zornitza Stark changed review comment from: There is debate about when AVMs form and whether they are congenital or not. However, at least one report identified of antenatal presentation with Vein of Galen malformation.; to: There is debate about when AVMs form and whether they are congenital or not. However, neonatal presentations reported, and at least one report identified of antenatal presentation with Vein of Galen malformation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1446 | ACVRL1 | Zornitza Stark changed review comment from: Typically presents post-natally.; to: There is debate about when AVMs form and whether they are congenital or not. However, at least one report identified of antenatal presentation with Vein of Galen malformation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1446 | ACAT1 | Zornitza Stark changed review comment from: Primarily manifests as metabolic decompensation, DD/ID reported in a few individuals, mostly normal cognition.; to: Primarily manifests as metabolic decompensation post-natally. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1441 | DCDC2 |
Zornitza Stark changed review comment from: Only one convincing case reported with a renal phenotype, functional data (zebrafish model has renal cysts).; to: Only one convincing case reported with a renal phenotype, functional data (zebrafish model has renal cysts). Most reports are of neonatal cholangitis. |
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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 v0.1422 | CHRNE | Zornitza Stark changed review comment from: Well established association with congenital myasthenia, some individuals reported with arthrogryposis but cannot find specific reports of multiple pterygium syndrome.; to: Well established association with congenital myasthenia, some individuals reported with arthrogryposis. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1400 | COLQ | Zornitza Stark changed review comment from: Well established gene-disease association, more than 10 families reported. However, cannot find reports of presentation with multiple pterygia specifically.; to: Well established gene-disease association, more than 10 families reported. However, contractures not reported, and variable age of onset/progression. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1395 | COLEC10 | Zornitza Stark changed review comment from: Cleft lip/palate are a feature.; to: Cleft lip/palate are a feature. At least 4 families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1395 | COLEC10 | Zornitza Stark changed review comment from: ID is not reported as a feature in molecularly confirmed cases with variants in this gene.; to: Cleft lip/palate are a feature. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1366 | COG5 | Zornitza Stark changed review comment from: More than 5 unrelated families reported, ID is a consistent feature.; to: More than 5 unrelated families reported, microcephaly reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.1361 | TTC12 |
Krithika Murali gene: TTC12 was added gene: TTC12 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TTC12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TTC12 were set to 31978331 Phenotypes for gene: TTC12 were set to Ciliary dyskinesia, primary, 45 - MIM#618801 Review for gene: TTC12 was set to RED Added comment: Four unrelated families reported, LoF variants, respiratory phenotype. Sources: Literature |
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| Fetal anomalies v0.1361 | TP73 |
Krithika Murali gene: TP73 was added gene: TP73 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TP73 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TP73 were set to 31130284; 34077761 Phenotypes for gene: TP73 were set to Ciliary dyskinesia, primary, 47, and lissencephaly - MIM# 619466 Review for gene: TP73 was set to GREEN Added comment: 7 unrelated families reported. In vitro ciliogenesis experiments demonstrated that epithelial cells from TP73 variant carriers had reduced number of ciliated cells and shortened cilia resulting in abnormal ciliary clearance of the airways compared to healthy controls. Clinical features included recurrent respiratory infections and respiratory dysfunction caused by defective mucociliary clearance in early childhood. Affected individuals also had neurologic features, such as impaired intellectual development and central hypotonia, associated with structural brain abnormalities, most notably lissencephaly and thin or absent corpus callosum. Sources: Literature |
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| Fetal anomalies v0.1361 | SPEF2 |
Krithika Murali gene: SPEF2 was added gene: SPEF2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SPEF2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPEF2 were set to 31151990; 31278745; 31048344; 31942643 Phenotypes for gene: SPEF2 were set to Spermatogenic failure 43, MIM#618751; Primary ciliary dyskinesia-like phenotype Review for gene: SPEF2 was set to RED Added comment: Biallelic variants associated with sperm morphological abnormalities. In some individuals recurrent sinopulmonary infections and bronchiectasis noted consistent with PCD-like phenotype. Mouse model showed infertility phenotype, hydrocephalus, sinusitis. No fetal phenotype reported. Sources: Literature |
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| Fetal anomalies v0.1360 | CNTN1 |
Zornitza Stark changed review comment from: Single family reported, some functional data, no further reports since 2008 identified. Some pathogenic variants reported in ClinVar by diagnostic laboratories. Severe perinatal presentation.; to: Single family reported, some functional data, further family recently reported as part of a cohort. Some pathogenic variants reported in ClinVar by diagnostic laboratories. Severe perinatal presentation. |
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| Fetal anomalies v0.1350 | CLTC |
Zornitza Stark changed review comment from: More than 10 unrelated individuals with de novo variants in this gene reported. Individuals with refractory epilepsy were found to carry variants in the first section of the clathrin light chain-binding domain, whereas truncating mutations affecting the C terminus tended to be associated with hypotonia, global developmental delay, and intellectual disability. Hydrocephalus in one individual.; to: More than 10 unrelated individuals with de novo variants in this gene reported. Individuals with refractory epilepsy were found to carry variants in the first section of the clathrin light chain-binding domain, whereas truncating mutations affecting the C terminus tended to be associated with hypotonia, global developmental delay, and intellectual disability. Hydrocephalus in one individual. Microcephaly is acquired. |
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| Fetal anomalies v0.1350 | CLTC |
Zornitza Stark changed review comment from: More than 10 unrelated individuals with de novo variants in this gene reported. Individuals with refractory epilepsy were found to carry variants in the first section of the clathrin light chain-binding domain, whereas truncating mutations affecting the C terminus tended to be associated with hypotonia, global developmental delay, and intellectual disability.; to: More than 10 unrelated individuals with de novo variants in this gene reported. Individuals with refractory epilepsy were found to carry variants in the first section of the clathrin light chain-binding domain, whereas truncating mutations affecting the C terminus tended to be associated with hypotonia, global developmental delay, and intellectual disability. Hydrocephalus in one individual. |
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| Fetal anomalies v0.1348 | CLPP |
Zornitza Stark changed review comment from: Most affected individuals have the combination of deafness/POF which would not be detectable antenatally.; to: Most affected individuals have the combination of deafness/POF which would not be detectable antenatally. However, microcephaly reported in some. |
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| Fetal anomalies v0.1348 | CLPP | Zornitza Stark changed review comment from: As far as I can ascertain, ID has only been reported in one consanguineous family and most affected individuals have the combination of deafness/POF.; to: Most affected individuals have the combination of deafness/POF which would not be detectable antenatally. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1319 | ERF |
Zornitza Stark changed review comment from: ID is not really part of the phenotype of either condition; mild learning difficulties described in some individuals affected by craniosynostosis 4.; to: Over 20 unrelated families reported. Craniosynostosis-4 includes lambdoid, sagittal, metopic, coronal, and multisuture forms. The overall prevalence of ERF mutations in patients with syndromic craniosynostosis is around 2%, and 0.7% in clinically nonsyndromic craniosynostosis. Variants in this gene are also associated with Chitayat syndrome, which has skeletal abnormalities as a feature. |
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| Fetal anomalies v0.1305 | ACTC1 | Zornitza Stark changed review comment from: Well established association with cardiomyopathies. Four families reported with ASD.; to: Well established association with cardiomyopathies. Four families reported with ASD. Two had the same variant, founder. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1278 | EXOSC3 | Belinda Chong changed review comment from: Pontocerebellar hypoplasia type 1B is a severe autosomal recessive neurologic disorder characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There is diffuse muscle weakness, progressive microcephaly, global developmental delay, and brainstem involvement.; to: Pontocerebellar hypoplasia type 1B is a severe autosomal recessive neurologic disorder characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There is diffuse muscle weakness, progressive microcephaly, global developmental delay, and brainstem involvement. PCH1B can be divided into mild, moderate, and severe subgroups that vary in age at onset, progression, clinical and neuroradiologic severity, and survival. Multiple families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1217 | CHD8 | Zornitza Stark changed review comment from: Congenital anomalies are not a prominent feature of this neurodevelopmental disorder.; to: Congenital anomalies are not a prominent feature of this neurodevelopmental disorder. Macrocephaly reported of prenatal onset. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1208 | CHD3 |
Zornitza Stark changed review comment from: 35 individuals from 33 unrelated families reported with heterozygous variants in this gene. Sources: Expert list; to: 35 individuals from 33 unrelated families reported with heterozygous variants in this gene. Macrocephaly in most individuals, otherwise no significant association with congenital anomalies. Sources: Expert list |
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| Fetal anomalies v0.1196 | CEP135 | Zornitza Stark commented on gene: CEP135: At least 3 families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1183 | CD96 |
Zornitza Stark changed review comment from: Intellectual disability is part of the phenotype. However, note one reported case ascribes causality based on translocation breakpoint, leaving only one other molecularly confirmed case with a missense variant. It is concerning no further cases have been reported, including in ClinVar, and no functional evidence is available.; to: The C syndrome, also known as Opitz trigonocephaly syndrome, is a malformation syndrome characterized by trigonocephaly, severe mental retardation, hypotonia, variable cardiac defects, redundant skin, and dysmorphic facial features, including upslanted palpebral fissures, epicanthal folds, depressed nasal bridge, and low-set, posteriorly rotated ears. However, note one reported case ascribes causality based on translocation breakpoint, leaving only one other molecularly confirmed case with a missense variant. It is concerning no further cases have been reported, including in ClinVar, and no functional evidence is available. |
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| Fetal anomalies v0.1172 | CCDC78 | Zornitza Stark changed review comment from: Single family reported in the literature only. Mild intellectual disability was part of the phenotype.; to: Single family reported in the literature only. Onset in early childhood. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1156 | CAMTA1 |
Zornitza Stark changed review comment from: Evidence predominantly from copy number variants. Recent report of four individuals with de novo variants in this gene (nonsense, frameshift, missense), phenotype predominantly ataxia with borderline DD/ID.; to: Evidence predominantly from copy number variants. Recent report of four individuals with de novo variants in this gene (nonsense, frameshift, missense), phenotype predominantly ataxia with borderline DD/ID. Congenital anomalies are not a feature, clinical presentation is typically post-natal. |
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| Fetal anomalies v0.1154 | CAMK2B | Zornitza Stark changed review comment from: More than 10 unrelated individuals reported.; to: More than 10 unrelated individuals reported. One with significant microcephaly, otherwise congenital anomalies are not specifically reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1142 | CACNA1D | Zornitza Stark changed review comment from: De novo GoF missense variants reported with a spectrum of neurodevelopmental conditions.; to: De novo GoF missense variants reported with a spectrum of neurodevelopmental conditions, cardiac defects and cardiomyopathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1123 | BPTF |
Zornitza Stark changed review comment from: Over 30 unrelated individuals reported, mostly de novo, some inherited variants. Clinical features include intellectual disability, seizures, poor growth with small head size, dysmorphic facial features, and mild abnormalities of the hands and feet.; to: Over 30 unrelated individuals reported, mostly de novo, some inherited variants. Clinical features include intellectual disability, seizures, poor growth with small head size, dysmorphic facial features, and mild abnormalities of the hands and feet. The onset of microcephaly is post-natal, most of the other physical features are relatively mild, unclear if would be identifiable antenatally. |
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| Fetal anomalies v0.1114 | BLOC1S6 |
Zornitza Stark changed review comment from: Same homozygous variant identified in two individuals with HPS, however, note that one of the articles has been retracted due to some of the data having been falsified. Another individual reported in 32245340 but pigmentary and platelet abnormalities only. Presentation for HPS in general is post-natal.; to: Same homozygous variant identified in two individuals with HPS, however, note that one of the articles has been retracted due to some of the data having been falsified. Another individual reported in 32245340 but pigmentary and platelet abnormalities only. Presentation of HPS in general is post-natal. |
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| Fetal anomalies v0.1104 | B9D1 | Zornitza Stark changed review comment from: PMID: 24886560 - 2 unrelated patients with mild Joubert syndrome patients found (1 hom missense, 1 chet inframe deletion/missense). Authors suggest biallelic null variants are lethal. PMID: 21493627 - 1 fetus with Meckell syndrome and chet for a splice/gene deletion. The splice variant proven to result in exon skipping -> PTC, but the deletion spans a large region including 18 other genes. Patient also had an additional variant in CEP290 called LP. Authors perform functional studies on patient cells but given the large deletion/CEP290 variant i dont see the results are usable PMID: 25920555 - another report of digenic inheritance - not usable, patient was only heterozygous for a single B9D1 variant Summary: 2 unrelated patients, AMBER; to: PMID: 24886560 - 2 unrelated patients with mild Joubert syndrome patients found (1 hom missense, 1 chet inframe deletion/missense). Authors suggest biallelic null variants are lethal. PMID: 21493627 - 1 fetus with Meckell syndrome and chet for a splice/gene deletion. The splice variant proven to result in exon skipping -> PTC, but the deletion spans a large region including 18 other genes. Patient also had an additional variant in CEP290 called LP. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.1091 | EBF3 | Zornitza Stark changed review comment from: Twenty unrelated families reported with mono-allelic variants in this gene and HADDS, a neurodevelopmental syndrome characterised by congenital hypotonia, delayed psychomotor development, variable intellectual disability with speech delay, variable dysmorphic facial features, and ataxia, often associated with cerebellar hypoplasia.; to: Twenty unrelated families reported with mono-allelic variants in this gene and HADDS, a neurodevelopmental syndrome characterised by congenital hypotonia, delayed psychomotor development, variable intellectual disability with speech delay, variable dysmorphic facial features, and ataxia, often associated with cerebellar hypoplasia. Microcephaly also reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1081 | DYM |
Zornitza Stark changed review comment from: Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests. More than 5 untreated families reported.; to: Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests. More than 5 untreated families reported. Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short limbs and trunk with barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest, features identical to those of Dyggve-Melchior-Clausen disease. The two conditions likely represent a spectrum rather than two distinct disorders. |
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| Fetal anomalies v0.1081 | DYM | Zornitza Stark changed review comment from: Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests; to: Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests. More than 5 untreated families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1079 | DPM1 |
Zornitza Stark changed review comment from: PMID: 16641202 - 2 siblings of consanguineous parents. One patient showed retarded motor skills at 1, 2 and 4 years old, with distal myopathy present at 3 years of age. The younger sister presented at 7 weeks of age with generalized hypotonia. Both had normal CK levels. Both siblings were progressively microcephalic. PMID: 10642602 - 2 chet siblings with hypotonia within the first year of life. Both had elevated CK. Both siblings were progressively microcephalic PMID: 10642597 - 2 unrelated patients. One had profound hypotonia at 3 years of age. The other patient was markedly hypotonic in infancy. Both were microcephalic and hd elevated CK levels.; to: PMID: 16641202 - 2 siblings of consanguineous parents. One patient showed retarded motor skills at 1, 2 and 4 years old, with distal myopathy present at 3 years of age. The younger sister presented at 7 weeks of age with generalized hypotonia. Both had normal CK levels. Both siblings were progressively microcephalic. PMID: 10642602 - 2 chet siblings with hypotonia within the first year of life. Both had elevated CK. Both siblings were progressively microcephalic PMID: 10642597 - 2 unrelated patients. One had profound hypotonia at 3 years of age. The other patient was markedly hypotonic in infancy. Both were microcephalic and hd elevated CK levels. Contractures also reported. |
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| Fetal anomalies v0.1077 | DPAGT1 |
Zornitza Stark changed review comment from: Type I CDG. More than 20 unrelated families reported. Most affected individuals have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. Additional features that may be observed include apnoea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties.; to: Type I CDG. More than 20 unrelated families reported. Most affected individuals have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. Additional features that may be observed include apnoea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties. Myasthenic syndrome, congenital, 13, with tubular aggregates, MIM 614750 is a milder allelic disorder. More than 5 unrelated families reported with this presentation. |
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| Fetal anomalies v0.1070 | DOK7 |
Zornitza Stark edited their review of gene: DOK7: Added comment: Association with congenital myasthenia: Over 30 unrelated families reported with bi-allelic variants. Note recent report of mild adult-onset disease and heterozygous variant PMID 32360404. Association with FADS: Two families reported with this phenotype, severe end of the spectrum for DOK7-related disorders.; Changed rating: GREEN; Changed publications: 16917026, 18626973, 20147321, 16794080, 31453852, 29395672, 32360404, 19261599, 31880392; Changed phenotypes: Myasthenic syndrome, congenital, 10, MIM# 254300, Fetal akinesia deformation sequence 3, MIM# 618389 |
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| Fetal anomalies v0.1069 | DOCK6 |
Zornitza Stark changed review comment from: Variable brain involvement, including ID. Transverse limb defects.; to: Variable brain involvement, including ID. Transverse limb defects. More than 10 unrelated families reported. |
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| Fetal anomalies v0.982 | SCNN1G |
Krithika Murali gene: SCNN1G was added gene: SCNN1G was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SCNN1G was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SCNN1G were set to 8640238; 11231969; 31522814; 7633160 Phenotypes for gene: SCNN1G were set to Pseudohypoaldosteronism, type I - MIM#264350 Review for gene: SCNN1G was set to AMBER Added comment: PMID 8640238 - same 3′ splice site mutation in SCNN1G identified in 3 unrelated families from the Indian subcontinent presenting with severe generalised PHA ?founder mutation PMID 11231969 - compound het in Japanese child diagnosed as neonate PMID 31522814 - homozygous variant identified in neonate presenting with nephropathy PMID 7633160 (1995) - PHA reported as likely cause of severe polyhydramnios in 5 patients from 3 unrelated families - not genotyped. SCNN1G related PHA rare diagnosis, possible to present as severe polyhydramnios. Early diagnosis beneficial as PHA can be a life-threatening condition in the neonatal period with therapeutic options available. Sources: Literature |
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| Fetal anomalies v0.965 | NEK10 |
Krithika Murali gene: NEK10 was added gene: NEK10 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: NEK10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEK10 were set to 31959991 Phenotypes for gene: NEK10 were set to Ciliary dyskinesia, primary, 44 - MIM#618781 Review for gene: NEK10 was set to RED Added comment: Nine individuals from 5 unrelated families with primary ciliary dyskinesia, some functional data. No features that can be ascertained antenatally reported. Sources: Literature |
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| Fetal anomalies v0.960 | ARID2 |
Zornitza Stark changed review comment from: More than 10 unrelated individuals reported.; to: More than 10 unrelated individuals reported. Short stature and minor dysmorphisms/congenital anomalies reported, e.g. micrognathia. |
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| Fetal anomalies v0.957 | MCIDAS |
Krithika Murali gene: MCIDAS was added gene: MCIDAS was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MCIDAS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MCIDAS were set to 32802948; 25048963; 30237576 Phenotypes for gene: MCIDAS were set to Hydrocephalus; Arachnoid cyst; Choroid plexus hyperplasia; Ciliary dyskinesia, primary, 42 - #618695 Review for gene: MCIDAS was set to GREEN Added comment: PMID 30237576 - Patient 17-1170 (Supplementary Table) Homozygous splice site variant in a child with progressive bronchiectasis, short stature and non-obstructive hydrocephalus on imaging. PMID 25048963 - 3 different homozygous variants reported in 4 unrelated families. Situs invertus not observed in any of the 9 individuals reported. Functional studies showed reduction of cilia. None of the variants identified were observed in gnomAD at unexpected frequency for a recessive condition. PMID 32802948 - Retrospective cohort study for 7 consecutive patients diagnosed with MCIDAS by the Leicester UK national PCD diagnostic laboratory. MRI-B showed that all 7 patients demonstrated choroid plexus hyperplasia, arachnoid cysts, hydrocephalus. x1 diagnosed antenatally with communicating hydrocephalus with a sibling who had increasing head circumference noted in infancy and baseline ultrasound scan showing CPH with bitempoeral arachnoid cysts. Another monozygotic twin from an unrelated family had seizures which self-resolved with D7 of life cranial U/S reported as within normal limits although mild dilatation of posterior horns of both lateral ventricles were noted. Both MZ twins had hydrocephalus diagnosed on MRI-B age 16 pre-lung transplant. Potential for younger age of ascertainment with earlier use of MRI-B. Sources: Literature |
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| Fetal anomalies v0.957 | DNAJB13 |
Krithika Murali gene: DNAJB13 was added gene: DNAJB13 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: DNAJB13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNAJB13 were set to 31342671; 27486783 Phenotypes for gene: DNAJB13 were set to Primary ciliary dyskinesia Review for gene: DNAJB13 was set to RED Added comment: Two families reported with PCD phenotype, but no mention of heterotaxy. Sources: Literature |
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| Fetal anomalies v0.957 | DNAH8 |
Krithika Murali gene: DNAH8 was added gene: DNAH8 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: DNAH8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNAH8 were set to 31178125; 24307375; 32619401; 32681648 Phenotypes for gene: DNAH8 were set to Spermatogenic failure 46 - OMIM# 619095; primary ciliary dyskinesia Review for gene: DNAH8 was set to RED Added comment: Associated with male infertility, primary ciliary dyskinesia - no fetal phenotype reported Sources: Literature |
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| Fetal anomalies v0.957 | DNAH1 |
Krithika Murali gene: DNAH1 was added gene: DNAH1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: DNAH1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNAH1 were set to 25927852; 31507630 Phenotypes for gene: DNAH1 were set to Situs inversus; primary ciliary dyskinesia; infertility Review for gene: DNAH1 was set to AMBER Added comment: PMID - 25927852 x2 siblings from consanguineous Saudi family with homozygous missense variants (p.Lys1154Gln). More detailed clinical information available for proband diagnosed with Kartagener syndrome - chronic respiratory infections, situs inversus and infertility. Sister also reported to have been diagnosed with Kartagener syndrome at a similar age but no additional clinical information provided. PMID: 31765523 - 1 patient with PCD with a single het missense. PMID: 24360805 - 7 patients (4 different variants) with homozygous variants and infertility due to defective sperm. Microscopy of sperm revealed dynein disorganization PMID: 31507630 - 1 chet patient with kartagener syndrome, a subtype of PCD. Variants were classified as VUS initially - now c.442C>T (p.Arg148Cys) remains VUS, c.3103C > T p.R1035C re-classified as likely benign. Additional patient was het for a single nonsense, authors acknowledge missed 2nd hit and that this alone was not causative. Currently listed as red gene in Heterotaxy panel Sources: Literature |
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| Fetal anomalies v0.957 | CFAP57 |
Krithika Murali gene: CFAP57 was added gene: CFAP57 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CFAP57 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CFAP57 were set to 21574244; 32764743 Phenotypes for gene: CFAP57 were set to Van der Woude syndrome; primary ciliary dyskinesia like Review for gene: CFAP57 was set to RED Added comment: Homozygous nonsense variants identified in a 38-year-old male with PCD phenotype (history of neonatal respiratory distress, otitis media, sinusitis and bronchiectasis) x1 Het VUS reported in an individual with van der Woude syndrome - reviewed ClinVar - remains classified as VUS Sources: Literature |
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| Fetal anomalies v0.957 | CFAP43 |
Krithika Murali gene: CFAP43 was added gene: CFAP43 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CFAP43 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: CFAP43 were set to 31884020; 28552195; 31004071; 29449551 Phenotypes for gene: CFAP43 were set to Hydrocephalus, normal pressure, 1 236690; Spermatogenic failure 19 617592 Review for gene: CFAP43 was set to RED Added comment: Associated with infertility. Only adult-onset hydrocephalus reported. Sources: Literature |
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| Fetal anomalies v0.957 | BRWD1 |
Krithika Murali gene: BRWD1 was added gene: BRWD1 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: BRWD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BRWD1 were set to 33389130 Phenotypes for gene: BRWD1 were set to Situs inversus; primary ciliary dyskinesia like Review for gene: BRWD1 was set to GREEN Added comment: Biallelic missense variants reported in 3 unrelated individuals. Apart from asthenoteratozoospermia, all 3 had PCD or "PCD-likely" symptoms of re-occurring airway infections, bronchiectasis, and rhinosinusitis. One individual had situs inversus. Studies on cells from one indivdidual showed abnormal respiratory cilia structure. BRWD1 staining was absent from respiratory cilia in this individual (present in controls). Sources: Expert list, Literature |
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| Fetal anomalies v0.952 | AP4S1 |
Zornitza Stark changed review comment from: Spastic quadriplegia-52 is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development. More than 10 families reported and a zebrafish model.; to: Spastic quadriplegia-52 is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe ID with poor or absent speech development. More than 10 families reported and a zebrafish model. Microcephaly is a feature. |
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| Fetal anomalies v0.949 | AP4M1 |
Zornitza Stark changed review comment from: Spastic paraplegia-50 is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe intellectual disability with poor or absent speech development. More than 5 unrelated families reported.; to: Spastic paraplegia-50 is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe intellectual disability with poor or absent speech development. More than 5 unrelated families reported. Microcephaly and ventriculomegaly are features. |
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| Fetal anomalies v0.946 | AP4B1 |
Zornitza Stark changed review comment from: Spastic paraplegia-47 is an autosomal recessive neurodegenerative disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe intellectual disability with poor or absent speech development. More than 10 unrelated families reported.; to: Spastic paraplegia-47 is an autosomal recessive neurodegenerative disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe intellectual disability with poor or absent speech development. More than 10 unrelated families reported. Microcephaly and ventriculomegaly are features. |
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| Fetal anomalies v0.944 | AP3B2 | Zornitza Stark changed review comment from: At least 8 unrelated families reported.; to: At least 8 unrelated families reported. Onset of symptoms is post-natal. Microcephaly reported in some, though onset is unclear. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.932 | GNB1 |
Zornitza Stark changed review comment from: Over 50 individuals reported with de novo variants in this gene. Developmental delay is moderate to severe, and more than half of patients reported in a recent series were non-ambulatory and nonverbal. The most observed substitution affected the p.Ile80 residue in exon 6, with 28% of individuals carrying a variant at this residue. Dystonia and growth delay were observed more frequently in individuals carrying variants in this residue, suggesting a potential genotype-phenotype correlation.; to: Over 50 individuals reported with de novo variants in this gene. Developmental delay is moderate to severe, and more than half of patients reported in a recent series were non-ambulatory and nonverbal. The most observed substitution affected the p.Ile80 residue in exon 6, with 28% of individuals carrying a variant at this residue. Dystonia and growth delay were observed more frequently in individuals carrying variants in this residue, suggesting a potential genotype-phenotype correlation. Multiple congenital anomalies, including cleft palate, congenital heart disease and craniosynostosis reported. |
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| Fetal anomalies v0.931 | GDF11 |
Zornitza Stark gene: GDF11 was added gene: GDF11 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: GDF11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GDF11 were set to 31215115; 34113007 Phenotypes for gene: GDF11 were set to Vertebral hypersegmentation and orofacial anomalies (VHO), MIM#619122 Review for gene: GDF11 was set to GREEN Added comment: Ravenscroft et al. (2021) report additional 6 probands who presented with craniofacial (5/6), vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6), and connective tissue abnormalities (3/6). They found de novo and inherited variants in GDF11. gdf11 mutant zebrafish showed craniofacial abnormalities and body segmentation defects that matched some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) allele whereas the missense variants are partial LOF variants. Sources: Expert Review |
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| Fetal anomalies v0.926 | TMEM260 | Zornitza Stark changed review comment from: Two families reported; predominant phenotype is that of complex severe congenital heart disease and renal anomalies. Although corpus callosum abnormalities/microcephaly were described in some, DD/ID not specifically reported.; to: Seven unrelated families reported. Clinical features: ventricular septal defects (12/12), mostly secondary to truncus arteriosus (10/12), elevated creatinine levels (6/12), horse-shoe kidneys (1/12) and renal cysts (1/12) in patients. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.923 | CSF1R |
Zornitza Stark gene: CSF1R was added gene: CSF1R was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CSF1R was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CSF1R were set to 30982609; 33749994; 34135456 Phenotypes for gene: CSF1R were set to Brain abnormalities, neurodegeneration, and dysosteosclerosis, MIM# 618476; BANDDOS Review for gene: CSF1R was set to GREEN Added comment: Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) is an autosomal recessive disorder characterized by brain abnormalities, progressive neurologic deterioration, and sclerotic bone dysplasia similar to dysosteosclerosis (DOS). The age at onset is highly variable: some patients may present in infancy with hydrocephalus, global developmental delay, and hypotonia, whereas others may have onset of symptoms in the late teens or early twenties after normal development. Neurologic features include loss of previous motor and language skills, cognitive impairment, spasticity, and focal seizures. Brain imaging shows periventricular white matter abnormalities and calcifications, large cisterna magna or Dandy-Walker malformation, and sometimes agenesis of the corpus callosum. Four unrelated families reported. Note mono-allelic variants cause an adult-onset disorder. Sources: Literature |
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| Fetal anomalies v0.919 | EIF5A |
Zornitza Stark gene: EIF5A was added gene: EIF5A was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: EIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: EIF5A were set to 33547280 Phenotypes for gene: EIF5A were set to Faundes-Banka syndrome, MIM# 619376; Intellectual disability; microcephaly; dysmorphism Review for gene: EIF5A was set to GREEN Added comment: 7 unrelated individuals reported with de novo variants in this gene and variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Sources: Expert Review |
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| Fetal anomalies v0.917 | EXTL3 |
Zornitza Stark gene: EXTL3 was added gene: EXTL3 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: EXTL3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EXTL3 were set to 28132690; 28148688 Phenotypes for gene: EXTL3 were set to Immunoskeletal dysplasia with neurodevelopmental abnormalities, MIM# 617425 Review for gene: EXTL3 was set to GREEN Added comment: 12 individuals from 7 families reported. Sources: Expert Review |
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| Fetal anomalies v0.915 | PRRX1 |
Zornitza Stark gene: PRRX1 was added gene: PRRX1 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: PRRX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PRRX1 were set to 21294718; 22211708; 22674740; 23444262 Phenotypes for gene: PRRX1 were set to Agnathia-otocephaly complex, MIM# 202650 Review for gene: PRRX1 was set to GREEN Added comment: Agnathia-otocephaly is a rare condition characterized by mandibular hypoplasia or agnathia, ventromedial auricular malposition (melotia) and/or auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia. Holoprosencephaly is the most commonly identified association, but skeletal, genitourinary, and cardiovascular anomalies, and situs inversus have been reported. The disorder is almost always lethal. Three unrelated individuals reported with heterozygous LoF variants, one family with bi-allelic variants. Sources: Expert Review |
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| Fetal anomalies v0.911 | SLC6A9 | Zornitza Stark commented on gene: SLC6A9: Dempsey et al 2020 (PMID: 31875334) report a fetus with persistently raised NT, hyperextended legs, unilateral talipes. Flexed arms. Small stomach. Consanguineous family. Other reports of SLC6A9 causing arthrogryposis multiplex congenita (presenting prenatally) include: Kurolap et al 2016, PMID: 27773429 (2 families); Hauf et al 2020, PMID: 32712301 (1 family); Mademont-Soler et al 2021, PMID: 33269555 (1 family) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.886 | SLIT3 |
Krithika Murali gene: SLIT3 was added gene: SLIT3 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: SLIT3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLIT3 were set to 33933663 Phenotypes for gene: SLIT3 were set to Congenital diaphragmatic hernia Review for gene: SLIT3 was set to AMBER Added comment: Two affected individuals, single family, supportive mouse model. Sources: Expert list, Literature |
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| Fetal anomalies v0.886 | TNFRSF11A |
Krithika Murali gene: TNFRSF11A was added gene: TNFRSF11A was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: TNFRSF11A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TNFRSF11A were set to 18606301; 32048120 Phenotypes for gene: TNFRSF11A were set to Osteopetrosis, autosomal recessive 7 - MIM# 612301 Review for gene: TNFRSF11A was set to AMBER Added comment: 8 patients from 7 unrelated families with severe osteoclast-poor osteopetrosis with homozygosity or compound heterozygosity for 7 different variants. The condition is associated with a defect in immunoglobulin production. Although antenatal diagnosis not specifically reported for this gene, diagnosis of severe osteopetrosis antenatally and during early infancy has been reported, including cases with no causative variants identified (PMID 23085203) Sources: Literature |
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| Fetal anomalies v0.886 | MPDZ |
Krithika Murali gene: MPDZ was added gene: MPDZ was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: MPDZ was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MPDZ were set to 28556411; 23240096; 30518636; 29499638 Phenotypes for gene: MPDZ were set to Hydrocephalus, congenital, 2, with or without brain or eye anomalies- #615219 Review for gene: MPDZ was set to GREEN Added comment: Five Saudi families reported with same homozygous variant, p.Gln210Ter, founder effect. Additional 4 families reported from different ethnic backgrounds and at least 4 different variants. Sources: Expert list, Literature |
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| Fetal anomalies v0.886 | EEF2 |
Krithika Murali gene: EEF2 was added gene: EEF2 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: EEF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: EEF2 were set to 33355653 Phenotypes for gene: EEF2 were set to Neurodevelopmental disorder; macrocephaly; hydrocephalus Review for gene: EEF2 was set to GREEN Added comment: De novo EEF2 missense variants reported in 3 unrelated children (3, 6 and 9 years of age) with a mild neurodevelopmental phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly. Sources: Literature, Expert list |
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| Fetal anomalies v0.886 | DLL1 |
Krithika Murali gene: DLL1 was added gene: DLL1 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: DLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DLL1 were set to 31353024 Phenotypes for gene: DLL1 were set to Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures - #618709 Review for gene: DLL1 was set to GREEN Added comment: 14 individuals from 11 families reported. All 11 patients who underwent brain imaging showed non-specific and variable abnormalities, including hydrocephalus, ventriculomegaly, thin, short, or dysplastic corpus callosum, subtle cortical dysplasia, and small cerebellum or pons. One patient had periventricular nodular heterotopia. Sources: Expert list, Literature |
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| 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 v0.886 | PLS3 |
Krithika Murali gene: PLS3 was added gene: PLS3 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: PLS3 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: PLS3 were set to 32655496; 25209159; 29736964; 29884797; 28777485; 24088043 Phenotypes for gene: PLS3 were set to Bone mineral density QTL18, osteoporosis - MIM#300910 Review for gene: PLS3 was set to AMBER Added comment: First reported in 2013 (PMID 24088043). Associated with childhood-onset primary osteoporosis with presentations of varying severity with a phenotype similar to osteogenesis imperfecta. No published reports of antenatal diagnosis. Sources: Expert list, Literature |
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| Fetal anomalies v0.886 | MMP9 |
Krithika Murali gene: MMP9 was added gene: MMP9 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: MMP9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MMP9 were set to 19615667; 28342220; 34407464 Phenotypes for gene: MMP9 were set to Metaphyseal anadysplasia 2 - MIM# 613073 Review for gene: MMP9 was set to GREEN Added comment: Biallelic variants in MMP9 associated with autosomal recessive, metaphyseal anadysplasia type 2. Usually associated with a milder phenotype characterised by normal birth length, transitory bowing of the legs, spontaneous regression and disappearance of metaphyseal alterations during adolescence. Phenotype of MAD type 2 cases secondary to biallelic MMP13 gene mutations (more reported cases associated with this gene) similar to MMP9 associated cases. MMP9-associated MAD type 2 cases reported so far: x2 sibs from 1 consanguineous Pakistani family diagnosed postnatally with normal stature, genu varum, metaphyseal fraying during infancy (PMID 19615667) x1 child from consanguineous family with homozygous nonsense variants diagnosed age 19 months with improvement of skeletal manifestations over a short period and by an early age (PMID 34407464) x2 siblings from x1 non-consanguineous Jewish Caucasian family reported with more severe phenotype than other previously reported cases for MAD type 2 (PMID 28342220). Both siblings diagnosed during 2nd trimester with shortening of long bones. x1 fetus terminated at 19 weeks gestation - dysmorphic face including micrognathia, flattened nose, hypertelorism, short neck and hypoplastic lungs. 2nd liveborn female - reduced body length at birth (-4 SD), facial dysmorphism, cleft palate, anteriorly placed anus and other anomalies. No radiographic metaphyseal anomalies. Both children identified as having the same homozygous MMP9 missense variants. Authors acknowledge the phenotype is more severe than other previously reported cases of MAD type 2 associated with MMP9 or MMP13 gene variants. Some dispute regarding this prenatal case as detailed by PMID 34407464 such as possibility of an alternative skeletal dysplasia diagnosis (Desbuquois dypslasia type 2) and presence of 5 homozygotes in gnomad with the same missense variants - ?founder mutation. Borderline amber-green gene in the prenatal setting based on current evidence. Sources: Expert list, Literature |
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| Fetal anomalies v0.870 | DLL3 |
Zornitza Stark changed review comment from: The spondylocostal dysostoses are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV), malalignment of the ribs with variable points of intercostal fusion, and often a reduction in rib number. ; to: The spondylocostal dysostoses are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV), malalignment of the ribs with variable points of intercostal fusion, and often a reduction in rib number. More than 10 unrelated families reported, well established gene-disease association. |
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| Fetal anomalies v0.870 | DLL3 |
Zornitza Stark changed review comment from: Single case report where CDH was observed in addition to the skeletal abnormalities, predates gene identification.; to: The spondylocostal dysostoses are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV), malalignment of the ribs with variable points of intercostal fusion, and often a reduction in rib number. |
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| Fetal anomalies v0.867 | DHFR | Zornitza Stark changed review comment from: Three unrelated families reported, neurological disease in some severe, others predominantly haematological presentation.; to: Three unrelated families reported, neurological disease in some severe, others predominantly haematological presentation. Earliest presentation was post-natal with acquired microcephaly. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.864 | SMAD2 |
Zornitza Stark gene: SMAD2 was added gene: SMAD2 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: SMAD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMAD2 were set to 29967133; 30157302; 23665959 Phenotypes for gene: SMAD2 were set to Aortic and arterial aneurysmal disease; connective tissue disease; congenital heart disease Review for gene: SMAD2 was set to GREEN Added comment: PMID: 30157302 - Two distinct phenotypes associated with pathogenic variants in SMAD2: complex congenital heart disease with or without laterality defects and other congenital anomalies, and a late-onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities. No genotype/phenotype correlation has been established so far. PMID: 30157302, PMID: 23665959 - 5 individuals reported with the CHD phenotype Sources: Expert Review |
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| Fetal anomalies v0.861 | DHCR24 |
Zornitza Stark changed review comment from: At least 4 families reported where contractures are a feature of the condition. Sources: Expert list; to: At least 4 families reported where contractures are a feature of the condition. Other congenital anomalies reported as well. Sources: Expert list |
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| Fetal anomalies v0.832 | ALG9 | Zornitza Stark changed review comment from: 11 patients from 7 families reported. DD/ID is part of the phenotype.; to: Bi-allelic variants and CDG: At least 7 unrelated families reported, 11 individuals. Clinical features include failure to thrive, dysmorphic features, seizures, hepatic and/or renal cysts; three patients died in utero from a lethal skeletal dysplasia. The severe end of the spectrum is referred to as Gillessen-Kaesbach-Nishimura syndrome and is characterised by skeletal dysplasia, dysmorphic facial features, and variable visceral abnormalities, including polycystic kidneys, diaphragmatic hernia, lung hypoplasia, and congenital heart defects. It may be lethal in utero or early in life. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.829 | ALG2 |
Zornitza Stark edited their review of gene: ALG2: Added comment: Association with myasthenia: Two families reported, same, likely founder variant. Onset of symptoms was in infancy rather than congenital. Association with CDG: one individual with multisystemic disorder with ID, seizures, coloboma of the iris, hypomyelination, hepatomegaly, and coagulation abnormalities reported in PMID 12684507. Fibroblasts showed severely reduced enzymatic activity.; Changed publications: 23404334, 24461433, 12684507 |
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| Fetal anomalies v0.827 | ALG13 |
Zornitza Stark changed review comment from: More than 10 families reported.; to: More than 10 families reported. Typical presentation is with refractory seizures at around 6 months of age and developmental delay. Majority of affected individuals have been females. Microcephaly reported in a male patient. |
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| Fetal anomalies v0.826 | ALG11 |
Zornitza Stark changed review comment from: Usually transferrin isoforms abnormal, however normal patterns have been reported in this condition. Abnormalities in fibroblasts accumulation of a N2M3 and N2M4 (N=N-acetylglucosamine, M=Mannose) LLO glycans Hypoglycosylation of GP130. Principal phenotypic features include: Developmental disability; Epilepsy; Dysmorphic features; Microcephaly; Hypotonia; Hypertonia, Hyperreflexia; Sensorineural deafness; Eye/Visual Problems; Feeding problems; to: Usually transferrin isoforms abnormal, however normal patterns have been reported in this condition. Abnormalities in fibroblasts accumulation of a N2M3 and N2M4 (N=N-acetylglucosamine, M=Mannose) LLO glycans Hypoglycosylation of GP130. Principal phenotypic features include: Developmental disability; Epilepsy; Dysmorphic features; Microcephaly; Hypotonia; Hypertonia, Hyperreflexia; Sensorineural deafness; Eye/Visual Problems; Feeding problems Onset is in first year of life, microcephaly rarely reported. |
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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 v0.818 | DCX | Zornitza Stark changed review comment from: Well established gene-disease association.; to: DCX mutations cause classic lissencephaly with mental retardation in hemizygous males and a milder phenotype known as subcortical band heterotopia in females, sometimes in the same family. The subcortical lamina heterotopia found in heterozygous females is also referred to as 'double cortex' (DC) syndrome. Multiple affected families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.813 | AIMP1 |
Zornitza Stark changed review comment from: Autosomal recessive hypomyelinating leukodystrophy-3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system. Abnormal nerve conduction demonstrated. More than 10 families reported. Note two families reported in PMID 26173967 primarily with ID phenotype without neurodegeneration/leukodystrophy, suggesting there is a spectrum of severity. Note both families had homozygous missense variants.; to: Autosomal recessive hypomyelinating leukodystrophy-3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system. Abnormal nerve conduction demonstrated. More than 10 families reported. Note two families reported in PMID 26173967 primarily with ID phenotype without neurodegeneration/leukodystrophy, suggesting there is a spectrum of severity. Note both families had homozygous missense variants. Progressive disorder, typical onset is in the first few months of life, microcephaly and joint contractures are features. |
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| Fetal anomalies v0.805 | ADAMTS3 |
Zornitza Stark changed review comment from: Two families reported with Hennekam syndrome associated with this gene, of which one was reported with antenatal hydrops, and in the other family, widespread oedema was present at birth. Sources: Expert list; to: Two families reported with Hennekam syndrome associated with this gene, of which one was reported with antenatal hydrops, and in the other family, widespread oedema was present at birth. Supportive functional data. Sources: Expert list |
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| Fetal anomalies v0.803 | ACVR1 |
Zornitza Stark changed review comment from: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner. Multiple unrelated families reported. The R206H variant is recurrent.; to: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner. Multiple unrelated families reported. The R206H variant is recurrent. Note variants in this gene are also associated with congenital heart disease, PMID 29089047. |
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| Fetal anomalies v0.774 | ELOVL4 |
Belinda Chong changed review comment from: OMIM 614457: ISQMR is a severe autosomal recessive disorder characterised by ichthyosis apparent from birth, profound psychomotor retardation with essentially no development, spastic quadriplegia, and seizures. 5 unrelated families reported, seizures in at least 4 of the families. OMIM 133190: Skin lesion appear shortly after birth and tend to disappear in young adulthood. In a large French-Canadian family, 14/19 individuals with a missense variant presented with erythrokeratodermia variabilis (PMID:24566826). At least two other individuals reported with erythrokeratodermia (and SCA34) as a result of a missense variant (PMID:26258735; 30065956). OMIM 600110: Stargardt disease-3 (STGD3) is an autosomal dominant juvenile macular dystrophy with onset most commonly in the second decade of life. Fundus examination reveals macular pigmentary changes and yellow flecks. Fluorescein angiography shows macular retinal pigment epithelium (RPE) defects; to: OMIM 614457: ISQMR is a severe autosomal recessive disorder characterised by ichthyosis apparent from birth, profound psychomotor retardation with essentially no development, spastic quadriplegia, and seizures. 5 unrelated families reported, seizures in at least 4 of the families. OMIM 133190: Skin lesion appear shortly after birth and tend to disappear in young adulthood. In a large French-Canadian family, 14/19 individuals with a missense variant presented with erythrokeratodermia variabilis (PMID:24566826). At least two other individuals reported with erythrokeratodermia (and SCA34) as a result of a missense variant (PMID:26258735; 30065956). OMIM 600110: Stargardt disease-3 (STGD3) is an autosomal dominant juvenile macular dystrophy with onset most commonly in the second decade of life. Fundus examination reveals macular pigmentary changes and yellow flecks. Fluorescein angiography shows macular retinal pigment epithelium (RPE) defects |
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| Fetal anomalies v0.774 | ACSL4 | Zornitza Stark Phenotypes for gene: ACSL4 were changed from ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS; MENTAL RETARDATION X-LINKED TYPE 63 to Mental retardation, X-linked 63 , MIM#300387 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.771 | ACSL4 | Zornitza Stark changed review comment from: Comment when marking as ready: At least three unrelated individuals reported.; to: Comment when marking as ready: At least three unrelated individuals reported. Microcephaly reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.764 | ABCD4 |
Zornitza Stark changed review comment from: Described clinical features include feeding difficulties, failure to thrive, hypotonia, seizures, developmental delay, and hematological abnormalities. Normal neurodevelopmental outcomes with treatment reported. At least 6 affected individuals reported.; to: Described clinical features include feeding difficulties, failure to thrive, hypotonia, seizures, developmental delay, and haematological abnormalities. Normal neurodevelopmental outcomes with treatment reported. At least 6 affected individuals reported. Congenital anomalies are very rarely reported, uncertain if they are part of the phenotype. |
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| Fetal anomalies v0.763 | AASS |
Zornitza Stark changed review comment from: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic. Given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality of symptoms. It has been suggested that hyperlysinemia is a benign metabolic variant rather than a disease entity.; to: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic. Given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality of symptoms. It has been suggested that hyperlysinemia is a benign metabolic variant rather than a disease entity. Given the uncertainty about whether this is a disease entity and lack of associated congenital anomalies or other features that would be detectable in the prenatal setting, downgraded to RED on this panel. |
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| Fetal anomalies v0.737 | PPIB |
Naomi Baker changed review comment from: Well established gene-disease association with lethal or severe phenotype. PMID: 19781681; reported biallelic loss-of-function variants in two consanguineous families. Multiple skeletal features were observed in fetal radiographs, including fractures of long bones, bowed tibiae, fibula and femora, and beaded ribs. PMID: 32392875; reported an identical biallelic missense variant in two Taiwanese families. Prenatal imaging showed small and collapsed thoracic cage, bowing of femoral bone, and platyspondyly of spine.; to: Well established gene-disease association with lethal or severe OI phenotype. PMID: 19781681; reported biallelic loss-of-function variants in two consanguineous families. Multiple skeletal features were observed in fetal radiographs, including fractures of long bones, bowed tibiae, fibula and femora, and beaded ribs. PMID: 32392875; reported an identical biallelic missense variant in two Taiwanese families. Prenatal imaging showed small and collapsed thoracic cage, bowing of femoral bone, and platyspondyly of spine. |
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| Fetal anomalies v0.720 | CTC1 |
Zornitza Stark edited their review of gene: CTC1: Added comment: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC), also known as Coats plus syndrome, is an autosomal recessive pleomorphic disorder characterized primarily by intracranial calcifications, leukodystrophy, and brain cysts, resulting in spasticity, ataxia, dystonia, seizures, and cognitive decline. Patients also have retinal telangiectasia and exudates (Coats disease) as well as extraneurologic manifestations, including osteopenia with poor bone healing and a high risk of gastrointestinal bleeding and portal hypertension caused by vasculature ectasias in the stomach, small intestine, and liver. Some individuals also have hair, skin, and nail changes, as well as anaemia and thrombocytopaenia. Multiple families reported.; Changed rating: GREEN; Changed publications: 22267198 |
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| Fetal anomalies v0.667 | UNC50 | Zornitza Stark edited their review of gene: UNC50: Added comment: Supportive functional data.; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.660 | EN1 |
Krithika Murali gene: EN1 was added gene: EN1 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: EN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EN1 were set to 33568816 Phenotypes for gene: EN1 were set to ?ENDOVE syndrome, limb-brain type - OMIM#619218 Review for gene: EN1 was set to GREEN Added comment: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype. An additional fourth individual had cerebellar hypoplasia in addition to the skeletal phenotype, and a bi-allelic LoF variant. Sources: Expert list, Literature |
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| Fetal anomalies v0.657 | PAX2 | Zornitza Stark edited their review of gene: PAX2: Added comment: Microphthalmia and CAKUT are reported features.; Changed rating: GREEN; Changed phenotypes: Papillorenal syndrome, MIM# 120330, Renal coloboma syndrome, MONDO:0007352 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.650 | SCN5A |
Krithika Murali gene: SCN5A was added gene: SCN5A was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: SCN5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SCN5A were set to 22064211; 15184283; 19419784 Phenotypes for gene: SCN5A were set to Sudden infant death syndrome, susceptibility to - #272120; Long QT syndrome 3 - #603830 Review for gene: SCN5A was set to GREEN Added comment: Three families reported with severe perinatal presentation, including hydrops Sources: Expert list, Literature |
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| Fetal anomalies v0.643 | PRF1 |
Krithika Murali gene: PRF1 was added gene: PRF1 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: PRF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRF1 were set to 19595804; 26199792; 30070073 Phenotypes for gene: PRF1 were set to Aplastic anemia - #609135; Hemophagocytic lymphohistiocytosis, familial, 2 - #603553 Review for gene: PRF1 was set to GREEN Added comment: Heeg et al report 12 patients presenting with FHLH2 in utero or in first 10 days of life from registry and publication data (these 12 genetically confirmed) PMID: 19595804 Vermulen et al report two siblings with homozygous PRF1 variants, first sib died in utero with hydrops and second sib presented in neonatal period PMID: 26199792 Iwatani et al report newborn infant with comp het PRF1 variants, and in utero ascites PMID: 30070073 Sources: Expert list, Literature |
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| Fetal anomalies v0.612 | ALPK3 |
Krithika Murali gene: ALPK3 was added gene: ALPK3 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: ALPK3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ALPK3 were set to PMID 26846950. Phenotypes for gene: ALPK3 were set to Cardiomyopathy, familial hypertrophic 27 - #618052 Review for gene: ALPK3 was set to GREEN Added comment: Severe neonatal presentation of cardiomyopathy with bi-allelic variants, including antenatal onset with hydrops in 2/7 reported individuals in PMID 26846950. PMID 28630369 reports male infant diagnosed antenatally with cardiomyopathy after birth. Born to a nonconsanguineous family with a past history of a male fetus that died because of cardiac abnormalities at 30 wk of gestation. Sources: Expert list, Literature |
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| Fetal anomalies v0.612 | ZBTB42 |
Krithika Murali gene: ZBTB42 was added gene: ZBTB42 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: ZBTB42 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZBTB42 were set to 25055871 Phenotypes for gene: ZBTB42 were set to ?Lethal congenital contracture syndrome 6- #616248 Review for gene: ZBTB42 was set to AMBER Added comment: Homozygous missense variant reported in a family with three stillbirths and a phenotype consistent with LCCS. Supportive zebrafish model. Sources: Expert list, Literature |
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| Fetal anomalies v0.612 | TOR1AIP1 |
Krithika Murali gene: TOR1AIP1 was added gene: TOR1AIP1 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: TOR1AIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TOR1AIP1 were set to 33215087; 32055997; 24856141; 31299614; 30723199; 27342937 Phenotypes for gene: TOR1AIP1 were set to ?Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures - #61707; congenital myasthenic syndrome Review for gene: TOR1AIP1 was set to GREEN Added comment: Gene is associated with multiple muscle phenotypes. Phenotype highly variable. Single family myasthenic syndrome and supportive mouse model data. Sources: Expert list, Literature |
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| Fetal anomalies v0.612 | STIM1 |
Krithika Murali gene: STIM1 was added gene: STIM1 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: STIM1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: STIM1 were set to 31448844; 20876309 Phenotypes for gene: STIM1 were set to Immunodeficiency 10 - #612783; Myopathy, tubular aggregate, 1 - #160565; Stormorken syndrome - #185070 Review for gene: STIM1 was set to GREEN Added comment: PMID 31448844 (comprehensive review, summarises all published cases, references functional evidence) Dominant STIM1 missense variants via a GOF mechanism cause a spectrum of myopathy covering tubular aggregate myopathy/TAM and Stormorken syndrome/STRMK (slowly progressive muscle weakness with variable multisystemic disease including non-specific dysmorphism, a/hyposplenia, ichthyosis, cytopenias) Recessive STIM1 variants via a LOF mechanism cause a combined immunodeficiency (recurrent and chronic infections, autoimmunity, ectodermal dysplasia, non-progressive myopathy) --> presentations can be severe, death from disseminated Kaposi sarcoma in an HIV negative 2 year old F reported. Highly variable phenotype - contractures have been reported in the more severely affected individuals. Sources: Expert list, Literature |
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| Fetal anomalies v0.612 | SCYL2 |
Krithika Murali gene: SCYL2 was added gene: SCYL2 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: SCYL2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SCYL2 were set to 31960134; 26203146 Phenotypes for gene: SCYL2 were set to Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum - #618766 Review for gene: SCYL2 was set to AMBER Added comment: 2 unrelated consanguineous families reported with AMC (PMID: 31960134). Constitutive mouse knockout of Scyl2 results in neonatal lethality and severe motor and sensory deficits (PMID: 26203146). Sources: Expert list, Literature |
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| Fetal anomalies v0.612 | PIP5K1C |
Krithika Murali gene: PIP5K1C was added gene: PIP5K1C was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: PIP5K1C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIP5K1C were set to 17701898 Phenotypes for gene: PIP5K1C were set to Lethal congenital contractural syndrome 3 - #611369 Review for gene: PIP5K1C was set to AMBER Added comment: Two families reported in 2007 with same homozygous variant, no reports since. Borderline Red/Amber. Sources: Expert list, Literature |
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| Fetal anomalies v0.610 | CRLF1 |
Zornitza Stark edited their review of gene: CRLF1: Added comment: Micrognathia, camptodactyly are features. Crisponi/cold-induced sweating syndrome is an autosomal recessive disorder characterized in the neonatal period by orofacial weakness with impaired sucking and swallowing resulting in poor feeding necessitating medical intervention. Affected infants show a tendency to startle, with contractions of the facial muscles in response to tactile stimuli or during crying, trismus, abundant salivation, and opisthotonus. During the first year, most infants have spiking fevers. These features, referred to as 'Crisponi syndrome' in infancy, can result in early death without advanced care. After the first 2 years, the abnormal muscle contractions and fevers abate, and most patients show normal psychomotor development. From childhood onward, the most disabling symptoms stem from impaired thermoregulation and disabling abnormal sweating, which can be treated with clonidine. Patients have hyperhidrosis, mainly of the upper body, in response to cold temperatures, and sweat very little with heat. Other features include characteristic facial anomalies, such as round face, chubby cheeks, micrognathia, high-arched palate, low-set ears, and depressed nasal bridge, dental decay, camptodactyly, and progressive kyphoscoliosis. Multiple unrelated families reported.; Changed rating: GREEN; Changed publications: 12509788, 17436251, 17436252 |
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| Fetal anomalies v0.607 | CREBBP |
Zornitza Stark changed review comment from: Well established gene-disease association with RTS, deletions reasonably frequent. Menke-Hennekam syndrome-1 (MKHK1) is an allelic disorder caused by heterozygous variants in exon 30 or 31 of the CREBBP gene, and characterised by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, hearing impairment, short stature, and microcephaly are also frequently seen. Over 20 individuals reported.; to: Well established gene-disease association with RTS, deletions reasonably frequent. Microcephaly is a feature. Menke-Hennekam syndrome-1 (MKHK1) is an allelic disorder caused by heterozygous variants in exon 30 or 31 of the CREBBP gene, and characterised by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, hearing impairment, short stature, and microcephaly are also frequently seen. Over 20 individuals reported. |
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| Fetal anomalies v0.603 | CPT2 |
Zornitza Stark changed review comment from: Carnitine palmitoyltransferase II deficiency is an inherited disorder of mitochondrial long-chain fatty acid oxidation. There is a spectrum of severity. The most severe, neonatal form presents shortly after birth with respiratory distress, seizures, altered mental status, hepatomegaly, cardiomegaly, cardiac arrhythmia, and, in many cases, dysmorphic features, renal dysgenesis, and migration defects. Some features such as microcephaly and polycystic kidneys may be detectable antenatally.; to: Carnitine palmitoyltransferase II deficiency is an inherited disorder of mitochondrial long-chain fatty acid oxidation. There is a spectrum of severity. The most severe, neonatal form presents shortly after birth with respiratory distress, seizures, altered mental status, hepatomegaly, cardiomegaly, cardiac arrhythmia, and, in many cases, dysmorphic features, renal dysgenesis, and migration defects. Some features such as microcephaly and polycystic kidneys may be detectable antenatally. Well established gene-disease association, multiple families reported. |
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| Fetal anomalies v0.601 | COX7B | Zornitza Stark changed review comment from: Single report of 4 affected individuals in 2012, of whom only two had dev delay/ID.; to: Single report of 4 affected individuals in 2012, multiple congenital anomalies. XLD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.587 | MMP13 |
Daniel Flanagan changed review comment from: At least 7 families described with either mono or biallelic variants reports. Autosomal dominant metaphyseal anadysplasia has been described as more severe, with dominant-negative missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency. Recessive metaphyseal anadysplasia has been described as a milder form, caused by biallelic loss of function of either MMP9 or MMP13.; to: At least 7 families described with either mono (Metaphyseal anadysplasia) or biallelic (Metaphyseal dysplasia, Spahr type) variants reports. Autosomal dominant metaphyseal anadysplasia has been described as more severe, with dominant-negative missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency. Recessive metaphyseal anadysplasia has been described as a milder form, caused by biallelic loss of function of either MMP9 or MMP13. |
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| Fetal anomalies v0.582 | MEGF10 |
Daniel Flanagan changed review comment from: At least 4 families reported with early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD). Two animal models. 1 patient reported to have a cleft palate and 3 with high-arched palates.; to: At least 4 families reported with early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD). Two animal models. 1/7 patients had a cleft palate and 3/7 with a high-arched palates. |
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| Fetal anomalies v0.581 | COL4A2 | Zornitza Stark Phenotypes for gene: COL4A2 were changed from PORENCEPHALY 2 to Brain small vessel disease 2, MIM# 614483; Porencephaly | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.578 | COL4A1 | Zornitza Stark changed review comment from: Microphthalmia reported.; to: Microphthalmia, porencephaly reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.578 | COL4A1 | Zornitza Stark edited their review of gene: COL4A1: Changed phenotypes: Brain small vessel disease with or without ocular anomalies, MIM#175780, Porencephaly | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.578 | COL4A1 | Zornitza Stark Phenotypes for gene: COL4A1 were changed from PORENCEPHALY 1 to Brain small vessel disease with or without ocular anomalies, MIM#175780; Porenecphaly | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.553 | COG1 | Zornitza Stark changed review comment from: Two unrelated families and supportive functional data.; to: Two unrelated families and supportive functional data. IUGR and congenital anomalies are a feature. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.551 | COASY |
Zornitza Stark changed review comment from: Two families reported with a severe, prenatal onset phenotype comprising PCH, microcephaly and arthrogryposis. Note gene is also associated with NBIA. Sources: Expert list; to: Two families reported with a severe, prenatal onset phenotype comprising PCH, microcephaly and arthrogryposis. Note gene is also associated with NBIA but this presents postnatally. Sources: Expert list |
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| Fetal anomalies v0.535 | ATP1A2 | Zornitza Stark commented on gene: ATP1A2: Three individuals from two unrelated families reported with balleliic LoF variants in this gene and hydrops/congenital abnormalities. Mouse model is perinatal lethal. This is a distinct phenotype from the mono allelic variants associated with alternating hemiplegia. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.532 | MED17 | Zornitza Stark changed review comment from: 5 individuals from 3 families now reported with intellectual disability and variable other neurological features including ataxia and seizures.; to: Over 10 families now reported with intellectual disability and variable other neurological features including ataxia, microcephaly and seizures. Note the c.1112T>C (p.L371P) variant is a founder variant in the Caucasus-Jewish families. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.532 | CNTNAP2 | Zornitza Stark changed review comment from: More than 10 unrelated families reported, with a Pitt-Hopkins like syndrome.; to: More than 10 unrelated families reported, with a Pitt-Hopkins like syndrome. Typical clinical features include delayed psychomotor development, intellectual disability, severe speech impairment or regression, and behavioural abnormalities. Most patients have onset of seizures within the first years of life. Some patients may have cortical dysplasia on brain imaging. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.530 | CNTNAP1 | Zornitza Stark changed review comment from: Multiple affected individuals reported; ID is part of the phenotype.; to: Multiple affected individuals reported, multiple contractures. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.525 | CNOT3 |
Zornitza Stark changed review comment from: Comment when marking as ready: 16 unrelated individuals reported.; to: 16 unrelated individuals reported. Skeletal and structural brain abnormalities in some. |
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| Fetal anomalies v0.519 | CLPB |
Zornitza Stark changed review comment from: Bi-allelic variants: 3-Methylglutaconic aciduria (MGCA7) is an autosomal recessive inborn error of metabolism characterized primarily by increased levels of 3-methylglutaconic acid (3-MGA) associated with neurologic deterioration and neutropenia. The phenotype is highly variable: most patients have infantile onset of a progressive encephalopathy with various movement abnormalities and delayed psychomotor development, although rare patients with normal neurologic development have been reported. Other common, but variable, features include cataracts, seizures, and recurrent infections. More than 10 unrelated families reported. Mono-allelic variants: six unrelated individuals reported with de novo variants and neutropaenia, epilepsy, developmental issues, and 3-methylglutaconic aciduria.; to: Bi-allelic variants: 3-Methylglutaconic aciduria (MGCA7) is an autosomal recessive inborn error of metabolism characterized primarily by increased levels of 3-methylglutaconic acid (3-MGA) associated with neurologic deterioration and neutropenia. The phenotype is highly variable: most patients have infantile onset of a progressive encephalopathy with various movement abnormalities and delayed psychomotor development, although rare patients with normal neurologic development have been reported. Other common, but variable, features include cataracts, seizures, and recurrent infections. Microcephaly is a feature. More than 10 unrelated families reported. Mono-allelic variants: six unrelated individuals reported with de novo variants and neutropaenia, epilepsy, developmental issues, and 3-methylglutaconic aciduria. |
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| Fetal anomalies v0.481 | IL1RAPL1 |
Ain Roesley changed review comment from: ID the main feature, with mild dysmorphism described. only CNVs have been reported; to: ID the main feature, with mild dysmorphism described. both SNV and intragenic CNVs have been reported |
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| 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 v0.443 | CHD7 | Zornitza Stark changed review comment from: Very rare reports of CDH in CHARGE syndrome, not a characteristic or common feature.; to: Well established gene-disease association, multiple congenital anomalies are a feature. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.442 | CHD4 |
Zornitza Stark changed review comment from: Many P/LP variants reported. Missense variants disrupt ATPase activity and decrease nucleosome remodelling ability. ~50% of missense variants occur between p.1127-1192 containing motifs V, Vb and VI.; to: Sifrim-Hitz-Weiss syndrome is an autosomal dominant intellectual developmental disorder with variable congenital defects affecting other systems, including cardiac, skeletal, and urogenital. Some patients may have short stature, enlarged head circumference, hearing loss, and nonspecific dysmorphic facial features. Many P/LP variants reported. Missense variants disrupt ATPase activity and decrease nucleosome remodelling ability. ~50% of missense variants occur between p.1127-1192 containing motifs V, Vb and VI. |
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| Fetal anomalies v0.419 | CEP152 | Zornitza Stark changed review comment from: Bi-allelic variants in this gene have been reported in both primary microcephaly (-5-7 SD) and in Seckel syndrome, at least 3 of each. ID is a feature of both disorders. Gene encodes centriole protein.; to: Bi-allelic variants in this gene have been reported in both primary microcephaly (-5-7 SD) and in Seckel syndrome, at least 3 of each. Gene encodes centriole protein. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.417 | CEP120 | Zornitza Stark edited their review of gene: CEP120: Added comment: More than 5 unrelated families with JBTS reported, and at least three families with SRTD. Functional data.; Changed publications: 27208211, 33486889, 29847808, 25361962, 27208211; Changed phenotypes: Joubert syndrome 31, MIM# 617761, Short-rib thoracic dysplasia 13 with or without polydactyly, MIM# 616300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.417 | CEP104 |
Zornitza Stark changed review comment from: Three unrelated individuals reported, ID is part of the phenotype. Sources: Expert list; to: Three unrelated individuals reported, structural brain abnormalities are part of the phenotype. Sources: Expert list |
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| Fetal anomalies v0.408 | CDKN1C |
Zornitza Stark edited their review of gene: CDKN1C: Added comment: LoF variants in this gene cause overgrowth and BWS. IMAGe syndrome: reported variants are gain-of-function missense on the maternal allele, and are located in a highly-conserved "hot-spot" within the PCNA-binding domain of CDKN1C between codons 272-279. Note 3 families reported with RSS phenotype without other IMAGE features, all with missense changes at amino acid positions 279 and 281. Can present antenatally with macrosomia/IUGR respectively.; Changed rating: GREEN; Changed publications: 10424811, 8841187, 22205991, 20503313, 19843502, 15372379, 23511928, 30794780, 33076988, 31976094, 31497289; Changed phenotypes: Beckwith-Wiedemann syndrome, MIM# 130650, IMAGe syndrome, MIM# 614732, Silver-Russell syndrome; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) |
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| Fetal anomalies v0.386 | CCDC40 | Zornitza Stark changed review comment from: Over 40 unrelated families reported.; to: Over 40 unrelated families reported. Approximately half had situs inversus. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.384 | CCDC39 | Zornitza Stark changed review comment from: Over 20 unrelated families reported.; to: Over 20 unrelated families reported. Situs inverses in approximately half. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.374 | CBL |
Zornitza Stark changed review comment from: Noonan syndrome-like disorder is a developmental disorder characterised by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, and ectodermal and musculoskeletal anomalies. Patients with heterozygous germline CBL mutations have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia. Over 20 affected individuals reported.; to: Noonan syndrome-like disorder is a developmental disorder characterised by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, and ectodermal and musculoskeletal anomalies. Patients with heterozygous germline CBL mutations have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia. Over 20 affected individuals reported. Can present antenatally with hydrops or congenital heart disease. |
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| Fetal anomalies v0.371 | CASK | Zornitza Stark changed review comment from: FG syndrome is listed in review articles of arthrogryposis-associated conditions, however I am unable to find specific reports of contractures, or mention of contractures in reviews of CASK-related disorders.; to: CASK-related disorders have microcephaly and structural brain abnormalities as features. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.362 | CA8 | Zornitza Stark changed review comment from: At least two unrelated families reported, and animal model.; to: Phenotype becomes apparent post-natally; two unrelated families reported, and animal model. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.358 | C8orf37 |
Zornitza Stark changed review comment from: Two unrelated individuals reported with BBS; note gene has an association with retinal ciliopathies. Sources: Expert list; to: Two unrelated individuals reported with BBS; note gene has an association with retinal ciliopathies, which would not be detectable antenatally. Sources: Expert list |
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| Fetal anomalies v0.358 | C5orf42 |
Zornitza Stark changed review comment from: Well established gene-disease associations both with prominent neurological features. More than 10 unrelated families reported with each association. New gene name is CPLANE1.; to: Well established gene-disease associations, structural brain abnormalities. More than 10 unrelated families reported with each association. New gene name is CPLANE1. |
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| Fetal anomalies v0.354 | C21orf2 |
Zornitza Stark changed review comment from: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on ERG. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. At least 7 unrelated families reported. New HGNC approved name is CFAP410.; to: Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on ERG. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora. At least 7 unrelated families reported. New HGNC approved name is CFAP410. Thoracic hypoplasia is present at birth so relevant to this panel. |
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| Fetal anomalies v0.342 | BRPF1 |
Zornitza Stark changed review comment from: Intellectual developmental disorder with dysmorphic facies and ptosis is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, delayed language, and dysmorphic facial features, most notably ptosis/blepharophimosis. Additional features may include poor growth, hypotonia, and seizures. At least 10 unrelated families reported.; to: Intellectual developmental disorder with dysmorphic facies and ptosis is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, delayed language, and dysmorphic facial features, most notably ptosis/blepharophimosis. Additional features may include poor growth, hypotonia, and seizures. At least 10 unrelated families reported. IUGR reported in some. |
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| Fetal anomalies v0.340 | BRCA2 |
Zornitza Stark changed review comment from: Single affected individual reported, although FA is a multiple congenital anomaly syndrome. Sources: Literature; to: Well established gene-disease association, FA is a multiple congenital anomaly syndrome. Sources: Literature |
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| 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 v0.331 | BMPER |
Zornitza Stark changed review comment from: Perinatal lethal skeletal dysplasia. The primary skeletal characteristics include small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases; to: Perinatal lethal skeletal dysplasia. The primary skeletal characteristics include small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases. At least 5 unrelated families reported. |
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| Fetal anomalies v0.329 | BMP4 |
Zornitza Stark changed review comment from: Variants in this gene are associated with both syndromic and non-syndromic CL/P, over 20 families reported. Note some of the variants reported with isolated CL/P are susceptibility alleles. Deletions reported.; to: Variants in this gene are associated with both syndromic and non-syndromic CL/P, over 20 families reported. Note some of the variants reported with isolated CL/P are susceptibility alleles. Deletions reported. |
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| Fetal anomalies v0.329 | BMP4 |
Zornitza Stark changed review comment from: Variants in this gene are associated with both syndromic and non-syndromic CL/P. Note some of the variants reported with isolated CL/P are susceptibility alleles.; to: Variants in this gene are associated with both syndromic and non-syndromic CL/P, over 20 families reported. Note some of the variants reported with isolated CL/P are susceptibility alleles. Deletions reported. |
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| Fetal anomalies v0.329 | BMP4 | Zornitza Stark edited their review of gene: BMP4: Added comment: Variants in this gene are associated with both syndromic and non-syndromic CL/P. Note some of the variants reported with isolated CL/P are susceptibility alleles.; Changed publications: 31053785, 19249007, 31909686, 21340693; Changed phenotypes: Orofacial cleft 11 600625, Microphthalmia, syndromic 6, MIM# 607932 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.322 | BMP1 | Zornitza Stark changed review comment from: Well established gene-disease association. Prenatal fractures reported.; to: Well established gene-disease association. Prenatal fractures reported, PMID 25402547. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.317 | BIN1 | Zornitza Stark changed review comment from: ID is generally not part of the phenotype of this myopathy, mild ID reported in one individual only.; to: Variable onset from congenital to childhood. Congenital contractures reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.295 | BCAP31 |
Zornitza Stark changed review comment from: More than 20 unrelated families reported. Clinical features include severe intellectual disability (ID), dystonia, deafness, and central hypomyelination. Female carriers are mostly asymptomatic but may present with deafness. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation.; to: More than 20 unrelated families reported. Clinical features include severe intellectual disability (ID), dystonia, deafness, and central hypomyelination. Female carriers are mostly asymptomatic but may present with deafness. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation. Microcephaly is a feature. |
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| Fetal anomalies v0.280 | BBS1 |
Zornitza Stark changed review comment from: Well established gene-disease association. Renal abnormalities reported. Some suggestion that heterozygotes may have an increased frequency of obesity, hypertension, diabetes mellitus, and renal disease.; to: Well established gene-disease association. Renal abnormalities and polydactyly. |
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| Fetal anomalies v0.275 | B3GAT3 | Zornitza Stark changed review comment from: Established gene-disease association.; to: Established gene-disease association. 26 patients from 13 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Multiple skeletal and cardiac abnormalities reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.214 | TOP2B |
Zornitza Stark gene: TOP2B was added gene: TOP2B was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: TOP2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TOP2B were set to 31409799 Phenotypes for gene: TOP2B were set to B-cell immunodeficiency, distal limb anomalies, and urogenital malformations, MIM# 609296 Review for gene: TOP2B was set to GREEN Added comment: Four individuals from three unrelated families reported, all the variants affected the TOPRIM domain, functional data including mouse model. Sources: Expert Review |
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| Fetal anomalies v0.209 | ATRX | Zornitza Stark changed review comment from: The hallmark of this condition is hypotonia. Contractures have been described but are not a key/prominent feature.; to: Multiple congenital anomalies reported in association with this condition. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.206 | ATP6V0A2 | Zornitza Stark changed review comment from: Defective glycosylation is part of the phenotype. More than 20 unrelated families reported.; to: More than 20 unrelated families reported. IUGR and skeletal anomalies are a feature. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.197 | ASXL1 | Zornitza Stark changed review comment from: Colobomas reported.; to: Bohring-Opitz syndrome is a malformation syndrome characterized by severe intrauterine growth retardation, poor feeding, profound ID, trigonocephaly, prominent metopic suture, exophthalmos, nevus flammeus of the face, upslanting palpebral fissures, hirsutism, and flexion of the elbows and wrists with deviation of the wrists and metacarpophalangeal joints -- many of these features would be identifiable antenatally. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.180 | ARSB |
Zornitza Stark changed review comment from: Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Clinical features and severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism. Intelligence is usually normal. Well established gene-disease association.; to: Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Clinical features and severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism. Intelligence is usually normal. Well established gene-disease association. Perinatal presentation is uncommon but reported with oedema and skeletal changes. |
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| Fetal anomalies v0.158 | ATAD1 |
Krithika Murali gene: ATAD1 was added gene: ATAD1 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: ATAD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATAD1 were set to 28180185; 29390050; 29659736 Phenotypes for gene: ATAD1 were set to Hyperekplexia 4 - #618011 Review for gene: ATAD1 was set to GREEN Added comment: Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Three unrelated families reported. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures. Severe progressive neurological disorder, severe/profound intellectual disability is a feature. Sources: Expert list, Literature |
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| Fetal anomalies v0.158 | ADCY6 |
Krithika Murali gene: ADCY6 was added gene: ADCY6 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: ADCY6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADCY6 were set to 24319099, 26257172, 31846058; 33820833 Phenotypes for gene: ADCY6 were set to Lethal congenital contracture syndrome 8 - #616287 Review for gene: ADCY6 was set to GREEN Added comment: PMID: 33820833 (2021) - Further 2 sibs reported with a homozygous c.3346C>T:p.Arg1116Cys variant in the ADCY6 gene. The family was identified from a cohort of 315 genetically undiagnosed and unrelated AMC families. Arthrogryposis and IUGR were detected prenatally. Laquerriere et al. (2014): 2 sibs from a consanguineous family with an axoglial form of lethal congenital contracture syndrome, and homozygous missense ADCY6 mutation (R1116C). The parents were heterozygous for the mutation. Knocked down ADCY6 orthologs in zebrafish showed a loss of myelin basic protein expression in the peripheral nervous system but no defects in Schwann cell migration and axonal growth. Gonzaga‐Jauregui et al. (2015): 1 patient with congenital hypotonia, distal joint contractures, hypomyelinating neuropathy, and vocal cord paralysis, and a homozygous missense ADCY6 variant. No functional studies. Deceased sister with a similar phenotype with hypotonia, areflexia, and hypomyelinating neuropathy who died at 18 months of respiratory insufficiency. Agolini et al. (2020): 1 patient with severe form of AMC, with two novel compound heterozygous variants in ADCY6 (parents confirmed carriers), but no functional studies. Sources: Expert list, Literature |
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| Fetal anomalies v0.156 | AP1S2 | Zornitza Stark changed review comment from: Contractures are mentioned in the OMIM summary for this disorder, but do not appear to be a common/prominent feature.; to: Dandy-Walker malformation, hydrocephalus, intracranial calcifications reported in some patients. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.149 | ANKRD11 |
Zornitza Stark changed review comment from: Single individual reported. Sources: Literature; to: Well established gene-disease association. Microcephaly and skeletal abnormalities are common, in addition to ID and dysmorphic features. Sources: Literature |
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| Fetal anomalies v0.140 | EFEMP2 |
Zornitza Stark gene: EFEMP2 was added gene: EFEMP2 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: EFEMP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EFEMP2 were set to 30140196; 23532871; 31548410; 19664000 Phenotypes for gene: EFEMP2 were set to Autosomal recessive cutis laxa type 1B (ARCL1B), MIM# 614437 Review for gene: EFEMP2 was set to GREEN Added comment: Associated with pulmonary hypoplasia, hypoplastic diaphragm and diffuse lung disease, fractures, arthrogryposis. Over 20 unrelated families reported in the literature. Sources: Expert Review |
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| Fetal anomalies v0.135 | QRICH1 |
Zornitza Stark changed review comment from: Eight unrelated individuals reported with expressive speech delay, moderate motor delay, learning difficulties/ mild ID, mild microcephaly, short stature and notable social behaviour deficits as clinical hallmarks. One individual reported with nephroblastoma.; to: Eight unrelated individuals reported with expressive speech delay, moderate motor delay, learning difficulties/ mild ID, mild microcephaly, short stature and notable social behaviour deficits as clinical hallmarks. One individual reported with nephroblastoma. IUGR rarely reported. Other features are unlikely to be detectable perinatally. |
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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 v0.130 | BICD2 | Zornitza Stark edited their review of gene: BICD2: Added comment: Prenatal presentations reported.; Changed rating: GREEN; Changed publications: 33547725 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.118 | ALX1 | Zornitza Stark changed review comment from: Two families reported with balletic variants in this gene and frontonasal dysplasia. Unclear whether intellectual disability is truly part of the phenotype or whether intellectual ability difficult to assess in presence of severe craniofacial abnormality.; to: Two families reported with balletic variants in this gene and frontonasal dysplasia, supportive animal models. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.107 | ALG6 |
Zornitza Stark changed review comment from: Over 100 affected individuals reported. PMID 27498540 summarises findings in 41 patients. Hypotonia and developmental delay were reported in all. Other common features include epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in <50 % of cases, without spontaneous bleedings. Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly. Cyclic behavioral change, with autistic features and depressive episodes. Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures. The oldest patient was a 40 year-old. The most common pathogenic protein alterations were p.A333V and p.I299Del, without any clear genotype-phenotype correlation.; to: Over 100 affected individuals reported. Mostly neurological features, though rare congenital anomalies such as missing phalanges reported. PMID 27498540 summarises findings in 41 patients. Hypotonia and developmental delay were reported in all. Other common features include epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in <50 % of cases, without spontaneous bleedings. Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly. Cyclic behavioral change, with autistic features and depressive episodes. Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures. The oldest patient was a 40 year-old. The most common pathogenic protein alterations were p.A333V and p.I299Del, without any clear genotype-phenotype correlation. |
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| Fetal anomalies v0.104 | ALG12 |
Zornitza Stark changed review comment from: Two individuals reported as part of a CDH cohort. Sources: Literature; to: Multiple congenital anomalies, including cardiac, skeletal, CDH reported. Sources: Literature |
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| Fetal anomalies v0.97 | ALDOA | Zornitza Stark changed review comment from: Only some patients have been reported to have developmental delay; some of these reports pre-date molecular characterisation of this disorder and therefore a firm link with ID is difficult to establish.; to: Typically presents with haemolytic anaemia post-natally. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.67 | AGTR1 |
Zornitza Stark gene: AGTR1 was added gene: AGTR1 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: AGTR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AGTR1 were set to 16116425 Phenotypes for gene: AGTR1 were set to Renal tubular dysgenesis, MIM# 267430 Added comment: Three unrelated families reported. Severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Sources: Expert Review |
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| Fetal anomalies v0.65 | AGT |
Zornitza Stark gene: AGT was added gene: AGT was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: AGT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AGT were set to 16116425; 34234805; 33163725 Phenotypes for gene: AGT were set to Renal tubular dysgenesis, MIM# 267430 Review for gene: AGT was set to GREEN Added comment: Well established gene-disease association, more than 10 unrelated families reported. Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios. Absence or paucity of differentiated proximal tubules is the histopathologic hallmark of the disorder and may be associated with skull ossification defects. Sources: Expert Review |
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| Fetal anomalies v0.63 | AGK | Zornitza Stark changed review comment from: Cognition is reported to be normal in this mitochondrial condition.; to: Severe perinatal disorder, including HCM. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.54 | ADGRG6 | Zornitza Stark changed review comment from: Three other families reported but with severe prenatal onset arthrogryposis, unclear if CNS features.; to: Three other families reported but with severe prenatal onset arthrogryposis. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.48 | ADAMTSL2 | Zornitza Stark changed review comment from: Variants in this gene cause a multi-system disorder involving the skeleton, skin, joints, and heart; however, theres is little evidence of intellectual disability in this disorder.; to: Variants in this gene cause a multi-system disorder involving the skeleton, skin, joints, and heart; perinatal presentation with skeletal and heart features reported. Multiple families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.36 | ACTC1 | Zornitza Stark changed review comment from: Well established association with cardiomyopathies. Three families reported with ASD.; to: Well established association with cardiomyopathies. Four families reported with ASD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.22 | ACTA2 |
Krithika Murali edited their review of gene: ACTA2: Added comment: Multisystemic smooth muscle dysfunction syndrome (MSMDS) presents with a recognizable pattern of complications, including congenital mydriasis, patent ductus arteriosus (PDA), pulmonary artery hypertension, aortic and other arterial aneurysms, moyamoya-like cerebrovascular disease, intestinal hypoperistalsis and malrotation, and hypotonic bladder. More than 40 unrelated individuals reported, missense at p.Arg179 position.; Changed rating: GREEN; Changed publications: 20734336, 29300374; Changed phenotypes: Multisystemic smooth muscle dysfunction syndrome - MIM# 613834 |
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| Fetal anomalies v0.0 | SELENON |
Zornitza Stark gene: SELENON was added gene: SELENON was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: SELENON was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SELENON were set to Myopathy, congenital, with fiber-type disproportion 255310; Muscular dystrophy, rigid spine 602771 |
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| Fetal anomalies v0.0 | COL4A4 |
Zornitza Stark gene: COL4A4 was added gene: COL4A4 was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: COL4A4 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: COL4A4 were set to ALPORT SYNDROME AUTOSOMAL RECESSIVE |
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| Fetal anomalies v0.0 | COL4A3 |
Zornitza Stark gene: COL4A3 was added gene: COL4A3 was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: COL4A3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: COL4A3 were set to ALPORT SYNDROME AUTOSOMAL DOMINANT; ALPORT SYNDROME AUTOSOMAL RECESSIVE |
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| Fetal anomalies v0.0 | ALAD |
Zornitza Stark gene: ALAD was added gene: ALAD was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp Mode of inheritance for gene: ALAD was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ALAD were set to ACUTE HEPATIC PORPHYRIA |
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| Fetal anomalies v0.0 | MAP3K20 |
Zornitza Stark gene: MAP3K20 was added gene: MAP3K20 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: MAP3K20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAP3K20 were set to 26755636; 27816943 Phenotypes for gene: MAP3K20 were set to Split-foot malformation-mesoaxial polydactyly syndrome, MONDO:0014816; Myopathy, centronuclear, 6, with fiber-type disproportion, MONDO:0054695; Centronuclear myopathy 6 with fiber-type disproportion, OMIM:617760; Split-foot malformation with mesoaxial polydactyly, OMIM:616890 |
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| Fetal anomalies v0.0 | FIG4 |
Zornitza Stark gene: FIG4 was added gene: FIG4 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: FIG4 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: FIG4 were set to Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Charcot-Marie-Tooth disease type 4J, MONDO:0012640; Yunis-Varon syndrome, OMIM:216340; Yunis-Varon syndrome, MONDO:0008995; ?Polymicrogyria, bilateral temporooccipital, OMIM:612691; Bilateral parasagittal parieto-occipital polymicrogyria, MONDO:0012986 |
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| Fetal anomalies v0.0 | ACSL4 |
Zornitza Stark gene: ACSL4 was added gene: ACSL4 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: ACSL4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: ACSL4 were set to ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS; MENTAL RETARDATION X-LINKED TYPE 63 |
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| Fetal anomalies v0.0 | UROS |
Zornitza Stark gene: UROS was added gene: UROS was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: UROS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: UROS were set to CONGENITAL ERYTHROPOIETIC PORPHYRIA |
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| Fetal anomalies v0.0 | TPM3 |
Zornitza Stark gene: TPM3 was added gene: TPM3 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TPM3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: TPM3 were set to Congenital fiber-type disproportion myopathy 255310 |
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| Fetal anomalies v0.0 | SLC16A2 |
Zornitza Stark gene: SLC16A2 was added gene: SLC16A2 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: SLC16A2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: SLC16A2 were set to MCT8 (SLC16A2)-SPECIFIC THYROID HORMONE CELL TRANSPORTER DEFICIENCY |
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| Fetal anomalies v0.0 | PORCN |
Zornitza Stark gene: PORCN was added gene: PORCN was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: PORCN was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Phenotypes for gene: PORCN were set to FOCAL DERMAL HYPOPLASIA |
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| Fetal anomalies v0.0 | POR |
Zornitza Stark gene: POR was added gene: POR was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: POR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: POR were set to Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis 201750; Disordered steroidogenesis due to cytochrome P450 oxidoreductase 613571 |
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| Fetal anomalies v0.0 | LRP5 |
Zornitza Stark gene: LRP5 was added gene: LRP5 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: LRP5 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: LRP5 were set to HIGH BONE MASS TRAIT; ENDOSTEAL HYPEROSTOSIS WORTH TYPE; VITREORETINOPATHY EXUDATIVE TYPE 4; OSTEOPETROSIS AUTOSOMAL DOMINANT TYPE 1; OSTEOPOROSIS-PSEUDOGLIOMA SYNDROME |
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| Fetal anomalies v0.0 | FOLR1 |
Zornitza Stark gene: FOLR1 was added gene: FOLR1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: FOLR1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: FOLR1 were set to NEURODEGENERATION DUE TO CEREBRAL FOLATE TRANSPORT DEFICIENCY |
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| Fetal anomalies v0.0 | COL4A2 |
Zornitza Stark gene: COL4A2 was added gene: COL4A2 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: COL4A2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: COL4A2 were set to 32732225 Phenotypes for gene: COL4A2 were set to PORENCEPHALY 2 |
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| Fetal anomalies v0.0 | COL4A1 |
Zornitza Stark gene: COL4A1 was added gene: COL4A1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: COL4A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: COL4A1 were set to 30266093; 32732225; 30712878 Phenotypes for gene: COL4A1 were set to PORENCEPHALY 1 |
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