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| Fetal anomalies v1.302 | LDB1 |
Zornitza Stark gene: LDB1 was added gene: LDB1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LDB1 were set to 39680505 Phenotypes for gene: LDB1 were set to Congenital hydrocephalus MONDO:0016349 Review for gene: LDB1 was set to GREEN Added comment: Exome-wide significant enrichment of LDB1 protein-altering de novo variants (p = 1.11 x 10-15) in a large cerebral ventriculomegaly cohort (>2,697 parent-proband trios). 8 unrelated cases with ventriculomegaly, developmental delay, and dysmorphic features with de novo variants (7 LoF variants truncate LDB1's carboxy-terminal LIM interaction domain & 1 missense). Sources: Literature |
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| Fetal anomalies v1.269 | KBTBD2 |
Ain Roesley gene: KBTBD2 was added gene: KBTBD2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: KBTBD2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KBTBD2 were set to 39313616 Phenotypes for gene: KBTBD2 were set to neurodevelopmental disorder MONDO:0700092, KBTBD2-related Review for gene: KBTBD2 was set to GREEN gene: KBTBD2 was marked as current diagnostic Added comment: 3 families - 2 compound hets and 1 hom phenotypes include: Microcephaly, hypotonia, failure to thrive, IUGR, delayed gross motor development, dysmorphism Sources: Literature |
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| 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 v1.252 | SERPINA11 |
Ain Roesley gene: SERPINA11 was added gene: SERPINA11 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: SERPINA11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SERPINA11 were set to 38831697 Phenotypes for gene: SERPINA11 were set to pericardial effusion; pleural effusion Review for gene: SERPINA11 was set to RED gene: SERPINA11 was marked as current diagnostic Added comment: 1 family with 2 fetuses. 1st fetus presented with isolated pericardial effusion and a TOP was opted. post mortem: mild subcutaneous edema with subtle facial dysmorphic features small gelatinous glistening cyst on the right pericardium. Bilateral pleural effusion and multiple similar cysts were noted on the lung surfaces 2nd fetus also presented with pleural and pericardial effusion and a TOP was opted post mortem findings were similar to fetus#1 homozygous nonsense variant in SERPINA11 was found p.(Tyr224*) Immunofluorescence of lung sections from fetus#1 and a gestation-matched fetus as a control demonstrated undetectable levels of SERPINA11 in the bronchiolar epithelium Sources: Literature |
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| Fetal anomalies v1.231 | FILIP1 | Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related to ANeuromuscular disorder, congenital, with dysmorphic facies, MIM# 620775 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.230 | FILIP1 | Zornitza Stark reviewed gene: FILIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuromuscular disorder, congenital, with dysmorphic facies, MIM# 620775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.206 | 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 v1.179 | 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 v1.177 | CNOT2 |
Zornitza Stark gene: CNOT2 was added gene: CNOT2 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: CNOT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CNOT2 were set to 31512373; 31145527; 28135719 Phenotypes for gene: CNOT2 were set to Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies 618608 Review for gene: CNOT2 was set to GREEN Added comment: Congenital heart disease and poor growth may be detectable prenatally. Sources: Expert Review |
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| Fetal anomalies v1.174 | RAP1B | Zornitza Stark Phenotypes for gene: RAP1B were changed from Syndromic disease, MONDO:0002254, RAP1B-related to Thrombocytopenia 1 with multiple congenital anomalies and dysmorphic facies, MIM# 620654 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.173 | RAP1B | Zornitza Stark reviewed gene: RAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Thrombocytopenia 1 with multiple congenital anomalies and dysmorphic facies, MIM# 620654; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.167 | WBP4 |
Lilian Downie gene: WBP4 was added gene: WBP4 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: WBP4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WBP4 were set to PMID: 37425688 Phenotypes for gene: WBP4 were set to Neurodevelopmental disorder, MONDO:0700092, WBP4-related Review for gene: WBP4 was set to GREEN Added comment: 11 individuals, with dysmorphic ID 3 presented in utero 2x IUGR, 1x ventriculomegaly and polyhydramnios 5 with brain anomalies (corpus callosum and cortical) Sources: Literature |
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| Fetal anomalies v1.148 | PPP1R13L | Zornitza Stark Phenotypes for gene: PPP1R13L were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 - PPP1R13L-related; Dilated cardiomyopathy, onset in infancy; Cleft lip and palate to Arrhythmogenic cardiomyopathy with or without ectodermal abnormalities, MIM#620519 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.132 | PHF5A |
Daniel Flanagan gene: PHF5A was added gene: PHF5A was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: PHF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: PHF5A were set to PMID: 37422718 Review for gene: PHF5A was set to GREEN Added comment: Nine subjects with congenital malformations, including hypospadias, growth abnormalities, and developmental delay who had de novo PHF5A variants. Prenatally, six subjects had intrauterine growth retardation. All subjects had motor and speech delay and developmental delay. Congenital abnormalities comprised hypospadias in three of four male subjects and heart defects, inguinal hernia, and sacral dimple in three subjects. Six of the nine subjects had short stature. Craniofacial dysmorphism is variable in the nine subjects, high forehead and preauricular skin tag(s) in five subjects. Sources: Expert list |
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| Fetal anomalies v1.129 | STX5 |
Ain Roesley gene: STX5 was added gene: STX5 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: STX5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STX5 were set to 34711829 Phenotypes for gene: STX5 were set to congenital disorder of glycosylation MONDO#0015286, STX5-related Review for gene: STX5 was set to AMBER gene: STX5 was marked as current diagnostic Added comment: 1x family with 3x deceased shortly after death + 3x spontaneous abortions + 2x abortions due to abnormal fatal ultrasound (US). Hom for NM_003164.4:c.163 A > G p.(Met55Val), which results in complete loss of short isoform (which uses Met55 as the start) phenotype: short long bones on US, dysmorphism, skeletal dysplasia, profound hypotonia, hepatomegaly elevated cholesterol. Post-natally they died of progressive liver failure with cholestasis and hyperinsulinemic hypoglycemias Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking Sources: Literature |
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| Fetal anomalies v1.122 | DCAF15 |
Chirag Patel gene: DCAF15 was added gene: DCAF15 was added to Fetal anomalies. Sources: Other Mode of inheritance for gene: DCAF15 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DCAF15 were set to Cornelia de Lange syndrome Review for gene: DCAF15 was set to AMBER Added comment: ESHG 2023: 3 unrelated cases with CdLS (1 x TOP with MCA, 1 x death @20mths, 1 x living child) Features suggestive of CdLS - DD, microcephaly, CHD, dysmorphism, visual/hearing impairment. WES identified recurrent de novo variant (p.Ser470Phe) in DCAF15 gene. This mediates ubiquitination and degradation of target proteins, and interacts with cohesin complex members (SMC1/SMC3). Protein analysis from individuals showed increased accumulation of ubiquitination-modified proteins and SM3 (GOF mechanism). EpiSign analysis showed same DNA methylation pattern as other CdLS cases/genes. Zebrafish model showed reduced body length, reduced head size, reduced oligodendrocytes, heart defect, aberrant motor neurons, and abnormal response to visual/auditory stimuli. Sources: Other |
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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 v1.105 | GATAD2A |
Zornitza Stark gene: GATAD2A was added gene: GATAD2A was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: GATAD2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372 Phenotypes for gene: GATAD2A were set to Neurodevelopmental disorder, MONDO:0700092, GATAD2A-related Review for gene: GATAD2A was set to AMBER Added comment: Inconsistent pattern of congenital abnormalities. https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5 PMID: 17565372 - null mouse model is embryonic lethal. Sources: Literature |
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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 v1.87 | EFCAB1 |
Zornitza Stark gene: EFCAB1 was added gene: EFCAB1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EFCAB1 were set to 36727596 Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related Review for gene: EFCAB1 was set to GREEN Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility. Sources: Literature |
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| Fetal anomalies v1.84 | ZNF668 | Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.76 | FRA10AC1 | Zornitza Stark Phenotypes for gene: FRA10AC1 were changed from Neurodevelopmental disorder, MONDO:0700092, FRA10AC1-related to Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, MIM# 620113 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.75 | FRA10AC1 | Zornitza Stark reviewed gene: FRA10AC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, MIM# 620113; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.71 | 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 v1.48 | PPP1R13L | Zornitza Stark Phenotypes for gene: PPP1R13L were changed from Dilated cardiomyopathy, onset in infancy; Cleft lip and palate to Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 - PPP1R13L-related; Dilated cardiomyopathy, onset in infancy; Cleft lip and palate | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.47 | PPP1R13L | Krithika Murali edited their review of gene: PPP1R13L: Changed phenotypes: Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 - PPP1R13L-related disorder, Dilated cardiomyopathy, onset in infancy, Cleft lip and palate | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.41 | 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 v1.36 | ADD1 |
Zornitza Stark gene: ADD1 was added gene: ADD1 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: ADD1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: ADD1 were set to 34906466 Phenotypes for gene: ADD1 were set to Neurodevelopmental disorder MONDO:0700092, ADD1-related Review for gene: ADD1 was set to GREEN Added comment: 4 unrelated individuals affected by ID and/or complete or partial agenesis of corpus callosum, and enlarged lateral ventricles. WES found loss-of-function variants - 1 recessive missense variant and 3 de novo variants. The recessive variant is associated with ACC and enlarged lateral ventricles, and the de novo variants were associated with complete or partial agenesis of corpus callosum, mild ID and attention deficit. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes. Three adducin genes (ADD1, ADD2, and ADD3) encode cytoskeleton proteins that are critical for osmotic rigidity and cell shape. ADD1, ADD2, and ADD3 form heterodimers (ADD1/ADD2, ADD1/ADD3), which further form heterotetramers. Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown Sources: Expert Review |
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| Fetal anomalies v1.31 | USP14 | Zornitza Stark Phenotypes for gene: USP14 were changed from Distal arthrogryposis, corpus callosum anomalies, and dysmorphic features; no OMIM # to Syndromic disease MONDO:0002254, USP14-related; Distal arthrogryposis, corpus callosum anomalies, and dysmorphic features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.29 | USP14 |
Chirag Patel gene: USP14 was added gene: USP14 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: USP14 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: USP14 were set to PMID: 35066879 Phenotypes for gene: USP14 were set to Distal arthrogryposis, corpus callosum anomalies, and dysmorphic features; no OMIM # Review for gene: USP14 was set to RED Added comment: 3 fetuses from 2 different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233_236delTTCC; p.Leu78Glnfs*11) in USP14, and sequencing of family members showed segregation with the phenotype. Ubiquitin-specific protease 14 (USP14) encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human multiple congenital contractures phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay. Sources: Literature |
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| Fetal anomalies v1.25 | FTO | Bryony Thompson reviewed gene: FTO: Rating: GREEN; Mode of pathogenicity: None; Publications: 19234441, 19559399, 26378117, 26697951, 26378117, 26740239; Phenotypes: Growth retardation, developmental delay, facial dysmorphism MIM#612938; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.25 | MAPKAPK5 | Zornitza Stark Phenotypes for gene: MAPKAPK5 were changed from Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic to Neurocardiofaciodigital syndrome, MIM# 619869 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.17 | RSPO2 |
Zornitza Stark gene: RSPO2 was added gene: RSPO2 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: RSPO2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RSPO2 were set to 29769720; 32457899 Phenotypes for gene: RSPO2 were set to Tetraamelia syndrome 2, MIM# 618021 Review for gene: RSPO2 was set to GREEN Added comment: Tetraamelia syndrome-2 (TETAMS2) is characterized by rudimentary appendages or complete absence of the limbs, usually symmetric, as well as bilateral agenesis of the lungs. There are abnormalities of the pulmonary vasculature and dysmorphic features, including bilateral cleft lip/palate, ankyloglossia, mandibular hypoplasia, microretrognathia, and labioscrotal fold aplasia. Four unrelated families and functional data including animal model. Sources: Expert Review |
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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 v0.4700 | 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 v0.4692 | 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 v0.4598 | 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 v0.4592 | PHIP | Zornitza Stark Phenotypes for gene: PHIP were changed from Developmental delay, ID, obesity and dysmorphic features to Chung-Jansen syndrome, MIM#617991 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4588 | PHIP |
Zornitza Stark changed review comment from: Recent large case series describing 20 individuals; variable expressivity, some inherited from mildly affected parents, most de novo. Sources: Expert list; to: Recent large case series describing 20 individuals; variable expressivity, some inherited from mildly affected parents, most de novo. ID, dysmorphism and obesity are the key features. Clinical presentation is typically post-natal. Sources: Expert list |
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| Fetal anomalies v0.4557 | POC1A | Zornitza Stark Phenotypes for gene: POC1A were changed from PRIMORDIAL DWARFISM; SHORT STATURE, ONYCHODYSPLASIA, FACIAL DYSMORPHISM, AND HYPOTRICHOSIS SYNDROME to Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis, MIM#614813 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4553 | 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 v0.4542 | PPP2R1A | Zornitza Stark Phenotypes for gene: PPP2R1A were changed from INTELLECTUAL DISABILITY to Mental retardation, autosomal dominant 36, MIM#616362; Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome, MONDO:0014605 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4478 | 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 v0.4404 | 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 v0.4372 | 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 v0.4356 | SMO | Zornitza Stark Marked gene: SMO as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4356 | SMO | Zornitza Stark Gene: smo has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4356 | SMO | Zornitza Stark Mode of inheritance for gene: SMO was changed from Other to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4355 | SMO | Zornitza Stark Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.4355 | SMO | Zornitza Stark Phenotypes for gene: SMO were changed from Curry-Jones Syndrome to Curry-Jones syndrome, somatic mosaic, MIM#601707 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4354 | SMO | Zornitza Stark Publications for gene: SMO were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4353 | SMO | Zornitza Stark Mode of pathogenicity for gene: SMO was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4352 | SMO | Zornitza Stark Mode of inheritance for gene: SMO was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4351 | SMOC1 | Zornitza Stark Marked gene: SMOC1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4351 | SMOC1 | Zornitza Stark Gene: smoc1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4351 | SMOC1 | Zornitza Stark Phenotypes for gene: SMOC1 were changed from OPHTHALMOACROMELIC SYNDROME to Microphthalmia with limb anomalies, MIM# 206920 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4350 | SMOC1 | Zornitza Stark Publications for gene: SMOC1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4317 | TUBGCP2 |
Chirag Patel gene: TUBGCP2 was added gene: TUBGCP2 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TUBGCP2 were set to PMID: 31630790 Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, OMIM # 618737 Review for gene: TUBGCP2 was set to GREEN Added comment: Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures (PAMDDFS) is an autosomal recessive neurologic disorder characterized by progressive microcephaly associated with abnormal facial features, hypotonia, and variable global developmental delay with impaired intellectual development. Brain imaging shows variable malformation of cortical development on the lissencephaly spectrum, mainly pachygyria and thin corpus callosum. 4 unrelated patients with homozygous or compound heterozygous mutations in the TUBGCP2 gene, found by WES and segregated with the disorder in all families. Functional studies of the variants were not performed, but analysis of patient fibroblasts derived from the patient with a splice site mutation demonstrated the production of several abnormal transcripts that were predicted to result in a loss of function. Sources: Expert list |
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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 v0.4293 | 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 v0.4273 | MAN2C1 |
Daniel Flanagan gene: MAN2C1 was added gene: MAN2C1 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: MAN2C1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAN2C1 were set to 35045343 Phenotypes for gene: MAN2C1 were set to MAN2C1-related neurodevelopmental disorder MONDO:0700092 Review for gene: MAN2C1 was set to GREEN Added comment: Six individuals from four different families, including two fetuses, exhibiting dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Variants include PTC and missense. *3 unrelated individuals presented polymicrogyria Sources: Expert list |
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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 | 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 v0.4265 | CDX2 | Zornitza Stark Phenotypes for gene: CDX2 were changed from Persistent cloaca to Genetic multiple congenital anomalies/dysmorphic syndrome, MONDO:0043005; Congenital abnormalities of anus, renal and urogenital system, vertebrae and/or the limbs | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4255 | PPP2R3C |
Chirag Patel gene: PPP2R3C was added gene: PPP2R3C was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PPP2R3C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPP2R3C were set to PMID: 30893644, 34714774, 34750818 Phenotypes for gene: PPP2R3C were set to Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy, OMIM # 618419 Review for gene: PPP2R3C was set to GREEN Added comment: Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy (GDRM) is characterized by 46,XY complete gonadal dysgenesis in association with extragonadal anomalies, low birth weight, typical facial gestalt, rod and cone dystrophy, sensorineural hearing loss, omphalocele, anal atresia, renal agenesis, skeletal abnormalities, dry and scaly skin, severe myopathy, and neuromotor delay. 11 unrelated families with syndromic complete gonadal dysgenesis. 9 families had 46,XY females with complete gonadal dysgenesis, but 2 families had 46,XX patients with hypergonadotropic hypogonadism, nonvisualized gonads, primary amenorrhea, and absence of secondary sexual characteristics. Variants segregated with disease in each family and were not found in ethnically matched controls or in public variant databases. The heterozygous fathers exhibited morphologic abnormalities of spermatozoa and reduced fertility. Sources: Literature |
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| Fetal anomalies v0.4207 | ZMIZ1 |
Krithika Murali gene: ZMIZ1 was added gene: ZMIZ1 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: ZMIZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZMIZ1 were set to 30639322; 31879022 Phenotypes for gene: ZMIZ1 were set to Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies - MIM#618659 Review for gene: ZMIZ1 was set to GREEN Added comment: Syndromic ID associated with multiple congenital malformations Sources: Literature, Expert list |
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| Fetal anomalies v0.4184 | PAM16 |
Chirag Patel gene: PAM16 was added gene: PAM16 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: PAM16 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PAM16 were set to PubMed: 24786642, 27354339 Phenotypes for gene: PAM16 were set to Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type, OMIM # 613320 Review for gene: PAM16 was set to GREEN Added comment: Megarbane-Dagher-Melki type of spondylometaphyseal dysplasia (SMDMDM) has chondrodysplasia, developmental delay, severe pre- and postnatal short stature, dysmorphic facial appearance, narrow chest, prominent abdomen, and short limbs. 5 patients from 3 unrelated families with homozygous missense mutations which segregate with disease. Sources: Expert list |
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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 v0.4157 | 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 v0.4122 | 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 v0.4106 | TAF1 | Zornitza Stark Phenotypes for gene: TAF1 were changed from Dysmorphic Features, Intellectual Disability, and Neurological Manifestations to Mental retardation, X-linked, syndromic 33, MIM# 300966 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4074 | 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 v0.4044 | TRAF7 | Zornitza Stark Phenotypes for gene: TRAF7 were changed from Developmental Delay, Congenital Anomalies, and Dysmorphic Features; Cardiac, facial, and digital anomalies with developmental delay, 618164 to Cardiac, facial, and digital anomalies with developmental delay, MIM# 618164 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4010 | 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 v0.3934 | 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 v0.3908 | 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 v0.3879 | STAR | Zornitza Stark Phenotypes for gene: STAR were changed from CHOLESTEROL DESMOLASE-DEFICIENT CONGENITAL ADRENAL HYPERPLASIA to Lipoid adrenal hyperplasia (MIM#201710) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3768 | TBCE | Zornitza Stark Phenotypes for gene: TBCE were changed from HYPOPARATHYROIDISM-RETARDATION-DYSMORPHISM SYNDROME; Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy; KENNY-CAFFEY SYNDROME TYPE 1 to Hypoparathyroidism-retardation-dysmorphism syndrome, OMIM #241410; Kenny-Caffey syndrome, type 1, OMIM #244460; Encephalopathy, progressive, with amyotrophy and optic atrophy OMIM #617207 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3721 | TBCE | Chirag Patel reviewed gene: TBCE: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12389028, 27666369; Phenotypes: Hypoparathyroidism-retardation-dysmorphism syndrome, OMIM #241410, Kenny-Caffey syndrome, type 1, OMIM #244460, Encephalopathy, progressive, with amyotrophy and optic atrophy OMIM #617207; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3697 | 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 v0.3639 | FBXO11 | Zornitza Stark Phenotypes for gene: FBXO11 were changed from Variable Neurodevelopmental Disorder to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities, MIM# 618089 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3636 | FBXO11 | Zornitza Stark reviewed gene: FBXO11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities, MIM# 618089; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3592 | RPS23 | Zornitza Stark Phenotypes for gene: RPS23 were changed from Microcephaly, hearing loss, and dysmorphic features to Brachycephaly, trichomegaly, and developmental delay, MIM# 617412 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3537 | TBX15 | Zornitza Stark Phenotypes for gene: TBX15 were changed from Cousin Syndrome; Craniofacial Dysmorphism, Hypoplasia of Scapula and Pelvis, and Short Stature to Cousin syndrome, MIM# 260660; Craniofacial Dysmorphism, Hypoplasia of Scapula and Pelvis, and Short Stature | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3507 | TMCO1 | Zornitza Stark Phenotypes for gene: TMCO1 were changed from CRANIOFACIAL DYSMORPHISM, SKELETAL ANOMALIES, AND MENTAL RETARDATION SYNDROME to Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome, MIM# 213980 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3505 | TMCO1 | Zornitza Stark reviewed gene: TMCO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20018682, 23320496, 24194475, 30556256, 31102500; Phenotypes: Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome, MIM# 213980; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3484 | 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 v0.3390 | MSMO1 | Zornitza Stark Marked gene: MSMO1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3390 | MSMO1 | Zornitza Stark Gene: msmo1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3390 | MSMO1 | Zornitza Stark Publications for gene: MSMO1 were set to 21285510; 24144731 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3389 | MSMO1 | Zornitza Stark Classified gene: MSMO1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.3389 | MSMO1 | Zornitza Stark Gene: msmo1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.3298 | ITCH | Zornitza Stark Phenotypes for gene: ITCH were changed from AUTOIMMUNE DISEASE, SYNDROMIC MULTISYSTEM to Autoimmune disease, multisystem, with facial dysmorphism, MIM#613385 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.3217 | 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 v0.3151 | 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 | 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 v0.3140 | 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 | INTS1 |
Krithika Murali gene: INTS1 was added gene: INTS1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: INTS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: INTS1 were set to 28542170; 30622326; 31428919 Phenotypes for gene: INTS1 were set to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies - MIM#618571 Review for gene: INTS1 was set to GREEN Added comment: PMID: 28542170 Oegema et al 2017 - 3 unrelated individuals with syndromic ID of Dutch ancestry showed the same homozygous truncating INTS1 mutation - 1/3 Cleft palate/lip, 1/3 renal malformation PMID: 30622326 – Krall et al 2019 - 5 patients from 4 families with biallelic sequence variants in INTS1. The patients manifested absent or severely limited speech, an abnormal gait, hypotonia and cataracts. Other phenotypic features included: o Micropthalmia – 2/5 o Frontal bossing 2/5 o Hypertelorism – 5/5 o Microretrognathia – 4/5 o Renal malformation 2/5 PMID: 31428919 – Zhang et al 2020 - 2 Chinese siblings with ID found to have INTST1 compound het variants, both had cataracts, facial dysmorphism, short stature, severe ID and anomalous genitalia Sources: Literature |
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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 | 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 | 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 | POLE | Zornitza Stark Phenotypes for gene: POLE were changed from severe growth failure of prenatal onset; IUGR; FILS syndrome, 615139; facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) to IMAGE-I syndrome 618336 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.3010 | PHF21A | Zornitza Stark Phenotypes for gene: PHF21A were changed from POTOCKI-SHAFFER SYNDROME to Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, MIIM# 618725 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.2993 | PGAP1 | Zornitza Stark Phenotypes for gene: PGAP1 were changed from Intellectual disability, encephalopathy, impaired GPI-anchor maturation to Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities, MIM# 615802 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2990 | PGAP1 | Zornitza Stark reviewed gene: PGAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 24784135, 25823418, 25804403, 26050939; Phenotypes: Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities, MIM# 615802; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.2949 | MTOR | Alison Yeung Phenotypes for gene: MTOR were changed from Smith-Kingsmore syndrome to Smith-Kingsmore syndrome, MIM# 616638 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2948 | MTOR | Alison Yeung reviewed gene: MTOR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Smith-Kingsmore syndrome, MIM#616638; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2880 | SHANK3 |
Zornitza Stark changed review comment from: Phelan-McDermid syndrome is a developmental disorder with variable features. Common features include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behaviour, and minor dysmorphic features. Well established gene-disease association, deletions are common.; to: Phelan-McDermid syndrome is a developmental disorder with variable features. Common features include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behaviour, and minor dysmorphic features. Well established gene-disease association, deletions are common. Clinical presentation is typically post-natal. |
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| Fetal anomalies v0.2869 | SETD1A | Zornitza Stark Phenotypes for gene: SETD1A were changed from INTELLECTUAL DISABILITY to Epilepsy, early-onset, with or without developmental delay, MIM# 618832; Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM# 619056 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2846 | 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 v0.2820 | 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 v0.2756 | 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 v0.2728 | 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 v0.2712 | 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 v0.2665 | 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 v0.2585 | Zornitza Stark removed gene:SMOC2 from the panel | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2581 | SZT2 | Zornitza Stark Phenotypes for gene: SZT2 were changed from INFANTILE ENCEPHALOPATHY WITH EPILEPSY AND DYSMORPHIC CORPUS CALLOSUM to Developmental and epileptic encephalopathy 18, MIM #615476 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2559 | OTUD6B | Zornitza Stark Phenotypes for gene: OTUD6B were changed from Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features to Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, OMIM #617452 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.2364 | 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 v0.2352 | MYOD1 | Ain Roesley reviewed gene: MYOD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26733463, 30403323, 31260566; Phenotypes: Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies MIM#618975; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2352 | MYO18B | Ain Roesley reviewed gene: MYO18B: Rating: GREEN; Mode of pathogenicity: None; Publications: 25748484, 27858739, 32637634, 32184166, 27879346, 33179433; Phenotypes: Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism MIM#616549; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2265 | DDX6 | Zornitza Stark Phenotypes for gene: DDX6 were changed from INTELLECTUAL DISABILITY to Intellectual developmental disorder with impaired language and dysmorphic facies, MIM#618653 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2240 | HCFC1 |
Zornitza Stark changed review comment from: Variants in the HCFC1 gene are associated with cases of syndromic and non-syndromic intellectual disability. Individuals present with severely delayed psychomotor development apparent in infancy, and severe neurological involvement including intractable epilepsy, facial dysmorphism, and intellectual disability.; to: Variants in the HCFC1 gene are associated with cases of syndromic and non-syndromic intellectual disability. Individuals present with severely delayed psychomotor development apparent in infancy, and severe neurological involvement including intractable epilepsy, facial dysmorphism, and intellectual disability. Microcephaly is a feature. |
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| Fetal anomalies v0.2238 | SCUBE3 | Chirag Patel reviewed gene: SCUBE3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33308444; Phenotypes: Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies, OMIM # 619184; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2217 | SMOC2 | Chirag Patel Classified gene: SMOC2 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2217 | SMOC2 | Chirag Patel Gene: smoc2 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2216 | SMOC2 | Chirag Patel reviewed gene: SMOC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.2195 | 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 v0.2193 | OTUD6B | Chirag Patel reviewed gene: OTUD6B: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 28343629, 32924626, 31147255; Phenotypes: Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, OMIM #617452; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1469 | ZNF699 |
Krithika Murali gene: ZNF699 was added gene: ZNF699 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF699 were set to 33875846 Phenotypes for gene: ZNF699 were set to DEGCAGS syndrome - #619488 Review for gene: ZNF699 was set to GREEN Added comment: DEGCAGS syndrome is an autosomal recessive syndromic neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anemia or pancytopenia, and immunodeficiency with recurrent infections. Sources: Literature, Expert list |
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| Fetal anomalies v0.1469 | UBR7 |
Krithika Murali gene: UBR7 was added gene: UBR7 was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: UBR7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UBR7 were set to 33340455 Phenotypes for gene: UBR7 were set to Li-Campeau syndrome - MIM#619189 Review for gene: UBR7 was set to GREEN Added comment: Biallalic variants associated with Li-Campeau syndrome - identified in 7 affected individuals from 6 unrelated families. Phenotypic features include cardiac defects (5/7 - VSD, ASD, PDA, PFO) Other phenotypic features include: short stature (ht <3rd centile), developmental delay, urogenital anomalies (cryptorchidism, small penis); seizures; hypotonia; hypothyroidism; ptosis; dysmorphic features Sources: Literature, Expert list |
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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 | SPRED2 |
Krithika Murali gene: SPRED2 was added gene: SPRED2 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: SPRED2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPRED2 were set to 34626534 Phenotypes for gene: SPRED2 were set to cardiac defects; skeletal anomalies Review for gene: SPRED2 was set to GREEN Added comment: Homozygous variants identified in four subjects from three families with a clinical phenotype that included developmental delay, ID, cardiac defects, short stature, skeletal anomalies and dysmorphic features. Cardiac defects and skeletal anomalies potentially ascertainable antenatally. Sources: Expert list, Literature |
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| Fetal anomalies v0.1469 | SPEN |
Krithika Murali gene: SPEN was added gene: SPEN was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: SPEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SPEN were set to 33596411 Phenotypes for gene: SPEN were set to Radio-Tartaglia syndrome - MIM#619312 Review for gene: SPEN was set to GREEN Added comment: Radio et al. (2021) reported heterozygous SPEN variants in 34 individuals from 33 unrelated families with had global developmental delay, ID, behavioural issues and dysmorphic features. Other features included hypotonia, gait imbalance, pyramidal signs and seizures. Findings potentially ascertainable antenatally: - Brain imaging abnormalities include polymicrogyria, heterotopia, cerebellar atrophy, periventricular white matter defects, agenesis of the corpus callosum, and tethered cord. - Congenital heart defects also present in a significant proportion. Sources: Expert list, Literature |
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| Fetal anomalies v0.1469 | PRKACB |
Krithika Murali gene: PRKACB was added gene: PRKACB was added to Fetal anomalies. Sources: Literature,Expert list Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PRKACB were set to 33058759 Phenotypes for gene: PRKACB were set to Cardioacrofacial dysplasia 2 - MIM#619143 Review for gene: PRKACB was set to GREEN Added comment: Heterozygous variants reported in 4 unrelated probands with Cardioacrofacial dysplasia-2 (CAFD2) - characterized by congenital cardiac defects (atrium or atrioventricular septal defect mainly); limb anomalies (including short limbs, brachydactyly, and postaxial polydactyly); and dysmorphic facial features. Developmental delay of variable severity has also been observed Sources: Literature, Expert list |
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| Fetal anomalies v0.1469 | PRKACA |
Krithika Murali gene: PRKACA was added gene: PRKACA was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: PRKACA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PRKACA were set to 33058759 Phenotypes for gene: PRKACA were set to Cardioacrofacial dysplasia 1-MIM#619142 Review for gene: PRKACA was set to GREEN Added comment: Heterozygous variants were identified in affected individuals from 3 unrelated families and associated with cardioacrofacial dysplasia-1 (CAFD1). Phenotype includes congenital cardiac defects (mainly atrium or atrioventricular septal defect), limb anomalies (short limbs, brachydactyly, postaxial polydactyly) and dysmorphic facial features. Fetal phenotype also reported. Sources: Expert list, Literature |
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| Fetal anomalies v0.1469 | MIB1 |
Krithika Murali gene: MIB1 was added gene: MIB1 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: MIB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MIB1 were set to 33057194 Phenotypes for gene: MIB1 were set to Congenital heart disease Review for gene: MIB1 was set to AMBER Added comment: Last reviewed March and Dec 2021 - no additional evidence Li 2018 (PMID: 30322850): - in 4 CHD patients: p.Q237H (gv2v3 absent), p.W271G (gv2v3 absent), p.S520R (v2 5 hets) and p.T312Kfs*55 (NMD-pred, absent but many comparables in gnomAD). - HEK293T cells transfection studies showed: T312Kfs*55 and W271G strongly impaired MIB1 function on substrate ubiquitination, while Q237H and S520R had slight or no obvious changes. Interaction between MIB1 and JAG1 is severely interrupted by p.T312Kfs*55 and p.W271G, but not really in the other 2 missense. - Overexpression of wt or mutant in zebrafish all resulted in dysmorphic pheno, therefore not informative. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). Sources: Expert list, Literature |
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| Fetal anomalies v0.1429 | CTU2 | Zornitza Stark Phenotypes for gene: CTU2 were changed from Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, 618142 to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, MIM#618142 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 | CTDP1 | Zornitza Stark Phenotypes for gene: CTDP1 were changed from CONGENITAL CATARACTS FACIAL DYSMORPHISM AND NEUROPATHY SYNDROME to Congenital cataracts, facial dysmorphism, and neuropathy, MIM# 604168 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1361 | ALDH1A2 |
Krithika Murali gene: ALDH1A2 was added gene: ALDH1A2 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: ALDH1A2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ALDH1A2 were set to 33565183; 19886994; 10192400 Phenotypes for gene: ALDH1A2 were set to Congenital heart defects; diaphragmatic eventration; pulmonary hypoplasia; thymus aplasia Review for gene: ALDH1A2 was set to GREEN Added comment: Biallellic variants in two unrelated, non-consanguineous families associated with multiple anomalies - including congenital heart disease, eventration of the diaphragm/diaphragmatic hernia, pulmonary hypoplasia dysmorphic features, thymus aplasia - a number of which were detected antenatally. Functional assays suggest the variants in the 2 families are hypomorphic. Knockout mouse model is embryonic lethal due to in utero defects in early heart morphogenesis. Sources: Expert list, Literature |
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| 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 v0.1126 | BPTF | Zornitza Stark Phenotypes for gene: BPTF were changed from Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features to Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies AD, MIM#617755 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.1107 | WLS |
Zornitza Stark gene: WLS was added gene: WLS was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WLS were set to 34587386 Phenotypes for gene: WLS were set to Zaki syndrome, MIM#619648 Review for gene: WLS was set to GREEN Added comment: - Homozygous mutations in 10 affected persons from 5 unrelated families. - Patients had multiorgan defects, including microcephaly, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. - The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Sources: Literature |
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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 v0.1077 | 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 v0.978 | BCAS3 |
Zornitza Stark gene: BCAS3 was added gene: BCAS3 was added to Fetal anomalies. Sources: Expert Review Mode of inheritance for gene: BCAS3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BCAS3 were set to 34022130 Phenotypes for gene: BCAS3 were set to Hengel-Maroofian-Schols syndrome, MIM# 619641 Review for gene: BCAS3 was set to GREEN Added comment: 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. Patient fibroblasts confirmed absence of BCAS3 protein. All patients had hyperreflexia, spasticity. Microcephaly and CC abnormalities may be detectable antenatally. Sources: Expert Review |
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| Fetal anomalies v0.968 | ASXL2 | Zornitza Stark Phenotypes for gene: ASXL2 were changed from Developmental delay, macrocephaly, and dysmorphic features to Shashi-Pena syndrome, MIM# 617190 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 | NFIX |
Daniel Flanagan changed review comment from: Sotos syndrome-2 (SOTOS2) is clinically characterized by overgrowth, advanced bone age, macrocephaly, and dysmorphic facial features. Patients develop marfanoid habitus, with long and slender body, very low body mass, long narrow face, and arachnodactyly, with age. Impaired intellectual development and behavior anomalies are present. Well established gene-disease association. Marshall-Smith syndrome is allelic. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype (Malan syndrome). Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall-Smith syndrome. Atrial septal defect; to: Sotos syndrome-2 (SOTOS2) is clinically characterized by overgrowth, advanced bone age, macrocephaly, and dysmorphic facial features. Patients develop marfanoid habitus, with long and slender body, very low body mass, long narrow face, and arachnodactyly, with age. Impaired intellectual development and behavior anomalies are present. Well established gene-disease association. Marshall-Smith syndrome is allelic. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype (Malan syndrome). Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall-Smith syndrome. |
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| Fetal anomalies v0.925 | CDK8 |
Zornitza Stark gene: CDK8 was added gene: CDK8 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CDK8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDK8 were set to 30905399 Phenotypes for gene: CDK8 were set to Intellectual disability; dysmorphism; congenital abnormalities; seizures Review for gene: CDK8 was set to GREEN Added comment: 12 unrelated individuals, missense variants demonstrated as de novo in 10. All variants localize to the ATP-binding pocket of the kinase domain. 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 v0.886 | 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 v0.863 | DHCR24 | Zornitza Stark Phenotypes for gene: DHCR24 were changed from DESMOSTEROLOSIS to Desmosterolosis, MIM# 602398 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.826 | 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 v0.612 | 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 v0.607 | 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 v0.540 | ATP1A2 | Zornitza Stark Phenotypes for gene: ATP1A2 were changed from Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602; Developmental and epileptic encephalopathy, polymicrogyria to Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602; Developmental and epileptic encephalopathy 98, MIM# 619605 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.539 | ATP1A2 | Zornitza Stark Phenotypes for gene: ATP1A2 were changed from hydrops fetalis; arthrogryposis; microcephaly; extensive cortical malformations to Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602; Developmental and epileptic encephalopathy, polymicrogyria | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.535 | ATP1A2 | Zornitza Stark edited their review of gene: ATP1A2: Changed phenotypes: Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602, Developmental and epileptic encephalopathy, polymicrogyria; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.535 | ATP1A2 | Zornitza Stark edited their review of gene: ATP1A2: Changed publications: 30690204, 31608932; Changed phenotypes: Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.528 | CNOT3 | Zornitza Stark Phenotypes for gene: CNOT3 were changed from CNOT3 syndrome; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, 618672 to Intellectual developmental disorder with speech delay, autism, and dysmorphic facies , MIM#618672 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.490 | INPPL1 | Seb Lunke Phenotypes for gene: INPPL1 were changed from OPSISMODYSPLASIA to Opsismodysplasia MIM#258480 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 | INPPL1 | Ain Roesley reviewed gene: INPPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23273567, 34529350, 34094554; Phenotypes: Opsismodysplasia MIM#258480; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.405 | CDK13 | Zornitza Stark Phenotypes for gene: CDK13 were changed from Syndromic INTELLECTUAL DISABILITY with or without congenital heart disease to Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, 617360 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.345 | BRPF1 | Zornitza Stark Phenotypes for gene: BRPF1 were changed from BRPF1 associated syndromic intellectual disability with ptosis to Intellectual developmental disorder with dysmorphic facies and ptosis, MIM# 617333; MONDO:0015022 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.327 | BMP2 | Zornitza Stark Phenotypes for gene: BMP2 were changed from Short stature, palatal anomalies, congenital heart disease, and skeletal malformations; Brachydactyly, type A2 112600 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1, MIM# 617877 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.324 | BMP2 | Zornitza Stark reviewed gene: BMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29198724; Phenotypes: Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1, MIM# 617877; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.149 | 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 v0.107 | 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 v0.72 | AHDC1 | Zornitza Stark Phenotypes for gene: AHDC1 were changed from Xia-Gibbs syndrome, MIM# 615829 to Xia-Gibbs syndrome, MIM# 615829; AHDC1-related intellectual disability, obstructive sleep apnoea, mild dysmorphism syndrome MONDO:0014358 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.59 | ADNP | Zornitza Stark Phenotypes for gene: ADNP were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT, 28 to Helsmoortel-van der Aa syndrome MIM#615873; MONDO:0014379 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.27 | ACTA2 | Zornitza Stark Phenotypes for gene: ACTA2 were changed from AORTIC ANEURYSM, FAMILIAL THORACIC 6; MOYAMOYA DISEASE 5 to Multisystemic smooth muscle dysfunction syndrome - MIM# 613834 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 | SZT2 |
Zornitza Stark gene: SZT2 was added gene: SZT2 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: SZT2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SZT2 were set to INFANTILE ENCEPHALOPATHY WITH EPILEPSY AND DYSMORPHIC CORPUS CALLOSUM |
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| Fetal anomalies v0.0 | SMOC2 |
Zornitza Stark gene: SMOC2 was added gene: SMOC2 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: SMOC2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SMOC2 were set to DENTIN DYSPLASIA, TYPE I, WITH MICRODONTIA AND MISSHAPEN TEETH |
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| Fetal anomalies v0.0 | SCUBE3 |
Zornitza Stark gene: SCUBE3 was added gene: SCUBE3 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SCUBE3 were set to 33308444 Phenotypes for gene: SCUBE3 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953 |
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| Fetal anomalies v0.0 | RPS23 |
Zornitza Stark gene: RPS23 was added gene: RPS23 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: RPS23 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: RPS23 were set to Microcephaly, hearing loss, and dysmorphic features |
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| Fetal anomalies v0.0 | POLE |
Zornitza Stark gene: POLE was added gene: POLE was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: POLE was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLE were set to 23230001; 25948378 Phenotypes for gene: POLE were set to severe growth failure of prenatal onset; IUGR; FILS syndrome, 615139; facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) |
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| Fetal anomalies v0.0 | OTUD6B |
Zornitza Stark gene: OTUD6B was added gene: OTUD6B was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: OTUD6B was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: OTUD6B were set to Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features |
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| Fetal anomalies v0.0 | MYOD1 |
Zornitza Stark gene: MYOD1 was added gene: MYOD1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: MYOD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYOD1 were set to 30403323; 26733463; 31260566 Phenotypes for gene: MYOD1 were set to Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies, OMIM:618975 |
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| Fetal anomalies v0.0 | MYO18B |
Zornitza Stark gene: MYO18B was added gene: MYO18B was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: MYO18B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYO18B were set to 27858739; 25748484; 27879346 Phenotypes for gene: MYO18B were set to Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome, MONDO:0014689; Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism, OMIM:616549 |
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| Fetal anomalies v0.0 | MSMO1 |
Zornitza Stark gene: MSMO1 was added gene: MSMO1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: MSMO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MSMO1 were set to 21285510; 24144731 Phenotypes for gene: MSMO1 were set to Microcephaly-congenital cataract-psoriasiform dermatitis syndrome, MONDO:0014793; Microcephaly, congenital cataract, and psoriasiform dermatitis, OMIM:616834 |
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| Fetal anomalies v0.0 | DPH1 |
Zornitza Stark gene: DPH1 was added gene: DPH1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: DPH1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DPH1 were set to 25558065; 32732226; 30877278; 29362492 Phenotypes for gene: DPH1 were set to Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901 |
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| Fetal anomalies v0.0 | CTU2 |
Zornitza Stark gene: CTU2 was added gene: CTU2 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, 618142 |
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| Fetal anomalies v0.0 | CTDP1 |
Zornitza Stark gene: CTDP1 was added gene: CTDP1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: CTDP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTDP1 were set to 20301787; 14517542; 24690360; 29174527 Phenotypes for gene: CTDP1 were set to CONGENITAL CATARACTS FACIAL DYSMORPHISM AND NEUROPATHY SYNDROME |
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| Fetal anomalies v0.0 | BPTF |
Zornitza Stark gene: BPTF was added gene: BPTF was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: BPTF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: BPTF were set to Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features |
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| Fetal anomalies v0.0 | ASXL2 |
Zornitza Stark gene: ASXL2 was added gene: ASXL2 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: ASXL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: ASXL2 were set to Developmental delay, macrocephaly, and dysmorphic features |
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| Fetal anomalies v0.0 | TRAF7 |
Zornitza Stark gene: TRAF7 was added gene: TRAF7 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TRAF7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TRAF7 were set to 29961569 Phenotypes for gene: TRAF7 were set to Developmental Delay, Congenital Anomalies, and Dysmorphic Features; Cardiac, facial, and digital anomalies with developmental delay, 618164 Mode of pathogenicity for gene: TRAF7 was set to Other - please provide details in the comments |
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| Fetal anomalies v0.0 | TMEM94 |
Zornitza Stark gene: TMEM94 was added gene: TMEM94 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TMEM94 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM94 were set to PMID: 30526868 Phenotypes for gene: TMEM94 were set to Intellectual developmental disorder with cardiac defects and dysmorphic facies, OMIM:618316 |
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| Fetal anomalies v0.0 | TMCO1 |
Zornitza Stark gene: TMCO1 was added gene: TMCO1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TMCO1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TMCO1 were set to CRANIOFACIAL DYSMORPHISM, SKELETAL ANOMALIES, AND MENTAL RETARDATION SYNDROME |
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| Fetal anomalies v0.0 | TBX15 |
Zornitza Stark gene: TBX15 was added gene: TBX15 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TBX15 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TBX15 were set to Cousin Syndrome; Craniofacial Dysmorphism, Hypoplasia of Scapula and Pelvis, and Short Stature |
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| Fetal anomalies v0.0 | TBCE |
Zornitza Stark gene: TBCE was added gene: TBCE was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TBCE was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TBCE were set to HYPOPARATHYROIDISM-RETARDATION-DYSMORPHISM SYNDROME; Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy; KENNY-CAFFEY SYNDROME TYPE 1 |
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| Fetal anomalies v0.0 | TAF1 |
Zornitza Stark gene: TAF1 was added gene: TAF1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: TAF1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: TAF1 were set to Dysmorphic Features, Intellectual Disability, and Neurological Manifestations |
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| Fetal anomalies v0.0 | STAR |
Zornitza Stark gene: STAR was added gene: STAR was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: STAR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: STAR were set to CHOLESTEROL DESMOLASE-DEFICIENT CONGENITAL ADRENAL HYPERPLASIA |
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| Fetal anomalies v0.0 | SMOC1 |
Zornitza Stark gene: SMOC1 was added gene: SMOC1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: SMOC1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SMOC1 were set to OPHTHALMOACROMELIC SYNDROME |
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| Fetal anomalies v0.0 | SMO |
Zornitza Stark gene: SMO was added gene: SMO was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: SMO was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: SMO were set to Curry-Jones Syndrome |
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| Fetal anomalies v0.0 | POC1A |
Zornitza Stark gene: POC1A was added gene: POC1A was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: POC1A was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: POC1A were set to PRIMORDIAL DWARFISM; SHORT STATURE, ONYCHODYSPLASIA, FACIAL DYSMORPHISM, AND HYPOTRICHOSIS SYNDROME |
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| Fetal anomalies v0.0 | PHIP |
Zornitza Stark gene: PHIP was added gene: PHIP was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: PHIP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: PHIP were set to Developmental delay, ID, obesity and dysmorphic features |
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| Fetal anomalies v0.0 | MTOR |
Zornitza Stark gene: MTOR was added gene: MTOR was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: MTOR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: MTOR were set to Smith-Kingsmore syndrome |
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| Fetal anomalies v0.0 | INPPL1 |
Zornitza Stark gene: INPPL1 was added gene: INPPL1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: INPPL1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: INPPL1 were set to OPSISMODYSPLASIA |
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| Fetal anomalies v0.0 | DHCR24 |
Zornitza Stark gene: DHCR24 was added gene: DHCR24 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: DHCR24 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DHCR24 were set to DESMOSTEROLOSIS |
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| Fetal anomalies v0.0 | CNOT3 |
Zornitza Stark gene: CNOT3 was added gene: CNOT3 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: CNOT3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: CNOT3 were set to CNOT3 syndrome; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, 618672 |
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| Fetal anomalies v0.0 | B3GAT3 |
Zornitza Stark gene: B3GAT3 was added gene: B3GAT3 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: B3GAT3 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: B3GAT3 were set to Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects 245600 |
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