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| Fetal anomalies v1.233 | PURA | Ain Roesley Phenotypes for gene: PURA were changed from Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (OMIM 616158) to Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (OMIM 616158) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.232 | PURA | Ain Roesley Phenotypes for gene: PURA were changed from Mental retardation, autosomal dominant 31, MIM# 616158 to Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (OMIM 616158) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v1.71 | 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 v1.67 | NODAL |
Zornitza Stark edited their review of gene: NODAL: Added comment: NODAL is a good biological candidate for heterotaxy disorders, and this is supported by animal models. The gene is depleted for LoF variants in gnomad. The missense variants reported in PMIDs 9354794 and 19064609 are present at a high population frequency in gnomad, including some in homozygous case: their association with disease is DISPUTED. A total of at least 7 families reported with severe CHD and high impact variants (stop gain, frameshift and canonical splice site). However, almost invariably these were inherited from unaffected or questionably affected parents (e.g. self reports of heart murmur in childhood), raising questions about whether these variants contribute to disease under a monogenic or polygenic model and/or about penetrance. Discussed at GenCC on 13/9/2022 and agreed on MODERATE assessment.; Changed rating: AMBER; Changed publications: 9354794, 19064609, 29368431, 19933292, 11311163, 30293987 |
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| Fetal anomalies 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 v0.4478 | LINGO1 |
Krithika Murali gene: LINGO1 was added gene: LINGO1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: LINGO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LINGO1 were set to 28837161; 31668702 Phenotypes for gene: LINGO1 were set to Mental retardation, autosomal recessive 64 - MIM#618103 Review for gene: LINGO1 was set to AMBER Added comment: 5 individuals reported from 2 families. 4 out of the 5 individuals had microcephaly. ID, developmentatl delay, spasticity, hypertonia, feeding problems also reported features. No antenatal information or birth growth parameters provided, but it is possible that microcephaly was antenatal/congenital in onset based on other phenotypic features reported. Sources: Literature |
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| Fetal anomalies v0.4295 | YIF1B |
Chirag Patel gene: YIF1B was added gene: YIF1B was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: YIF1B were set to PMID: 32006098; 26077767 Phenotypes for gene: YIF1B were set to Kaya-Barakat-Masson syndrome, MIM# 619125 Review for gene: YIF1B was set to GREEN Added comment: Kaya-Barakat-Masson syndrome (KABAMAS) is a severe autosomal recessive neurodevelopmental disorder characterized by profoundly impaired global development, peripheral spasticity, dystonia, impaired intellectual development with absent speech, poor eye contact, and feeding difficulties, resulting in poor overall growth, sometimes with microcephaly. Additional more variable features include early-onset seizures, ocular anomalies, foot deformities, and nonspecific brain imaging findings, such as thin corpus callosum and cerebral, cerebellar, or pontine atrophy. Some patients may die in infancy or early childhood. 6 individuals (from 5 families) with biallelic YIF1B truncating variants reported. Presenting features: hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3. Affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function. Sources: Expert list |
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| Fetal anomalies v0.4290 | PIDD1 |
Daniel Flanagan gene: PIDD1 was added gene: PIDD1 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010 Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum Review for gene: PIDD1 was set to AMBER Added comment: Doesn't appear to have an antenatal onset. Clinical findings in supplementary table for PMID: 34163010 doesn't mention any prenatal findings. For family M278, two affected siblings were "born at term after uneventful pregnancies, neonatal periods and normal development." Mean age of cohort was 13.2 years. Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested. The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families]. Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants. Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder. PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage. There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation. Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants. Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26 Evidence so far provided includes: - Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern. - Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability. - Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp] - Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain. - Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD. Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects. Sources: Expert list |
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| Fetal anomalies v0.4273 | DICER1 |
Krithika Murali gene: DICER1 was added gene: DICER1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DICER1 were set to 27960159; 29343557; 26227654; 33208384; 35114704; 31232238; 24676357 Phenotypes for gene: DICER1 were set to GLOW syndrome, somatic mosaic - MIM#618272; Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors - MIM#138800; Pleuropulmonary blastoma - MIM#601200 Review for gene: DICER1 was set to GREEN Added comment: Heterozygous pathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic somatic missense DICER1 variants in the RNase IIIb domain are linked to GLOW syndrome (global developmental delay, lung cysts, overgrowth, and Wilms’ tumor) syndrome. While the DICER1 syndrome is classically caused by frameshift, nonsense or other mutations that ablate DICER1 function in a true heterozygous state, GLOW-syndrome mutations occur at specific residues within the RNase IIIb domain that only affect the function of this domain. Both syndromes have been reported to have features that can be detected prenatally. PMID 33208384 - report a patient with heterozygous germline DICER1 variant. The patient was born at gestational week 39 after a difficult delivery due to macrocephaly. Clinical findings at birth included two blood vessels in the umbilical cord, undescended testis, inguinal hernia, postaxial polydactyly, ear pits and rocker bottom feet. PMID: 34331184 - report 4 unrelated families with germline DICER1 variants. In family 1 - one child was born with Pierre Robin sequence, shortening of the left arm and leg and bilateral hip dysplasia. In Family 2 a child had macrosomia and macrocephaly at birth. Family 4 - born at 33 weeks, dysmorphic facies including hypertelorism and macroglossia. PMID 24676357 - report 2 unrelated children with GLOW syndrome. Patient 1 was noted to have enlarged kidneys on 24 week ultrasound. At birth was found to have renal and pulmonary cysts. Patient 2 - macrocephaly was noted at birth. DICER1 implicated in ~60% of PPB - reports of PPB detecteed antenatally, although no reports in the context of confirmed DICER1 syndrome. Sources: Literature |
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| Fetal anomalies v0.4271 | COLGALT1 | Zornitza Stark commented on gene: COLGALT1: 3 unrelated cases with biallelic variants, and supporting functional assays. The main features of the cases were porencephalic cysts, leukoencephalopathy, lacunar infarcts, cerebral microbleeds/haemorrhages and calcifications. A null mouse model was embryonic lethal, but had defects in the vascular networks of the embryos. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4235 | NACC1 | Alison Yeung Phenotypes for gene: NACC1 were changed from Infantile Epilepsy, Cataracts, and Profound Developmental Delay to Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination delayed brain myelination, MIM# 617393) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4198 | RASGRP2 | Zornitza Stark Phenotypes for gene: RASGRP2 were changed from ?Bleeding disorder, platelet-type, 18 - MIM#615888 to Bleeding disorder, platelet-type, 18 - MIM#615888 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.4132 | RASGRP2 |
Krithika Murali gene: RASGRP2 was added gene: RASGRP2 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: RASGRP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RASGRP2 were set to 28637664; 28726538; 28762304; 30046681; 34066320; 33711653; 33376940; 32609603; 30849270; 30046681 Phenotypes for gene: RASGRP2 were set to ?Bleeding disorder, platelet-type, 18 - MIM#615888 Review for gene: RASGRP2 was set to RED Added comment: Postnatal presentation only with no antenatal features reported. Sources: Literature |
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| Fetal anomalies v0.4132 | FERMT3 |
Krithika Murali gene: FERMT3 was added gene: FERMT3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FERMT3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FERMT3 were set to 31068971; 34485203; 33391282; 31724816; 30412664; 25854317; 28095295; 26359933; 25072369; 22134107; 20216991; 19234463; 19234460; 18779414 Phenotypes for gene: FERMT3 were set to Leukocyte adhesion deficiency, type III - MIM#612840 Review for gene: FERMT3 was set to RED Added comment: Biallelic variants associated with LAD3 syndrome (primary immunodeficiency and platelet function defects). Symptom onset reported from birth, no antenatal features reported. --- PMID: 34485203 Yahya et al 2021 - no antenatal issues reported PMID: 33391282 Kambli et al 2020 - no antenatal features reported for 5 individuals with LAD3 PMID 31068971 Shahid et al 2019 - no antenatal features PMID: 31724816 Manukjan et al 2019 - no antenatal issues reported in 1 affected individual PMID: 28095295 Palagano et al 2017 - report female proband with infantile-onset osteopetrosis and symptomatic haematological anomalies at birth requiring bone marrow transplant. Authors postulate in utero onset but no antenatal features reported. PMID: 26359933 Suratannon et al 2016 - report a female Thai proband with a milder/atypical phenotype, no antenatal features reported PMID: 25854317 Crazzolara et al 2015 - presented D7 of life with infection, bleeeding issues and noted radiologically to have dense bones. No antenatal features. PMID: 25072369 Stepensky et al 2015 - report 3 individuals with bleeding tendency from birth and onset of recurrent infections as an infant, normal antenatal history. PMID: 20357244 McDowall et al 2010 - symptom onset from birth, no antenatal features PMID: 20216991 Jurk et al 2010 - 2 affected siblings, no antenatal features reported. PMID: 19234463 Svensson et al 2009 - no antenatal features reported PMID: 19234460 Malinin et al 2009 - no antenatal features reported PMID: 19064721 Kuijpers et al 2009 - 9 individuals from 7 unrelated families, no antenatal features reported. Sources: Literature |
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| Fetal anomalies v0.3908 | MAPK1 |
Krithika Murali gene: MAPK1 was added gene: MAPK1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAPK1 were set to 32721402 Phenotypes for gene: MAPK1 were set to Noonan syndrome 13 - MIM#619087 Review for gene: MAPK1 was set to GREEN Added comment: Associated with Noonan syndrome including congenital heart defects. No new publications since last PanelApp review Aug 2020 -- Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants. The phenotype corresponded to a neurodevelopmental disorder and - as the authors comment - consistently included DD, ID , behavioral problems. Postnatal growth delay was observed in approximately half. Hypertelorism, ptosis, downslant of palpebral fissures, wide nasal bridge as low-set/posteriorly rotated ears were among the facial features observed (each in 3 or more subjects within this cohort). Together with short/webbed neck and abnormalities of skin (lentigines / CAL spots) and growth delay these led to clinical suspicion of Noonan s. or disorder of the same pathway in some. Congenital heart defects (ASD, mitral valve insufficiency, though not cardiomyopathy) occurred in 4/7. Bleeding diathesis and lymphedema were reported only once. MAPK1 encodes the mitogen-activated protein kinase 1 (also known as ERK2) a serine/threonine kinase of the RAS-RAF-MEK-(MAPK/)ERK pathway. MAPK1 de novo variants were identified in all individuals following trio exome sequencing (and extensive previous genetic investigations which were non-diagnostic). The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome). Sources: Literature |
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| Fetal anomalies v0.3847 | NR2F1 |
Zornitza Stark changed review comment from: Recent review of 54 affected individuals with Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS): 22 individuals with point mutations or in-frame deletions in the DNA-binding domain (DBD), and 32 individuals with other types of variants including whole-gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. A more severe phenotype appears to be associated with DBD variants. Clinical characteristics include developmental delay, intellectual disability, autism spectrum disorder diagnoses/features thereof, cognitive/behavioral anomalies, hypotonia, feeding difficulties, abnormal brain MRI findings, and seizures. Vision phenotype includes optic nerve hypoplasia, optic atrophy, and cortical visual impairment; rarely, alacrima and latent nystagmus (fusional maldevelopment). The behavioural phenotypic spectrum includes a love of music, an unusually good long-term memory, sleep difficulties, a high pain tolerance, and touch sensitivity.; to: Recent review of 54 affected individuals with Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS): 22 individuals with point mutations or in-frame deletions in the DNA-binding domain (DBD), and 32 individuals with other types of variants including whole-gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. A more severe phenotype appears to be associated with DBD variants. Clinical characteristics include developmental delay, intellectual disability, autism spectrum disorder diagnoses/features thereof, cognitive/behavioral anomalies, hypotonia, feeding difficulties, abnormal brain MRI findings, and seizures. Vision phenotype includes optic nerve hypoplasia, optic atrophy, and cortical visual impairment; rarely, alacrima and latent nystagmus (fusional maldevelopment). The behavioural phenotypic spectrum includes a love of music, an unusually good long-term memory, sleep difficulties, a high pain tolerance, and touch sensitivity. Clinical presentation is typically post-natal. |
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| Fetal anomalies v0.2898 | SLC25A4 | Zornitza Stark changed review comment from: Variants in this gene cause both dominant and recessive disease. MIM#617184 reported as causing profound hypotonia and frequent need for respiratory support; the other two conditions, one AR and the other AD, appear less severe. Not convinced ID is an intrinsic part of the phenotype.; to: Variants in this gene cause both dominant and recessive disease. MIM#617184 reported as causing profound hypotonia and frequent need for respiratory support; the other two conditions, one AR and the other AD, appear less severe. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2331 | EED | Zornitza Stark Marked gene: EED as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2331 | EED | Zornitza Stark Gene: eed has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2331 | EED | Zornitza Stark Publications for gene: EED were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2330 | EED | Zornitza Stark Mode of inheritance for gene: EED was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2329 | EED | Zornitza Stark Classified gene: EED as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2329 | EED | Zornitza Stark Gene: eed has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.2249 | HRAS | Zornitza Stark changed review comment from: Well established gene-disease association, over 100 affected individuals reported with a characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and developmental disability. Facial warts, particularly nasolabial, are often present in childhood.; to: Well established gene-disease association, over 100 affected individuals reported with a characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and developmental disability. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1604 | FLNA | Zornitza Stark Phenotypes for gene: FLNA were changed from PERIVENTRICULAR NODULAR HETEROTOPIA TYPE 1; EPILEPTIC ENCEPHALOPATHY; FG SYNDROME TYPE 2; X-LINKED CONGENITAL IDIOPATHIC INTESTINAL PSEUDOOBSTRUCTION; MELNICK-NEEDLES SYNDROME; FRONTOMETAPHYSEAL DYSPLASIA; OTOPALATODIGITAL SYNDROME TYPE 2; TERMINAL OSSEOUS DYSPLASIA; OTOPALATODIGITAL SYNDROME TYPE 1 to Melnick-Needles syndrome, 309350; Otopalatodigital syndrome, type I 311300; Otopalatodigital syndrome, type II 304120; Terminal osseous dysplasia 300244; Heterotopia, periventricular, 1 MIM# 300049 Cardiac valvular dysplasia, X-linked MIM# 314400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1602 | FLNA |
Zornitza Stark changed review comment from: Melnick-Needles associated with radial shortening in affected women. Male fetuses reported with absent thumbs Sources: Expert list; to: Multiple FLNA-related disorders are relevant to this panel. Melnick-Needles associated with radial shortening in affected women. Male fetuses reported with absent thumbs Sources: Expert list |
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| Fetal anomalies v0.1602 | FLNA | Zornitza Stark edited their review of gene: FLNA: Changed phenotypes: Melnick-Needles syndrome, 309350, Otopalatodigital syndrome, type I 311300, Otopalatodigital syndrome, type II 304120, Terminal osseous dysplasia 300244, Heterotopia, periventricular, 1 MIM# 300049 Cardiac valvular dysplasia, X-linked MIM# 314400 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.1469 | 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 v0.1077 | 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 v0.826 | 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 v0.764 | ABCD4 |
Zornitza Stark changed review comment from: Described clinical features include feeding difficulties, failure to thrive, hypotonia, seizures, developmental delay, and hematological abnormalities. Normal neurodevelopmental outcomes with treatment reported. At least 6 affected individuals reported.; to: Described clinical features include feeding difficulties, failure to thrive, hypotonia, seizures, developmental delay, and haematological abnormalities. Normal neurodevelopmental outcomes with treatment reported. At least 6 affected individuals reported. Congenital anomalies are very rarely reported, uncertain if they are part of the phenotype. |
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| Fetal anomalies v0.720 | CTC1 |
Zornitza Stark edited their review of gene: CTC1: Added comment: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC), also known as Coats plus syndrome, is an autosomal recessive pleomorphic disorder characterized primarily by intracranial calcifications, leukodystrophy, and brain cysts, resulting in spasticity, ataxia, dystonia, seizures, and cognitive decline. Patients also have retinal telangiectasia and exudates (Coats disease) as well as extraneurologic manifestations, including osteopenia with poor bone healing and a high risk of gastrointestinal bleeding and portal hypertension caused by vasculature ectasias in the stomach, small intestine, and liver. Some individuals also have hair, skin, and nail changes, as well as anaemia and thrombocytopaenia. Multiple families reported.; Changed rating: GREEN; Changed publications: 22267198 |
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| Fetal anomalies v0.610 | CRLF1 |
Zornitza Stark edited their review of gene: CRLF1: Added comment: Micrognathia, camptodactyly are features. Crisponi/cold-induced sweating syndrome is an autosomal recessive disorder characterized in the neonatal period by orofacial weakness with impaired sucking and swallowing resulting in poor feeding necessitating medical intervention. Affected infants show a tendency to startle, with contractions of the facial muscles in response to tactile stimuli or during crying, trismus, abundant salivation, and opisthotonus. During the first year, most infants have spiking fevers. These features, referred to as 'Crisponi syndrome' in infancy, can result in early death without advanced care. After the first 2 years, the abnormal muscle contractions and fevers abate, and most patients show normal psychomotor development. From childhood onward, the most disabling symptoms stem from impaired thermoregulation and disabling abnormal sweating, which can be treated with clonidine. Patients have hyperhidrosis, mainly of the upper body, in response to cold temperatures, and sweat very little with heat. Other features include characteristic facial anomalies, such as round face, chubby cheeks, micrognathia, high-arched palate, low-set ears, and depressed nasal bridge, dental decay, camptodactyly, and progressive kyphoscoliosis. Multiple unrelated families reported.; Changed rating: GREEN; Changed publications: 12509788, 17436251, 17436252 |
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| Fetal anomalies v0.607 | CREBBP |
Zornitza Stark changed review comment from: Well established gene-disease association with RTS, deletions reasonably frequent. Menke-Hennekam syndrome-1 (MKHK1) is an allelic disorder caused by heterozygous variants in exon 30 or 31 of the CREBBP gene, and characterised by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, hearing impairment, short stature, and microcephaly are also frequently seen. Over 20 individuals reported.; to: Well established gene-disease association with RTS, deletions reasonably frequent. Microcephaly is a feature. Menke-Hennekam syndrome-1 (MKHK1) is an allelic disorder caused by heterozygous variants in exon 30 or 31 of the CREBBP gene, and characterised by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, hearing impairment, short stature, and microcephaly are also frequently seen. Over 20 individuals reported. |
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| Fetal anomalies v0.197 | ASXL1 | Zornitza Stark changed review comment from: Colobomas reported.; to: Bohring-Opitz syndrome is a malformation syndrome characterized by severe intrauterine growth retardation, poor feeding, profound ID, trigonocephaly, prominent metopic suture, exophthalmos, nevus flammeus of the face, upslanting palpebral fissures, hirsutism, and flexion of the elbows and wrists with deviation of the wrists and metacarpophalangeal joints -- many of these features would be identifiable antenatally. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v0.107 | 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 v0.0 | EED |
Zornitza Stark gene: EED was added gene: EED was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: EED was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: EED were set to Cohen-Gibson syndrome, MONDO:0060510; Cohen-Gibson syndrome, OMIM:617561 |
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| Fetal anomalies v0.0 | FLNA |
Zornitza Stark gene: FLNA was added gene: FLNA was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: FLNA was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: FLNA were set to 30712878; 28425981 Phenotypes for gene: FLNA were set to PERIVENTRICULAR NODULAR HETEROTOPIA TYPE 1; EPILEPTIC ENCEPHALOPATHY; FG SYNDROME TYPE 2; X-LINKED CONGENITAL IDIOPATHIC INTESTINAL PSEUDOOBSTRUCTION; MELNICK-NEEDLES SYNDROME; FRONTOMETAPHYSEAL DYSPLASIA; OTOPALATODIGITAL SYNDROME TYPE 2; TERMINAL OSSEOUS DYSPLASIA; OTOPALATODIGITAL SYNDROME TYPE 1 |
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