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| Arthrogryposis v4.3 | KIF21A |
Hannah Robinson gene: KIF21A was added gene: KIF21A was added to Arthrogryposis. Sources: Literature,NHS GMS Mode of inheritance for gene: KIF21A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIF21A were set to 34740919 Phenotypes for gene: KIF21A were set to Arthrogryposis; fetal akinesia Penetrance for gene: KIF21A were set to unknown Review for gene: KIF21A was set to GREEN gene: KIF21A was marked as current diagnostic Added comment: Falb et al 2023 (PMID: 34740919) describe two unrelated families in which biallelic loss of function variants segregated with a severe form of fetal akinesia characterised by arthrogryposis multiplex, pulmonary hypoplasia and variable facial dysmorphisms. Exeter Genomics Laboratory has identified an unrelated third case homozygous for a nonsense variant in KIF21A. The patient had an antenatal diagnosis of talipes, arthrogryposis, polyhydramnios and lack of fetal movements. At birth, all joints displayed fixed flexion deformities, no primitive reflexes, poor muscle bulk and care was re-oriented shortly after birth. Taken together, three unrelated cases including segregation evidence in the published families provides sufficient evidence for the gene-disease association. Sources: Literature, NHS GMS |
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| Arthrogryposis v3.122 | ERGIC1 |
Zornitza Stark gene: ERGIC1 was added gene: ERGIC1 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: ERGIC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ERGIC1 were set to 28317099; 34037256 Phenotypes for gene: ERGIC1 were set to Arthrogryposis multiplex congenita 2, neurogenic type; OMIM # 208100 Review for gene: ERGIC1 was set to AMBER Added comment: 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 |
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| Arthrogryposis v3.90 | UNC50 | Arina Puzriakova Added comment: Comment on list classification: Rating Red awaiting further evidence. Only a single variant described in 2 individuals (PMIDs: 29016857; 33820833). Additional cases with different variants or strong functional support required to validate pathogenicity. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v3.88 | UNC50 |
Arina Puzriakova gene: UNC50 was added gene: UNC50 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: UNC50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UNC50 were set to 29016857; 33820833 Phenotypes for gene: UNC50 were set to Arthrogryposis multiplex congenita Review for gene: UNC50 was set to AMBER Added comment: UNC50 is currently not associated with any phenotype in OMIM (last edited on 02/01/2018) or Gene2Phenotype. - PMID: 29016857 (2017) - Homozygosity mapping of disease loci combined with WES in a single male from a consanguineous family presenting with lethal AMC revealed a homozygous frameshift deletion in UNC50 gene (c.750_751del:p.Cys251Phefs*4). Functional studies in C. elegans showed the variant caused loss of acetylcholine receptor expression in the muscle. - PMID: 33820833 (2021) - Single individual reported with the same homozygous c.750_751del:p.Cys251Phefs*4 variant in UNC50 as previously described. The case was identified from a cohort of 315 genetically undiagnosed and unrelated AMC families. Arthrogryposis and tetra ventricular dilation were detected prenatally. -- Note: it isn't definitively clear whether these are different individuals. Both are singleton males born to consanguineous parents, with the same variant and similar phenotype. Also both infants died at 28 w.g. However, the 2021 paper (PMID:33820833) states their patient was selected from a cohort of cases without a molecular diagnosis and indicate the UNC50 gene had already previously been identified in relation to this phenotype, highlighting the earlier paper (PMID:29016857). There is also no mention of tetra ventricular dilation in the first case, so it is likely that these do represent distinct individuals. Additional cases needed to provide clarity. Sources: Literature |
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| Arthrogryposis v3.75 | KIDINS220 |
Eleanor Williams gene: KIDINS220 was added gene: KIDINS220 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: KIDINS220 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIDINS220 were set to 32909676; 33205811; 28934391; 22048169 Phenotypes for gene: KIDINS220 were set to brain ventriculomegaly and limb contractures Review for gene: KIDINS220 was set to GREEN Added comment: Associated with Spastic paraplegia, intellectual disability, nystagmus, and obesity #617296 in OMIM for monoallelic cases. 3 biallelic cases associated with cerebral ventriculomegaly and limb contractures, plus a mouse model that shows some phenotypic overlap: PMID: 32909676 - El-Dessouky et al 2020 - report a consanguineous family of Egyptian origin with several miscarriages. Prenatal ultrasonography revealed limb contractions and ventriculomegaly aswell as cerebellar anomalies, cardiac anomalies and hydrops fetalis. Using WES a homozygous deleterious frameshift variant (c.208del; p.Asp70Ilefs*18) in KIDINS220 gene was identified. Both parents were heterozygous for this variant. PMID: 33205811 - Jacquemin et al 2021 - report a consanguineous family of Pakistani origin in which 3 fetuses presented with brain ventriculomegaly and limb contractures. Autopsy of one fetus identifed bilateral club feet and club hands. They were found by WES to share a very rare homozygous variant of KIDINS220 (c.2327_2336del, Gln713_Leu715del). Parents and healthy siblings were heterozygous for this variant. Severe ventriculomegaly was diagnosed as early as 14 weeks. Binding of KIDINS220 to TrkA is decreased by the deletion mutation. PMID: 28934391 - Mero et al 2017 - report a consanguineous couple in which 4 fetuses presented with enlarged cerebral ventricles and limb contractures. Exome sequencing in two of the fetuses found a shared homozygous frameshift variant in exon 24 in KIDINS220 ((NM_020738:c.3394_3403del; p.Gln1132Serfs*30). Healthy family members were either carriers or homozygous for the wild-type allele. It is thought that the variant leads to NMD and complete loss of KIDINS220 protein. PMID: 22048169 - Cesca et al 2011 - report a Kidins220 mutant mouse. Kidins220 -/- mice die at late stages of gestation and show extensive neuronal cell death in the central and peripheral nervous systems, as well as heart malformations. Sources: Literature |
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| Arthrogryposis v3.65 | MYL1 | Arina Puzriakova Added comment: Comment on list classification: Only mild contractures described in 1/2 individuals with variants in this gene. Therefore, there is only enough evidence for a RED rating on this panel at present. These cases would still expected to be picked up via the 'Congenital myopathy' or 'Fetal anomalies' routes for which this gene is Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v3.44 | ATP1A2 |
Arina Puzriakova Added comment: Comment on list classification: Two additional unrelated families reported by Chatron et al PMID: 31608932 with affected fetuses described as having polymicrogyria, microcephaly, polyhydramnios and FADS. Two individuals from one family also presented hand contractures and rocker-bottom feet, bringing the total to 3 unrelated families with relevant phenotype. As number of cases now reaches threshold for inclusion as diagnostic-grade, ATP1A2 should be promoted to Green at the next GMS panel update (added 'for-review' tag) |
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| Arthrogryposis v3.10 | ATP1A2 |
Rebecca Foulger gene: ATP1A2 was added gene: ATP1A2 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: ATP1A2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATP1A2 were set to 30690204 Phenotypes for gene: ATP1A2 were set to arthrogryposis, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency Added comment: Added to panel based on PMID:30690204 (Monteiro et al., 2020) who describe 3 newborns from 2 unrelated families who died neontally, presenting in utero with fetal hydrops, seizures and polyhydramnios. At birth they had arthrogryposis, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic LOF variants in ATP1A2 were found upon WES. Sources: Literature |
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| Arthrogryposis v2.104 | BICD2 |
Zerin Hyder changed review comment from: PMID:27751653 (Ravenscroft et al., 2016) report two unrelated probands (a German male and a boy from a Welsh mother and NZ/European father) that presented in utero with reduced fetal movement. Both cases had arthrogryposis multiplex congenita (AMC) and hypotonia diagnosed at birth . The same missense de novo variant in BICD2 (p.Arg694Cys) was present in both probands. PMID:29274205 (Ahmed et al., 2018) report a stillborn female fetus (case 4) with pterygia and arthrogryposis with a heterozygous likely-pathogenic variant in BICD2. Phenotypes included an abnormal fetal position with fixed limbs, hydrops fetalis and polyhydramnios. A heterozygous p.Asn700Lys variant in BICD2 was revealed. However, compound het variants of unknown significance in AGRN were also identified, so the authors can not be certain that BICD2 is the causative variant. PMID:28635954 (Storbeck et al., 2017) describe 3 individuals of independent families with severe severe arthrogryposis multiplex congenita (AMC), respiratory insufficiency, and early lethality caused by three BICD2 variants (p.Arg694Cys, p.Gln194Arg and p.Cys542Trp, 2 of which are proven to be de novo). They also describe an asymptomatic women with subclinical findings with the previously described p.(Thr703Met) variant. PMID: 30054298. In 2 unrelated patients with muscular atrophy and arthrogryposis Koboldt et al. (2018) identified a de novo heterozygous c.1636_1638delAAT variant in the BICD2 gene. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but protein modeling indicated that the variant is within a region that interacts with the molecular kinesin motor and that the mutation would alter protein structure.; to: PMID:27751653 (Ravenscroft et al., 2016) report two unrelated probands (a German male and a boy from a Welsh mother and NZ/European father) that presented in utero with reduced fetal movement. Both cases had arthrogryposis multiplex congenita (AMC) and hypotonia diagnosed at birth . The same missense de novo variant in BICD2 (p.Arg694Cys) was present in both probands. PMID:29274205 (Ahmed et al., 2018) report a stillborn female fetus (case 4) with pterygia and arthrogryposis with a heterozygous likely-pathogenic variant in BICD2. Phenotypes included an abnormal fetal position with fixed limbs, hydrops fetalis and polyhydramnios. A heterozygous p.Asn700Lys variant in BICD2 was revealed. However, compound het variants of unknown significance in AGRN were also identified, so the authors can not be certain that BICD2 is the causative variant. PMID:28635954 (Storbeck et al., 2017) describe 3 individuals of independent families with severe arthrogryposis multiplex congenita (AMC), respiratory insufficiency, and early lethality caused by three BICD2 variants (p.Arg694Cys, p.Gln194Arg and p.Cys542Trp, 2 of which are proven to be de novo). They also describe an asymptomatic woman with subclinical findings with the previously described p.(Thr703Met) variant. PMID: 30054298. In 2 unrelated patients with muscular atrophy and arthrogryposis Koboldt et al. (2018) identified a de novo heterozygous c.1636_1638delAAT variant in the BICD2 gene. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but protein modeling indicated that the variant is within a region that interacts with the molecular kinesin motor and that the mutation would alter protein structure. |
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| Arthrogryposis v2.88 | ATAD1 | Rebecca Foulger Added comment: Comment on list classification: Demoted ATAD1 from Green to Amber following review and advice from Zerin Hyder (Genomics England Clinical Team). The AMC phenotype is not yet well enough described for inclusion on the panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v2.84 | DHCR24 | Zerin Hyder changed review comment from: Schaaf et al: one case with dermosterolsis with relative macrocephaly, mild arthrogryposis, and dysmorphic facial features. The diagnosis of desmosterolosis was established by detection of significant elevation of plasma desmosterol levels and reduced enzyme activity of DHCR24 upon expression of the patient's DHCR24 cDNA. The patient was found to be a compound heterozygote for c.281G>A (p.R94H) and c.1438G>A (p.E480K) mutations. 4 individuals in Bedouin kindred with dermosterolsis and distal contractures. Two other reports 12457401; 29175559 in association with milder phenotype of AMC.; to: Schaaf et al: patient with dermosterolsis with relative macrocephaly, mild arthrogryposis, and dysmorphic facial features. The diagnosis of desmosterolosis was established by detection of significant elevation of plasma desmosterol levels and reduced enzyme activity of DHCR24 upon expression of the patient's DHCR24 cDNA. The patient was found to be a compound heterozygote for c.281G>A (p.R94H) and c.1438G>A (p.E480K) mutations. 4 individuals in Bedouin kindred with dermosterolsis and distal contractures. Two other reports 12457401; 29175559 in association with milder phenotype of AMC. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v2.84 | DHCR24 | Zerin Hyder reviewed gene: DHCR24: Rating: GREEN; Mode of pathogenicity: None; Publications: 21671375, 12457401, 29175559, 21559050; Phenotypes: Desmosterolosis 602398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v2.32 | COASY |
Louise Daugherty gene: COASY was added gene: COASY was added to Arthrogryposis. Sources: Literature watchlist tags were added to gene: COASY. Mode of inheritance for gene: COASY was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COASY were set to 30089828; 24360804 Phenotypes for gene: COASY were set to Severe prenatal onset pontocerebellar hypoplasia, microcephaly, arthrogryposis Review for gene: COASY was set to AMBER Added comment: From Dijk et al. (2018) PMID: 30089828 variants in the gene Coenzyme A (CoA) synthase (COASY) gene, an enzyme essential in CoA synthesis. A single variant was identified in 4 individuals in 2 unrelated families with PCH, prenatal onset microcephaly, and arthrogryposis. In both families, the variant c.[1549_1550delAG]; [1486-3 C>G] segregated wth the phenotype. No CoA synthase protein was detected in patient cells by immunoblot analysis and CoA synthase activity was virtually absent. Partial CoA synthase defects were previously described by Dusi et al. (2014) PMID: 24360804 as a cause of COASY Protein-Associated Neurodegeneration (CoPAN), a type of Neurodegeneration and Brain Iron Accumulation (MIM: 615643). Dijk et al. (2018) PMID: 30089828 demonstrate that near complete loss of function variants in COASY are associated with lethal PCH and arthrogryposis. Sources: Literature |
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| Arthrogryposis | DES | Alice Gardham marked DES as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis | DES | Alice Gardham classified DES as red | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis | DES | Alice Gardham commented on DES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||