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| Arthrogryposis v0.410 | PSMF1 |
Zornitza Stark gene: PSMF1 was added gene: PSMF1 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: PSMF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PSMF1 were set to https://www.medrxiv.org/content/10.1101/2024.06.19.24308302v1 Phenotypes for gene: PSMF1 were set to Complex neurodevelopmental disorder with motor features, MONDO:0100516, PSMF1-related Review for gene: PSMF1 was set to GREEN Added comment: 22 individuals from 15 families reported with a range of neurological phenotypes ranging from early-onset Parkinson's disease; childhood conditions typified by ID and a range of movement disorders; through to perinatal lethal presentations with arthrogryposis multiplex. Genotype-phenotype correlation: biallelic missense variants resulted in the milder phenotypes, while bi-allelic LoF variants in the more severe phenotypes. Supportive functional data. Sources: Expert list |
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| Arthrogryposis v0.399 | SENP7 |
Elena Savva gene: SENP7 was added gene: SENP7 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: SENP7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SENP7 were set to PMID: 37460201 Phenotypes for gene: SENP7 were set to Arthrogryposis multiplex congenita, MONDO:0015168, SENP7-related Review for gene: SENP7 was set to AMBER Added comment: PMID: 37460201 - 1 family (4 affecteds, sibling pair and 1st cousin) with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia. Fetus could not be tested, so 3 confirmed genetically. - Homozygous for a PTC, decreased mRNA from one sample supports an NMD outcome. - Additional studies performed supporting downstream proteins expression being affected - Neutropenia observed in 2/3 patients Sources: Literature |
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| Arthrogryposis v0.394 | ACTC1 |
Lilian Downie gene: ACTC1 was added gene: ACTC1 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ACTC1 were set to PMID: 36945405 Phenotypes for gene: ACTC1 were set to MONDO:0019942 ACTC1 related distal arthrogrypsis Penetrance for gene: ACTC1 were set to Incomplete Review for gene: ACTC1 was set to GREEN Added comment: 5 new families (8 individuals) with a distral arthrogryposis phenotype: multiple congenital contractures, neck pterygia, scoliosis, and congenital heart defects/cardiomyopathy, short stature All missense variants One variant p.Arg185Trp previously reported in patient with cardiac phenotype only Sources: Literature |
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| Arthrogryposis v0.392 | FILIP1 |
Paul De Fazio gene: FILIP1 was added gene: FILIP1 was added to Arthrogryposis. 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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| Arthrogryposis v0.384 | SLC35A3 |
Chirag Patel gene: SLC35A3 was added gene: SLC35A3 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: SLC35A3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC35A3 were set to PMID: 28777481, 24031089, 28328131, 33416188 Phenotypes for gene: SLC35A3 were set to Arthrogryposis, impaired intellectual development, and seizures, OMIM #615553 Review for gene: SLC35A3 was set to GREEN Added comment: Arthrogryposis, impaired intellectual development, and seizures (AMRS) is an autosomal recessive disorder characterized by skeletal abnormalities, including arthrogryposis, short limbs, and vertebral malformations, impaired intellectual development, and seizures consistent with early-onset epileptic encephalopathy in some patients. Other features may include cleft palate, micrognathia, posterior embryotoxon, talipes valgus, rocker-bottom feet, and dysmorphic facies. 4 families with 12 affected individuals reported with biallelic variants in SLC35A3 gene. Functional studies in one family showed patient cells showed no normal transcript, indicating that they had no functional SLC35A3 protein. Golgi vesicles derived from patient fibroblasts showed significantly reduced transport of UDP-GlcNAc compared to controls. Sources: Expert list |
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| Arthrogryposis v0.383 | LIFR |
Chirag Patel gene: LIFR was added gene: LIFR was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: LIFR was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LIFR were set to PMID: 9674905, 9674906, 14740318, 24988918, 35663789 Phenotypes for gene: LIFR were set to Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome, OMIM #601559 Review for gene: LIFR was set to GREEN Added comment: Patients reported as having either neonatal SJS or STWS presented a combination of a severe, prenatal-onset neuromuscular disorder with congenital joint contractures, respiratory and feeding difficulties, tendency to hyperthermia, and frequent death in infancy and a distinct campomelic-metaphyseal skeletal dysplasia. Multiple families with biallelic variants in LIFR gene reported. Sources: Expert list |
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| Arthrogryposis v0.378 | CNTN1 |
Chirag Patel gene: CNTN1 was added gene: CNTN1 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: CNTN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CNTN1 were set to PMID:19026398 Phenotypes for gene: CNTN1 were set to Congenital myopathy 12, OMIM #612540 Review for gene: CNTN1 was set to RED Added comment: Congenital myopathy-12 (CMYP12) is an autosomal recessive disorder characterized by severe neonatal hypotonia resulting in feeding difficulties and respiratory failure within the first months of life. There is evidence of the disorder in utero, with decreased fetal movements and polyhydramnios. Additional features may include high-arched palate and contractures. Skeletal muscle biopsy shows myopathic changes with disrupted sarcomeres and minicore-like structures. One family reported with homozygous mutation in the CNTN1 gene. Sources: Expert list |
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| Arthrogryposis v0.375 | B3GALT6 |
Chirag Patel gene: B3GALT6 was added gene: B3GALT6 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: B3GALT6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: B3GALT6 were set to PMID: 29443383, 25149931 Phenotypes for gene: B3GALT6 were set to Al-Gazali syndrome, OMIM #609465 Review for gene: B3GALT6 was set to AMBER Added comment: Al-Gazali syndrome (ALGAZ) is characterized by prenatal growth retardation, skeletal anomalies including joint contractures, camptodactyly, and bilateral talipes equinovarus, small mouth, anterior segment eye anomalies, and early lethality. In an infant with Al-Gazali syndrome, Sellars et al. (2014) identified compound heterozygous missense mutations in the B3GALT6 gene. The mutation, which was found by exome sequencing, segregated with the disorder in the family. In 1 of the Palestinian infants with Al-Gazali syndrome reported by al-Gazali et al. (1999), Ben-Mahmoud et al. (2018) identified homozygosity for a missense mutation in the B3GALT6 gene. The parents were heterozygous for the mutation. Sources: Expert list |
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| Arthrogryposis v0.374 | VRK1 |
Chirag Patel gene: VRK1 was added gene: VRK1 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: VRK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VRK1 were set to PMID: 21937992, 21937992 Phenotypes for gene: VRK1 were set to Pontocerebellar hypoplasia type 1A, OMIM# 607596 Review for gene: VRK1 was set to AMBER Added comment: contractures reported and mutation found in 2 families Sources: Expert list |
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| Arthrogryposis v0.371 | PMM2 |
Chirag Patel gene: PMM2 was added gene: PMM2 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: PMM2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PMM2 were set to Congenital disorder of glycosylation, type Ia, OMIM #212065 Review for gene: PMM2 was set to GREEN Added comment: Arthrogryposis reported Sources: Expert list |
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| Arthrogryposis v0.369 | LMNA |
Chirag Patel gene: LMNA was added gene: LMNA was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: LMNA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LMNA were set to PMID:18551513 Phenotypes for gene: LMNA were set to Muscular dystrophy, congenital, OMIM #613205 Review for gene: LMNA was set to GREEN Added comment: Arthrogryposis reported Sources: Expert list |
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| Arthrogryposis v0.365 | BIN1 |
Chirag Patel gene: BIN1 was added gene: BIN1 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: BIN1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: BIN1 were set to Centronuclear myopathy 2; OMIM #255200 Review for gene: BIN1 was set to GREEN Added comment: Arthrogryposis reported Sources: Expert list |
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| Arthrogryposis v0.358 | CAMLG |
Manny Jacobs gene: CAMLG was added gene: CAMLG was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CAMLG were set to 35262690 Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation type IIz, OMIM #: 620201 Penetrance for gene: CAMLG were set to unknown Review for gene: CAMLG was set to RED Added comment: PMID: 35262690 (2022) Report one patient with hom splice variant. No other reported patients. GDD, seizures, contractures, hypotonia and brain malformations. Sources: Literature |
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| Arthrogryposis v0.353 | KCNK3 |
Krithika Murali gene: KCNK3 was added gene: KCNK3 was added to Arthrogryposis. 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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| Arthrogryposis v0.350 | ADAMTS15 |
Naomi Baker changed review comment from: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: ontractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5). Sources: Literature; to: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: contractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5). Sources: Literature |
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| Arthrogryposis v0.350 | ADAMTS15 |
Naomi Baker gene: ADAMTS15 was added gene: ADAMTS15 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: ADAMTS15 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAMTS15 were set to PMID: 35962790 Phenotypes for gene: ADAMTS15 were set to Arthrogryposis (MONDO:0008779), ADMATS15-related Review for gene: ADAMTS15 was set to GREEN Added comment: PMID: 35962790; Four different homozygous variants identified in five affected individuals from four unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. All patients also had a mild appearance of fetal finger pads and clinodactyly of the fifth finger. Other reported phenotypes include: ontractures of knee, Achilles tendon, and ankle (4/5), spine involvement (kyphoscoliosis and/or spinal stiffness) (4/5), and orthodontic features (small mouth, dental crowding, missing teeth, or arched palate) (4/5). Sources: Literature |
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| Arthrogryposis v0.341 | COASY |
Ain Roesley changed review comment from: 5 more families with arthrogryposis reported in 4x. But 1x family did not have the affecteds sequenced, presumed homozygous as parents are carriers. c.1486-3C>G is the variant identified in all families; to: 5 more families with PCH and arthrogryposis reported in 4x. But 1x family did not have the affecteds sequenced, presumed homozygous as parents are carriers. c.1486-3C>G is the variant identified in all families |
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| Arthrogryposis v0.340 | COASY |
Ain Roesley changed review comment from: 5 more families. But 1 family did not have the affecteds sequenced, presumed homozygous as parents are carriers. arthrogryposis reported in 4 families c.1486-3C>G is the variant identified in all families; to: 5 more families with arthrogryposis reported in 4x. But 1x family did not have the affecteds sequenced, presumed homozygous as parents are carriers. c.1486-3C>G is the variant identified in all families |
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| Arthrogryposis v0.337 | PIEZO2 |
Zornitza Stark commented on gene: PIEZO2: Bi-allelic variants: more than 5 unrelated families reported. Mono-allelic variants: DA5, more than 20 families reported. DA3, more than 10 families reported, R2686H is recurrent. |
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| Arthrogryposis v0.332 | TNNI1 |
Krithika Murali gene: TNNI1 was added gene: TNNI1 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: TNNI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TNNI1 were set to 34934811 Phenotypes for gene: TNNI1 were set to arthrogryposis; joint contractures Review for gene: TNNI1 was set to AMBER Added comment: No OMIM gene disease association reported PMID 34934811 Nishimori et al report 2 individuals from a Japanese family with joint contractures, elevated CK and a novel heterozygous TNNI1 variant. The proband was born with clasped thumbs (gestational age not stated) requiring surgical correction at 5 months of age. At age 14 was diagnosed with contractures of the neck, trunk, hip and knee with elevated serum CK (1689 IU/L). No muscle weakness noted. Muscle biopsy showed moth-eaten appearance of type I fibres and electron microscopy showed type 1 fibre Z disk streaming. Trio exome sequencing identified a paternally heterozygous nonsense TNNI1 variant (c.523A>T p.K175*). The proband's father and paternal grandfather (not genotyped) also have a history of joint contractures with elevated CK. The affected amino acid residue is in the tropomyosin binding site near the C-terminus and is highly conserved. The variant is absent from gnomAD. rt-PCR products of mRNA from the patient's muscle biopsy showed presence of both mutated and normal transcripts. Sources: Literature |
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| Arthrogryposis v0.320 | KIF26B |
Zornitza Stark gene: KIF26B was added gene: KIF26B was added to Arthrogryposis. Sources: Expert Review Mode of inheritance for gene: KIF26B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KIF26B were set to 30151950 Phenotypes for gene: KIF26B were set to Progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis Review for gene: KIF26B was set to RED Added comment: 1 report only of infant with progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis secondary to the involvement of anterior horn cells and ventral (motor) nerves. Whole exome sequencing on the trio identified a de novo KIF26B missense variant (p.Gly546Ser). Functional analysis of the variant protein in cultured cells revealed a reduction in the KIF26B protein's ability to promote cell adhesion, a defect that potentially contributes to its pathogenicity. Sources: Expert Review |
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| Arthrogryposis v0.310 | SLC6A9 | Zornitza Stark edited their review of gene: SLC6A9: Added comment: Dempsey et al 2020 (PMID: 31875334) report a fetus with persistently raised NT, hyperextended legs, unilateral talipes. Flexed arms. Small stomach. Consanguineous family. Other reports of SLC6A9 causing arthrogryposis multiplex congenita (presenting prenatally) include: Kurolap et al 2016, PMID: 27773429 (2 families); Hauf et al 2020, PMID: 32712301 (1 family); Mademont-Soler et al 2021, PMID: 33269555 (1 family); Changed rating: GREEN; Changed publications: 27773429, 27481395, 31875334, 32712301, 33269555 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v0.295 | ERGIC1 |
Chirag Patel 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 PMID: 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 v0.284 | ZBTB42 |
Zornitza Stark gene: ZBTB42 was added gene: ZBTB42 was added to Arthrogryposis. Sources: Expert Review Mode of inheritance for gene: ZBTB42 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZBTB42 were set to 25055871 Phenotypes for gene: ZBTB42 were set to Lethal congenital contracture syndrome 6, MIM# 616248 Review for gene: ZBTB42 was set to AMBER Added comment: Homozygous missense variant reported in a family with three stillbirths and a phenotype consistent with LCCS. Supportive zebrafish model. Sources: Expert Review |
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| Arthrogryposis v0.264 | UNC50 |
Zornitza Stark 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. Unclear if these are two separate cases or the same case reported twice or ?founder variant. Sources: Literature |
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| Arthrogryposis v0.254 | KIDINS220 | Zornitza Stark edited their review of gene: KIDINS220: Added comment: Third family with severe prenatal phenotype and bi-allelic variants reported in PMID 32909676.; Changed rating: GREEN; Changed publications: 33205811, 28934391, 28934391, 32909676 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v0.253 | KIDINS220 |
Zornitza Stark 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 33205811; 28934391; 28934391 Phenotypes for gene: KIDINS220 were set to cerebral ventriculomegaly; limb contractures Review for gene: KIDINS220 was set to AMBER Added comment: 2 biallelic cases associated with cerebral ventriculomegaly and limb contractures, plus a mouse model that shows some phenotypic overlap: 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: 28934391 - 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. Note mono-allelic variants are associated with Spastic paraplegia, intellectual disability, nystagmus, and obesity #617296. Sources: Literature |
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| Arthrogryposis v0.248 | POR | Zornitza Stark Marked gene: POR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v0.248 | POR | Zornitza Stark Gene: por has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v0.248 | POR | Zornitza Stark Phenotypes for gene: POR were changed from to Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis, MIM#201750 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v0.247 | POR | Zornitza Stark Mode of inheritance for gene: POR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v0.246 | POR | Zornitza Stark reviewed gene: POR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis, MIM#201750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v0.242 | LMX1B | Zornitza Stark changed review comment from: Nail-patella syndrome (NPS) is an autosomal-dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Varying degrees of proteinuria or hematuria are present, and can occasionally progress to chronic renal failure. Some variants in the homeodomain of LMX1B cause isolated nephropathy without nail, patellar or skeletal abnormality (LMX1B-associated nephropathy). >300 families reported.; to: Nail-patella syndrome (NPS) is an autosomal-dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Varying degrees of proteinuria or hematuria are present, and can occasionally progress to chronic renal failure. >300 families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v0.242 | LMX1B | Zornitza Stark edited their review of gene: LMX1B: Added comment: Nail-patella syndrome (NPS) is an autosomal-dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Varying degrees of proteinuria or hematuria are present, and can occasionally progress to chronic renal failure. Some variants in the homeodomain of LMX1B cause isolated nephropathy without nail, patellar or skeletal abnormality (LMX1B-associated nephropathy). >300 families reported.; Changed phenotypes: Nail-patella syndrome, MIM# 161200 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v0.242 | MYMK |
Zornitza Stark changed review comment from: Distal contractures are part of the phenotype of this muscle disorder. Sources: Expert list; to: Carey-Fineman-Ziter syndrome (CFZS) is a multisystem congenital disorder characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive. Intellect has been normal in molecularly confirmed cases. Defect in myoblast fusion. 6 unrelated families reported with CFZ phenotype and bi-allelic MYMK variants. p.Pro91Thr is a common founder variant, which is hypomorphic. Distal contractures are part of the phenotype of this muscle disorder. Sources: Expert list |
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| Arthrogryposis v0.218 | NEK9 |
Zornitza Stark gene: NEK9 was added gene: NEK9 was added to Arthrogryposis. Sources: Expert Review Mode of inheritance for gene: NEK9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NEK9 were set to 26908619; 21271645 Phenotypes for gene: NEK9 were set to Lethal congenital contracture syndrome 10, MIM# 617022; Arthrogryposis, Perthes disease, and upward gaze palsy, MIM# 614262 Review for gene: NEK9 was set to AMBER Added comment: PMID 26908619: Two Irish traveller families, 5 affected individuals, same homozygous variant identified (founder effect). Limited functional data. PMID 21271645: Another Saudi family described with which 2 sisters and a female cousin who had a similar disorder characterised by arthrogryposis apparent since early childhood, avascular necrosis of the hip (Perthes disease), and upward gaze palsy. Homozygous missense variant segregated with the phenotype. Given the small number of reports, it is unclear whether this represents a distinct association is part of a spectrum with includes the more severe phenotype described in the Irish traveller families. Sources: Expert Review |
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| Arthrogryposis v0.215 | SCN1A |
Zornitza Stark gene: SCN1A was added gene: SCN1A was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: SCN1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SCN1A were set to 32928894; 29543227 Phenotypes for gene: SCN1A were set to Arthrogryposis multiplex congenita Review for gene: SCN1A was set to GREEN Added comment: Note SCN1A is a well-established cause of Dravet syndrome, MIM# 607208 ----- PMID: 32928894 (2020) - De novo missense variants in SCN1A (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three unrelated patients with AMC which was diagnosed from the second trimester of pregnancy. One patient developed intractable epilepsy from birth and died at 21 days, while the other two pregnancies were terminated. Note we have reported this association previously in PMID 29543227 (Supplementary info) in an infant presenting with AMC and severe EE, and de novo p.(Ile1347Asn) variant which at the time was thought to only partially explain the phenotype, but in light of this new report, likely fully explains the phenotype. Given the presence of severe seizure disorder in the two infants who were phenotype in the newborn period, this likely represents the severe end of the spectrum of SCN1A-related disorders rather than a distinct association. Sources: Literature |
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| Arthrogryposis v0.199 | B3GNT2 | Zornitza Stark edited their review of gene: B3GNT2: Added comment: Gene previously known as B3GNT1. Two families reported, arthrogryposis not a prominent feature.; Changed publications: 23359570, 23877401; Changed phenotypes: Muscular dystrophy-dystroglycanopathy; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v0.197 | MYLPF |
Crystle Lee gene: MYLPF was added gene: MYLPF was added to Arthrogryposis. Sources: Expert Review Mode of inheritance for gene: MYLPF was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: MYLPF were set to 32707087 Phenotypes for gene: MYLPF were set to Distal arthrogryoposis Review for gene: MYLPF was set to GREEN Added comment: 2 different homozygous variants reported in 6 consanguineous families with DA and an additional 2 different dominantly inherited variants in 2 families, with supporting animal model. Sources: Expert Review |
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| Arthrogryposis v0.169 | SLC9A6 | Zornitza Stark commented on gene: SLC9A6: Contractures are reported but condition does not | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v0.165 | SLC6A9 |
Zornitza Stark gene: SLC6A9 was added gene: SLC6A9 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: SLC6A9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC6A9 were set to 27773429; 27481395 Phenotypes for gene: SLC6A9 were set to Glycine encephalopathy with normal serum glycine, MIM#617301; arthrogryposis Review for gene: SLC6A9 was set to AMBER Added comment: Two of the reported families have had arthrogryposis as a manifesting feature. Sources: Expert list |
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| Arthrogryposis v0.149 | MYL1 |
Zornitza Stark gene: MYL1 was added gene: MYL1 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: MYL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYL1 were set to 30215711 Phenotypes for gene: MYL1 were set to Myopathy, congenital, with fast-twitch (type II) fiber atrophy, MIM# 618414 Review for gene: MYL1 was set to RED Added comment: Two families and a zebrafish model. Predominant finding is that of hypotonia, mild contractures reported in one. Sources: Expert list |
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| Arthrogryposis v0.147 | MAGEL2 |
Zornitza Stark gene: MAGEL2 was added gene: MAGEL2 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: MAGEL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAGEL2 were set to 24076603; 27195816; 26365340 Phenotypes for gene: MAGEL2 were set to Schaaf-Yang syndrome Review for gene: MAGEL2 was set to GREEN Added comment: Fountain et al. (2017) reported 18 patients with SHFYNG ascertained on the basis of genetic studies from several different research groups or laboratories. Joint contractures were present in almost all patients, and ranged from only the interphalangeal joints to lethal fetal akinesia with severe arthrogryposis. Mejlachowicz et al (2015) reported two unrelated families with lethal AMC and heterozygous truncating frameshift MAGEL2 mutations on paternal allele. Sources: Expert list |
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| Arthrogryposis v0.124 | ERCC5 |
Zornitza Stark changed review comment from: Single family reported with 5 affected fetuses and severe COFS including arthrogryposis. Sources: Expert list; to: A family reported with 5 affected fetuses and severe COFS including arthrogryposis in PMID:24700531. Further two included in a recent review of severe neonatal presentations of nucleotide excision-repair disorders (PMID:32557569). Sources: Expert list |
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| Arthrogryposis v0.123 | ERCC5 |
Zornitza Stark gene: ERCC5 was added gene: ERCC5 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: ERCC5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ERCC5 were set to 24700531 Phenotypes for gene: ERCC5 were set to Cerebrooculofacioskeletal syndrome 3, MIM# 616570 Review for gene: ERCC5 was set to AMBER Added comment: Single family reported with 5 affected fetuses and severe COFS including arthrogryposis. Sources: Expert list |
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| Arthrogryposis v0.109 | DYNC1H1 |
Zornitza Stark gene: DYNC1H1 was added gene: DYNC1H1 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: DYNC1H1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DYNC1H1 were set to 25609763; 25512093; 28554554 Phenotypes for gene: DYNC1H1 were set to Charcot-Marie-Tooth disease, axonal, type 20, MIM# 614228; Mental retardation, autosomal dominant 13, MIM# 614563; Spinal muscular atrophy, lower extremity-predominant 1, MIM# 158600 Review for gene: DYNC1H1 was set to GREEN Added comment: Phenotypes associated with DYNC1H1 range from spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (HMSN), cortical malformations, or a combination of these. Multiple families reported where arthrogryposis is a prominent feature. Sources: Expert list |
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| Arthrogryposis v0.101 | DHCR24 |
Zornitza Stark gene: DHCR24 was added gene: DHCR24 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: DHCR24 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DHCR24 were set to 21671375; 12457401; 29175559; 21559050 Phenotypes for gene: DHCR24 were set to Desmosterolosis, MIM# 602398 Review for gene: DHCR24 was set to GREEN Added comment: At least 4 families reported where contractures are a feature of the condition. Sources: Expert list |
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| Arthrogryposis v0.95 | COASY |
Zornitza Stark gene: COASY was added gene: COASY was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: COASY was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COASY were set to 30089828 Phenotypes for gene: COASY were set to Pontocerebellar hypoplasia; microcephaly; arthrogryposis Review for gene: COASY was set to AMBER Added comment: Two families reported with a severe, prenatal onset phenotype comprising PCH, microcephaly and arthrogryposis. Note gene is also associated with NBIA. Sources: Expert list |
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| Arthrogryposis v0.72 | ALG3 |
Zornitza Stark gene: ALG3 was added gene: ALG3 was added to Arthrogryposis. Sources: Expert list Mode of inheritance for gene: ALG3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ALG3 were set to 16006436; 26453362; 28742265 Phenotypes for gene: ALG3 were set to Congenital disorder of glycosylation, type Id 601110 Review for gene: ALG3 was set to GREEN Added comment: Multiple families reported with this CDG and contractures. Sources: Expert list |
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| Arthrogryposis v0.70 | TOR1A |
Michelle Torres changed review comment from: 5 patients reported by multiple authors supporting that biallelic mutations (missense, inframe del and protein truncating) in TOR1A cause severe arthrogryposis. Other variable features are developmental delay, strabismus and tremor. Parents carriers do not have symptoms of autosomal dominant dystonia, also associate with this gene and known to have incomplete penetrance (OMIM). Sources: Literature; to: 5 families reported by multiple authors supporting that biallelic mutations (missense, inframe del and protein truncating) in TOR1A cause severe arthrogryposis. Other variable features are developmental delay, strabismus and tremor. Parents carriers do not have symptoms of autosomal dominant dystonia, also associate with this gene and known to have incomplete penetrance (OMIM). Sources: Literature |
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| Arthrogryposis v0.70 | TOR1A |
Michelle Torres gene: TOR1A was added gene: TOR1A was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: TOR1A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TOR1A were set to PMID: 30244176 Phenotypes for gene: TOR1A were set to Arthrogryposis Review for gene: TOR1A was set to GREEN Added comment: 5 patients reported by multiple authors supporting that biallelic mutations (missense, inframe del and protein truncating) in TOR1A cause severe arthrogryposis. Other variable features are developmental delay, strabismus and tremor. Parents carriers do not have symptoms of autosomal dominant dystonia, also associate with this gene and known to have incomplete penetrance (OMIM). Sources: Literature |
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| Arthrogryposis v0.61 | ASCC1 |
Elena Savva gene: ASCC1 was added gene: ASCC1 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: ASCC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ASCC1 were set to PMID: 28218388; 30327447; 26924529 Phenotypes for gene: ASCC1 were set to Spinal muscular atrophy with congenital bone fractures 2 MIM#616867 Review for gene: ASCC1 was set to GREEN Added comment: PMID: 28218388 - 1 Portuguese child with a homozygous PTC and mild arthrogryposis, and ongenital generalized hypotonia, lack of spontaneous movements and atrophic muscle fibres. Papers reviews another report (PMID: 26924529) where the Turkish patient also had arthrogryposis and the same homozygous PTC PMID: 30327447 - 3 unrelated families with severe prenatal onset muscle weakness, neonatal hypotonia and arthrogryposis. All families had biallelic PTCs, where one family was homozygous and another compound heterozygous for the recurring p.Glu53fs*19 mutation. Sources: Literature |
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| Arthrogryposis v0.60 | NUP88 |
Zornitza Stark changed review comment from: Two unrelated families and a zebrafish model reported. Sources: Literature; to: Two unrelated families, functional data on the variants support pathogenicity as does a zebrafish model. Sources: Literature |
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| Arthrogryposis v0.60 | NUP88 |
Zornitza Stark gene: NUP88 was added gene: NUP88 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: NUP88 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NUP88 were set to 30543681 Phenotypes for gene: NUP88 were set to Fetal akinesia deformation sequence 4, MIM# 618393 Review for gene: NUP88 was set to AMBER Added comment: Two unrelated families and a zebrafish model reported. Sources: Literature |
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| Arthrogryposis v0.48 | TOR1AIP1 |
Zornitza Stark gene: TOR1AIP1 was added gene: TOR1AIP1 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: TOR1AIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TOR1AIP1 were set to 24856141; 31299614; 30723199; 27342937; 32055997 Phenotypes for gene: TOR1AIP1 were set to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Progeroid appearance; Cataracts; Microcephaly; Deafness; Contractures Review for gene: TOR1AIP1 was set to GREEN Added comment: Multiple families reported but highly variable phenotype; joint contractures observed in multiple individuals. Sources: Literature |
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| Arthrogryposis v0.46 | SCYL2 |
Kristin Rigbye gene: SCYL2 was added gene: SCYL2 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: SCYL2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SCYL2 were set to 31960134; 26203146 Phenotypes for gene: SCYL2 were set to Arthrogryposis multiplex congenita (AMC); Zain syndrome Review for gene: SCYL2 was set to AMBER Added comment: 2 unrelated consanguineous families reported with AMC (PMID: 31960134). Constitutive mouse knockout of Scyl2 results in neonatal lethality and severe motor and sensory deficits (PMID: 26203146). Sources: Literature |
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| Arthrogryposis v0.44 | B4GAT1 | Zornitza Stark changed review comment from: Two families reported.; to: Two families and two animal models. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v0.36 | SMPD4 |
Alison Yeung gene: SMPD4 was added gene: SMPD4 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: SMPD4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SMPD4 were set to 31495489 Phenotypes for gene: SMPD4 were set to Microcephaly; congenital arthrogryposis, intellectual disability Review for gene: SMPD4 was set to GREEN gene: SMPD4 was marked as current diagnostic Added comment: Expansion of phenotype in known neurodevelopment disease gene 12 unrelated families reported. Arthrogryposis is a feature in 85% Sources: Literature |
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| Arthrogryposis v0.2 | SYNE1 |
Zornitza Stark gene: SYNE1 was added gene: SYNE1 was added to Arthrogryposis_VCGS. Sources: Literature Mode of inheritance for gene: SYNE1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SYNE1 were set to 27782104 Phenotypes for gene: SYNE1 were set to Distal arthrogryposis Review for gene: SYNE1 was set to GREEN Added comment: Three families reported with bi-allelic distal truncating variants in this gene (KASH domain). This appears to be a specific genotype-phenotype correlation with variants elsewhere in the gene causing different phenotypes. Sources: Literature |
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| Arthrogryposis v0.0 | POR |
Zornitza Stark gene: POR was added gene: POR was added to Arthrogryposis_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: POR was set to Unknown |
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