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Intellectual disability - microarray and sequencing v2.1022 | KARS | Louise Daugherty Tag new-gene-name tag was added to gene: KARS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.1022 | KARS | Louise Daugherty commented on gene: KARS: Added new-gene-name tag, new approved HGNC gene symbol for KARS is KARS1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.965 | DEGS1 | Rebecca Foulger commented on gene: DEGS1: PMID:30620338: Karsai et al., 2019 identified a homozygous p.Ala280Val variant in DEGS1 in a Turkish patient of consanguineous parents. Both parents and healthy siblings were heterozygous carriers of the variant. Leading symptoms were early-onset developmental delay, movement disorder, progressive spasticity, and epilepsy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.953 | DEGS1 |
Konstantinos Varvagiannis gene: DEGS1 was added gene: DEGS1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DEGS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DEGS1 were set to 30620337; 30620338; 31186544 Phenotypes for gene: DEGS1 were set to Leukodystrophy hypomyelinating 18, MIM 618404) Penetrance for gene: DEGS1 were set to Complete Review for gene: DEGS1 was set to GREEN Added comment: Several individuals with biallelic pathogenic DEGS1 variants have been reported to date, in the following studies : [1] Pant et al. 2019 (PMID: 30620337) : 19 patients from 13 unrelated families [2] Karsai et al. 2019 (PMID: 30620338) : 1 individual [3] Dolgin et al. 2019 (PMID: 31186544) : 4 individuals belonging to a large consanguineous kindred As summarized in the first article and OMIM, affected individuals may have very poor psychomotor development, dystonia, spasticity, seizures with hypomyelinating leukodystrophy upon brain imaging and/or progressive atrophy of corpus callosum, thalami and cerebellum. Although a severe form overall was reported for many individuals in the first study, variable severity (eg. mild to severe ID) was reported among individuals belonging to the same kindred in the report by Dolgin et al. DEGS1 encodes Δ4-dehydroceramide desaturase which catalyzes conversion of dihydroceramide (DhCer) to ceramide (Cer) in the de novo ceramide biosynthetic pathway. Ceramide is the central unit of all sphingolipids, which are components of cellular membranes and play key roles in several processes incl. cell differentiation, neuronal signaling and myelin sheath formation. Sphingolipid balance is important for the CNS as demonstrated in the case of lysosomal disorders (eg. Gaucher, Niemann Pick, Farber) one enzymatic step away from DEGS1. Variants of all types (missense, stopgain, frameshift) have been reported with the majority/almost all located in the fatty acid desaturase (FAD) domain. Extensive studies have been carried out and demonstrated: - impaired DEGS1 activity in patients' fibroblasts and muscle suggested by increased DhCer/Cer ratio and compatible broader biochemical effects (higher levels of dihydrosphingosine, dihydrosphingomyelins, etc. and lower levels of sphingosine, monohexosylceramides, etc). - increased ROS production in patient fibroblasts (similar to a Drosophila model of excess DhCer), - high expression of the gene in child and adult CNS tissues from control individuals (evaluated by RT-qPCR in Ref. 1). A previous study has suggested that DEGS1 expression is upregulated during the 4-9th week of human embryogenesis (PMID cited: 20430792) which may suggest an important role for neural system development. - decreased expression for some variants either evaluated at the mRNA (RT-qPCR) / protein level (by Western Blot) - In zebrafish loss of Degs1 resulted in increased DhCer/Cer ratio, locomotor disability and impaired myelination similar to the patients' phenotype. Fingolimod, a sphingosine analog inhibiting Cer synthase (one step prior to DEGS1 in the de novo ceramide biosynthesis pathway, and converting sphingosine to ceramide in the salvage pathway) reduced the DhCer/Cer imbalance, ameliorated the locomotor phenotype and increased the number of myelinating oligodendrocytes in zebrafish, while it reduced the ROS levels in patient fibroblasts. Previous animal models: Apart from the zebrafish model (Pant et al.), higher DhCer/Cer ratios have been shown in homozygous Degs1 -/- mice similar to what is also observed in D. melanogaster. As summarized in MGI (and the previous studies as well) "mice homozygous for a knock-out allele exhibit premature death, decreased to absent ceramide levels, decreased body weight, scaly skin, sparse hair, tremors, hematological and blood chemistry abnormalities, decreased bone mineral content and density and decreased liver function." (PMIDs cited: 17339025, 28507162). ---- The respective OMIM entry is Leukodystrophy, hypomyelinating, 18 (#618404). DEGS1 is not associated with any phenotype in G2P. ---- As a result, DEGS1 can be considered for inclusion in the ID and epilepsy panels probably as green (relevant phenotype, sufficient number of individuals, supportive expression and biochemical studies, animal models, etc). Sources: Literature |
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Intellectual disability - microarray and sequencing v2.644 | KARS | Ivone Leong Classified gene: KARS as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.644 | KARS | Ivone Leong Added comment: Comment on list classification: Promoted from amber to green based on the evidence provided by Zornitza Stark (Australian Genomics) and Konstantinos Varvagiannis (Other). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.644 | KARS | Ivone Leong Gene: kars has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.643 | KARS | Ivone Leong Phenotypes for gene: KARS were changed from ?Charcot-Marie-Tooth disease, recessive intermediate, B, 613641; Deafness, autosomal recessive 89, 613916 to Global developmental delay; Intellectual disability; Seizures; ?Charcot-Marie-Tooth disease, recessive intermediate, B, 613641; Deafness, autosomal recessive 89, 613916 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.640 | KARS | Ivone Leong Publications for gene: KARS were set to 29615062; 30252186; 28496994; 28887846, 25330800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.639 | KARS | Ivone Leong Publications for gene: KARS were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.588 | KARS | Zornitza Stark Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.588 | KARS | Zornitza Stark Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.588 | KARS | Zornitza Stark Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.588 | KARS | Zornitza Stark Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.588 | KARS | Zornitza Stark commented on gene: KARS: At least 6 individuals reported with a childhood-onset disorder characterised by intellectual disability, seizures, leucoencephalopathy, microcephaly and bi-allelic variants in this gene. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.588 | KARS | Zornitza Stark commented on gene: KARS: At least 6 individuals reported with childhood-onset intellectual disability, seizures, leucoencephalopathy, microcephaly. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.588 | KARS | Zornitza Stark commented on gene: KARS: At least 6 patients reported with a childhood-onset disorder, characterised by intellectual disability, seizures, leucoencephalopathy, and microcephaly. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.588 | KARS | Zornitza Stark commented on gene: KARS: At least 6 individuals reported with childhood-onset intellectual disability, seizures, leucoencephalopathy, microcephaly. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.588 | KARS | Zornitza Stark reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 28887846, 25330800, 29615062, 30252186, 28496994; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing v2.510 | KARS | Konstantinos Varvagiannis reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 29615062, 30252186, 28496994; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Charcot-Marie-Tooth disease, recessive intermediate, B - 613641, Deafness, autosomal recessive 89 - 613916; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing | KARS | BRIDGE consortium edited their review of KARS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing | KARS | BRIDGE consortium edited their review of KARS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing | KARS | Louise Daugherty classified KARS as amber | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing | KARS | Louise Daugherty commented on KARS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intellectual disability - microarray and sequencing | KARS | BRIDGE consortium reviewed KARS |