Activity

Filter

Cancel
Date Panel Item Activity
13 actions
Early onset or syndromic epilepsy v1.263 KARS Louise Daugherty Tag new-gene-name tag was added to gene: KARS.
Early onset or syndromic epilepsy v1.263 KARS Louise Daugherty commented on gene: KARS
Early onset or syndromic epilepsy v1.191 KARS Rebecca Foulger Source Wessex and West Midlands GLH was added to KARS.
Early onset or syndromic epilepsy v1.190 KARS Rebecca Foulger Source NHS GMS was added to KARS.
Early onset or syndromic epilepsy v1.189 KARS Rebecca Foulger reviewed gene: KARS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 KARS Tracy Lester reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: ; Publications: 29615062; Phenotypes: ?Charcot-Marie-Tooth disease, recessive intermediate, 613641, Deafness, 613916; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.167 DEGS1 Konstantinos Varvagiannis gene: DEGS1 was added
gene: DEGS1 was added to Genetic epilepsy syndromes. 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, 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
Early onset or syndromic epilepsy v0.550 KARS Sarah Leigh Marked gene: KARS as ready
Early onset or syndromic epilepsy v0.550 KARS Sarah Leigh Added comment: Comment when marking as ready: Although seizures are not present in all cases of ?Charcot-Marie-Tooth disease, recessive intermediate, B 613641 or Deafness, autosomal recessive 89 613916, seizures have been reported in at least 5 cases carrying a total of 10 KARS variants AS compound heterozygotes.
Early onset or syndromic epilepsy v0.550 KARS Sarah Leigh Gene: kars has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.550 KARS Sarah Leigh Classified gene: KARS as Green List (high evidence)
Early onset or syndromic epilepsy v0.550 KARS Sarah Leigh Gene: kars has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.505 KARS Konstantinos Varvagiannis gene: KARS was added
gene: KARS was added to Genetic Epilepsy Syndromes. Sources: Literature,Expert Review
Mode of inheritance for gene: KARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KARS were set to 29615062; 30252186; 28496994
Phenotypes for gene: KARS were set to Global developmental delay; Intellectual disability; Seizures; Charcot-Marie-Tooth disease, recessive intermediate, B - 613641; Deafness, autosomal recessive 89 - 613916
Penetrance for gene: KARS were set to Complete
Review for gene: KARS was set to GREEN
Added comment: Several individuals with biallelic pathogenic variants in KARS have been reported (summarized in PMIDs : 29615062, 30252186, 28496994).

Developmental delay and/or intellectual disability are among the (most) frequent features, although not universal.

Seizures are part of the phenotype (15-30% of the individuals) according to the tables provided in these 3 publications.

As a result it can be considered for inclusion in the epilepsy panel as green (or amber).
Sources: Literature, Expert Review