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| Early onset or syndromic epilepsy v1.331 | DEGS1 | Rebecca Foulger Source Wessex and West Midlands GLH was added to DEGS1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.330 | DEGS1 | Rebecca Foulger Source NHS GMS was added to DEGS1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.314 | DEGS1 | Rebecca Foulger commented on gene: DEGS1: Kept rating as Green based on Green post-Webex review from Helen Lord. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.262 | DEGS1 | Rebecca Foulger edited their review of gene: DEGS1: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.261 | DEGS1 | Helen Lord reviewed gene: DEGS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.180 | DEGS1 | Rebecca Foulger Classified gene: DEGS1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.180 | DEGS1 | Rebecca Foulger Added comment: Comment on list classification: DEGS1 was added to the panel and rated Green by Konstantinos Varvagiannis. Seizures are a common part of the Leukodystrophy phenotype, as reported in unrelated individuals from multiple papers (PMIDs 30620338,30620337,31186544). Therefore sufficient evidence to rate Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.180 | DEGS1 | Rebecca Foulger Gene: degs1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.179 | DEGS1 | Rebecca Foulger Phenotypes for gene: DEGS1 were changed from Leukodystrophy hypomyelinating 18, 618404 to Leukodystrophy hypomyelinating 18, 618404; seizures | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.178 | DEGS1 | Rebecca Foulger changed review comment from: PMID:31186544: Dolgin et al., 2019 describe four individuals from a consanguineous family. All four had mild to severe ID, spastic quadriplegia, scoliosis and epilepsy in most. WES identified a homozygous missense variant in DEGS1 (in isoforms N219S, N255S); to: PMID:31186544: Dolgin et al., 2019 describe four individuals from a consanguineous family. All four had mild to severe ID, spastic quadriplegia, scoliosis and epilepsy in most. WES identified a homozygous missense variant in DEGS1 (in isoforms N219S, N255S). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.178 | DEGS1 | Rebecca Foulger commented on gene: DEGS1: PMID:31186544: Dolgin et al., 2019 describe four individuals from a consanguineous family. All four had mild to severe ID, spastic quadriplegia, scoliosis and epilepsy in most. WES identified a homozygous missense variant in DEGS1 (in isoforms N219S, N255S) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.178 | DEGS1 | Rebecca Foulger commented on gene: DEGS1: PMID:30620337: Pant et al., 2019 report DEGS1 variants as the cause of ypomyelinating leukodystrophy in 19 patients from 13 unrelated families. Of the 19 affected patients, seizures were frequently observed (80%) and include clonic tonic, status epilepticus and partial (plus one febrile case in family 12). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.178 | DEGS1 | Rebecca Foulger commented on gene: DEGS1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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