Early onset or syndromic epilepsy

Gene: DEGS1

Green List (high evidence)

AR HLD18. Karsai et al, 2019 (30620338) - 22 year old man with consang Turkish parents - developed seizures aged 5 - hom missense variant, A280V - analysis of patient fibribalsts showed decreased expression of mutant protein and decreased enzyme activity compared to wt. In vitro cellular expression of the mutant resulted in decreased protein lelves compared to controls suggesting instability of the mutant protein. Pant et al, 2019 (30620337) -19 patients from 13 unrelated families - 8 families were consang (Egyptian, Moroccan, Indian, Pakistani or Middle Eastern descent). Patients had a similar phenotype - with onset in early life. 80% developed resistant seizures in the first year of life. Hom or compound het variants identified - 3 fs, 4 nonsense and 6 missense. 12/13 were located in the FAD domain, and all missense variants occured at highly conserved residues.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

I don't know

Kept rating as Green based on Green post-Webex review from Helen Lord.

Created: 9 Sep 2019, 10:19 a.m. | Last Modified: 9 Sep 2019, 10:19 a.m.

Panel Version: 1.314

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.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

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.

Created: 23 Jul 2019, 11 a.m. | Last Modified: 23 Jul 2019, 11 a.m.

Panel Version: 1.180

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).

Created: 23 Jul 2019, 10:58 a.m. | Last Modified: 23 Jul 2019, 10:58 a.m.

Panel Version: 1.178

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).

Created: 23 Jul 2019, 10:58 a.m. | Last Modified: 23 Jul 2019, 10:58 a.m.

Panel Version: 1.178

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. Motor developmental delay was observed in the patient age 6 months and he developed progressive spasticity. He also developed a pathological EEG epilepsy and grand mal seizures with onset 5 years.

Created: 23 Jul 2019, 10:57 a.m. | Last Modified: 23 Jul 2019, 10:57 a.m.

Panel Version: 1.178

Green List (high evidence)

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).
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The respective OMIM entry is Leukodystrophy, hypomyelinating, 18 (#618404). DEGS1 is not associated with any phenotype in G2P.
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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

Created: 16 Jul 2019, 8:58 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leukodystrophy hypomyelinating 18, 618404

Publications

• 30620337
• 30620338
• 31186544