CERS1 was first reported in relation to autosomal recessive (AR) progressive myoclonus epilepsy in 2014 (Vanni et al., PMID: 24782409). Phenotypic features in individuals with biallelic CERS1 variants include action myoclonus, myoclonic jerks, seizures (tonic clonic and febrile), truncal and appendicular ataxia, dysarthria, nystagmus, and progressive cognitive deterioration with onset in early to late childhood (Vanni et al., PMID: 24782409; Ferlazzo et al., PMID: 27618929; Goderio Junior et al., PMID: 30800706; Courage et al., PMID: 33798445). Cerebellar and brainstem atrophy have been reported on brain MRI. Seven affected individuals from 3 families with unique homozygous variants are included in this curation (Vanni et al., PMID: 24782409; Ferlazzo et al., PMID: 27618929; Goderio Junior et al., PMID: 30800706; Courage et al., PMID: 33798445). The mechanism of pathogenicity appears to be loss of function of CerS1 activity responsible for the synthesis of C18 ceramides (Vanni et al., PMID: 24782409). This gene-disease relationship is also supported by mouse models (Zhao et al., PMID: 21625621; Ginkel et al., PMID: 23074226). A frameshift variant expected to result in nonsense mediated decay arose spontaneously in “flincher” mice at Jackson Laboratory and, although homozygous mice do not develop spontaneous seizures, they developed cerebellar ataxia and cerebellar degeneration. A second CerS1 deficient mouse model homozygous for a deletion of the catalytic domain demonstrates decreased synthesis of gangliosides, cerebellar degeneration, and behavior and locomotion defects. The genetic evidence score is 4.2 points, and the experimental evidence score is 2 points for a total of 6.2 points. This score falls between the limited and moderate classification. The GCEP elected to classify this gene as moderate as the collective evidence supports a valid gene disease relationship, but this condition appears to be very rare. In summary, there is moderate evidence supporting the relationship between CERS1 and autosomal recessive progressive myoclonus epilepsy. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date July 16, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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