Curation EPM CSNK1E

One Azerbaijani EPM proband with onset at 10 years carried a heterozygous CSNK1E CGG expansion in exon 1/5'UTR (longest allele CGG n=745) after exome and long-read analyses found no other plausible EPM-related variant; functional methylation data were reported. Expansion was also present in an unaffected sibling, consistent with incomplete penetrance.

Population comparison using 908 1KGP ONT genomes found no comparable large CSNK1E CGG expansions; 98.7% had <20 repeats and the longest observed alleles were CGG n=48 and n=47, versus CGG n=745 in the proband and n=980 in an unaffected sibling. Matching and penetrance limitations remain.

A de novo CSNK1E splice-site SNV in West syndrome epileptic encephalopathies with RT-PCR evidence of abnormal splicing and gene-level brain/coexpression analyses. This evidence supports a regulatory impact of CSNK1E variants in an individual with epileptic encephalopathy but is not specific to the CGG expansion.

CSNK1E CGG expansion, methylation, and reduced expression was observed in a FRA22A carrier. Phenotypic data was not provided, therefore this provides support for the regulatory impact of the specific expansion but is not EPM-specific.

Non-patient/control comparison in the FRA22A study showed control samples were unmethylated at the CSNK1E CGG region; the population methylation screen also identified six individuals with gain of methylation overlapping the CSNK1E 5'UTR CGG repeat. Evidence is locus-specific but not EPM-specific.