A CGG Repeat Expansion in CSNK1E Associated with Progressive Myoclonic Epilepsy with Incomplete Penetrance

<h4>Background</h4>Progressive myoclonic epilepsy is a heterogeneous neurodegenerative disorder characterized by early-onset myoclonus, epilepsy, generalized tonic-clonic seizures, and progressive neurological deterioration. Recently, a CGG repeat expansion and increased CSNK1E DNA methylation have been shown to be associated with developmental and epileptic encephalopathies.<h4>Objective</h4>To identify structural variants or repeat expansions associated with progressive myoclonic epilepsy in an Azerbaijani family using long-read sequencing.<h4>Methods</h4>Known genetic causes of progressive myoclonic epilepsy were ruled out through quadro-exome sequencing in an individual exhibiting tonic-clonic seizures, dementia, and cerebellar ataxia with an age at onset of 10 years. After ruling out the presence of any other pathogenic mutation, long-read whole genome sequencing was performed to investigate structural variants or repeat expansions potentially associated with the disease.<h4>Results</h4>We identified a heterozygous expanded (CGG)_n repeat in exon 1 of CSNK1E in the proband (longest repeat length, n = 745) and her unaffected sister (longest repeat length, n = 980). The unaffected father was wild-type, while the unaffected mother had an intermediate-sized repeat expansion (n = 131), which might have expanded to a pathogenic length in the siblings upon transmission. The expanded allele exhibited higher methylation levels than the wild-type, with globally elevated methylation in both siblings compared with parental samples.<h4>Conclusions</h4>We suggest the association of the CSNK1E-CGG expansion with incomplete penetrance in an Azerbaijani case with progressive myoclonic epilepsy, broadening its phenotypic spectrum. Our findings support the utility of long-read sequencing and methylation analysis as powerful approaches to identifying and characterizing disease-associated expanded repeats. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.