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

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.

To identify structural variants or repeat expansions associated with progressive myoclonic epilepsy in an Azerbaijani family using long-read sequencing.

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.

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.

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.