Movement disorders : official journal of the Movement Disorder Society · 2025
A CGG Repeat Expansion in CSNK1E Associated with Progressive Myoclonic Epilepsy with Incomplete Penetrance.
СтатьяКлинический случайНазвание и аннотация: Перевод в очереди
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Akçimen Fulya, Alvarez Jerez Pilar, Guliyeva Ulviyya, Lee Jasmine, Malik Laksh, Baker Breeana, Salayev Kamran, Guliyeva Sughra, Billingsley Kimberley J, Houlden Henry, Singleton Andrew B, Blauwendraat Cornelis, Bandres-Ciga Sara, Kaiyrzhanov Rauan
Аннотация
BACKGROUND: 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.
OBJECTIVE: To identify structural variants or repeat expansions associated with progressive myoclonic epilepsy in an Azerbaijani family using long-read sequencing.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
OBJECTIVE: To identify structural variants or repeat expansions associated with progressive myoclonic epilepsy in an Azerbaijani family using long-read sequencing.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.