Pentanucleotide repeat instability and transmission in benign adult familial myoclonic epilepsy types 1, 4, and 8

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OBJECTIVE: Benign adult familial myoclonic epilepsy (BAFME) is a rare autosomal dominant disorder characterized by tremor and myoclonic seizures. To date, seven genetic subtypes have been identified, all caused by noncoding pentanucleotide repeat expansions-typically TTTTA expansions with additional TTTCA insertions-across distinct loci. Although aberrant repeat expansions are a shared hallmark, it remains unclear whether different BAFME subtypes exhibit similar patterns of repeat length variability and inheritance. We aimed to characterize pentanucleotide repeat structure, repeat length variability across reads, and intergenerational transmission patterns across multiple BAFME subtypes, and to determine whether these mutational dynamics differ among BAFME1, BAFME4, and BAFME8. METHODS: We performed whole-genome long-read sequencing and targeted adaptive sampling long-read sequencing on 18 affected individuals from three multigenerational families with BAFME1 (SAMD12), BAFME4 (YEATS2), and BAFME8 (RAI1). Repeat structure, repeat length variability across reads, and intergenerational transmission dynamics were analyzed. RESULTS: Across patients, 7-33 long reads containing expanded repeats were identified. Several differences in repeat length distributions across reads were observed among the families studied. The BAFME1 family showed comparatively narrower distributions, whereas broader variability was observed in the BAFME4 and BAFME8 families. In BAFME1 and BAFME8, TTTCA repeat length showed a positive correlation with age, consistent with age-associated increases in repeat length variability across reads. Parent-to-offspring transmissions were often associated with increases in repeat length, most prominently in BAFME8. Sibling comparisons further indicated higher variability in TTTCA than in TTTTA repeats. SIGNIFICANCE: Our study demonstrates distinct patterns of repeat length variability and inheritance across the families analyzed. These findings suggest that the genomic context of pentanucleotide expansions may influence repeat behavior and could contribute to phenotypic variability in BAFME.

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