Phenotypic and genotypic characterization of familial adult myoclonus epilepsy in a Chinese case series.

Familial adult myoclonus epilepsy is a type of repeat expansion disorders caused by insertion of the causative pentanucleotide TTTCA repeat into an intronic polymorphic TTTTA repeat in different genes. We aimed to characterize the clinical features and elucidate the exact genetic basis of TTTTA/TTTCA repeat expansion in familial adult myoclonus epilepsy from mainland China. Eighty-five individuals including 36 patients and 49 normal phenotype relatives from seven pedigrees with familial adult myoclonus epilepsy, were recruited in a case series from mainland China. Repeat-primed PCR was used for initial screening. Long-range PCR-based enrichment, followed by targeted deep HiFi long-read sequencing, was performed to precisely clarify the detailed information of causative pentanucleotide TTTTA/TTTCA repeat expansion. The results indicated there exists obvious clinical heterogeneity both within and between families in our patient group. All patients were genetically diagnosed with familial adult myoclonus epilepsy type 1. The number of pentanucleotide repeats was extremely unstable, with median TTTCA repeat sizes ranging from 10 to 647 in the affected members of our case series under a mean sequence depth of coverage above 50 000. The [(TTTTA)exp (TTTCA)exp] motif was the only configuration of expanded repeats in our case series. An inverse correlation was found between the age of onset and the number of TTTCA repeats and the total number of TTTTA/TTTCA repeats. Clinical anticipation was observed for tremor and seizure symptoms. However, we did not demonstrate a link between parent-offspring differences in repeat sizes and their changes in age of onset. In summary, we determined the nature of the expanded repeats and a reliable phenotype-genotypic correlation in our case series of familial adult myoclonus epilepsy through targeted deep HiFi long-read sequencing technologies.