Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy

Abstract

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

Long-read sequencing identified intronic repeat expansions inSAMD12from Chinese pedigrees affected with familial cortical myoclonic tremor with epilepsy

“…The structure of repeat expansion could be clearly recognised. However, variation of repeat length was observed in our data, which was also described in the Japanese study,10 suggesting the possible existence of additional somatic expansion (online supplementary figure 4). Nevertheless, the pattern of the expanded repeat was clearly recognised as ‘(TTTCA )exp (TTTTA) exp ’, which is consistent with the reported configuration in the Japanese study 10…”

“…Causative SV was also identified in a patient using LRS 22. Furthermore, two causative repeat configurations in SAMD12 were accurately verified by Nanopore LRS 10. In our study, we developed a strategy combining RepeatHMM and inScan to detect this causative repeat expansion through LRS.…”

“…However, no structural variants were detected as the likely causative mutation in our initial analysis. The report of causative intronic repeat expansion in FCMTE10 helped us focus on STRs in the candidate linkage region with more detailed examination. RepeatHMM was an effective and efficient algorithm to find repeat expansions, but it may generate false-positives in LRS data 19.…”

“…However, none of causative mutations had been reported for FCMTE1, although the disease locus has been mapped to 8q24 in genetic linkage studies. Recently, expansions of intronic TTTCA and TTTTA repeat motifs were found to be involved in the pathogenesis of FCMTE1 in Japanese pedigrees 10. A more recent report also identified this causative mutation in FCMTE1 pedigrees of another ethic background 11…”

Epilepsy in families: Age at onset is a familial trait, independent of syndrome

“…30 Repeat expansions, the best-known mechanism of anticipation, 31,32 are not common causes of epilepsy, but were recently identified as the mechanism of benign adult familial myoclonic epilepsy, 33 and may be a more common mechanism of epilepsy than previously thought. This raises the possibility of anticipation, a well-known genetic phenomenon.…”