Objective: To ascertain whether intronic TTTCA repeat insertions in the SAMD12, TNRC6Aand RAPGEF2 genes cause benign adult familial myoclonic epilepsy (BAFME) and progressive myoclonic epilepsy in the UK.

Background: The core clinical features of BAFME include cortical myoclonus and seizure. However, this hereditary syndrome has heterogeneous genetic loci. Recently, Ishiuraet al. identified expansions of intronic TTTCA and TTTTA repeats in the SAMD12,TNRC6Aand RAPGEF2 genes in 51 Japanese families with BAFME. It is not known if the same pentanucleotide repeats are responsible for BAFME in the European population.

Method: We performed Sanger sequencing to exclude the known mutations in ACMSD c.77G>A, ADRA2B indel, c.675_686delTGGTGGGG, CTNND2 p.Glu1044Lys, CNTN2 c.503_503delG, SCN8A p.Pro1719Arg in the 14 probands with BAFME . Using repeat-primed PCR (RP-PCR), we screened for the TTTCA and TTTTA repeats in the BAFME (n=14) and progressive myoclonic epilepsy (n=214) cohorts. Probands with BAFME have deep phenotypic data from standardized clinical assessments, neuroimaging and electrophysiological investigations.

Results: In a UK population, we did not find TTTCA repeat in subjects with BAFME or progressive myoclonic epilepsy.

Conclusion: Our negative search for the pentanucleotide expansions supports the hypothesis of a founder effect in BAFME with TTTCA repeat insertion. Families from Japan and China with BAFME are mapped to chromosome 8q24; however, families of European origins have different genetic loci (2q11.2; 5p15.31-p15.1; 3q26.32-q28 and 1q32.1). Thereby, the same repeat insertion in different genes may still be responsible for BAFME in the UK. In future, long read whole-genome sequencing of our BAFME patients with bioinformatics software focusing on tandem repeat copy number changes may help resolve this proposition.

References: ISHIURA, H., DOI, K., MITSUI, J., et al. 2018. Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat Genet, 50, 581-590.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/intronic-pentanucleotide-tttca-repeat-insertions-do-not-cause-familial-and-sporadic-cortical-myoclonic-tremor-with-epilepsy-in-the-uk/