Abstracts

Rationale: Repeat expansions are experiencing increased research interest with multiple novel repeat expansion discoveries in 2018 and 2019, partially facilitated by the development of novel research tools to detect repeat expansions. Of particular relevance to epilepsy is the recent publication of the second repeat expansion that causes epilepsy with the finding that Familial adult myoclonic epilepsy 1 (FAME1) is caused by a TTTCA repeat insertion in intron 4 of SAMD12 in 49 Japanese families (Ishiura et al, 2018). This finding was subsequently extended to 18 Chinese families (Cen et al. 2018).  The precise geographic range of the FAME1 repeat expansion remains unknown. It is important to screen Asian FAME patients for the FAME1 repeat expansion, which can be performed with a repeat-primed PCR assay or, using recently developed bioinformatic analysis tools, which can be applied to generic sequencing data, and may be more easily accessible for some researchers.  Methods: We applied our repeat expansion pipeline and analysis method, exSTRa (Tankard et al. AJHG, 2018, available from: https://github.com/bahlolab/exSTRa), to four affected and one unaffected individual from two families from Sri Lanka and India, who presented with FAME, and underwent whole genome sequencing. We also estimated the time when the repeat expansion occurred using the method from Gandolfo et al. Genetics, 2014.  Results: We demonstrate the ability of our bioinformatic method, exSTRa, to identify repeat expansions by identifying causal FAME1 repeat expansions in all affected individuals in the two families but not the unaffected individuals. These findings were replicated by three other repeat expansion detection tools. We also did not identify any additional repeat expansions at the other known repeat expansion loci, which we also examined. These FAME1 findings were validated with repeat-primed PCR. We estimate that this expansion arose 17,000 years ago.  Conclusions: We demonstrate the efficient identification of FAME1 repeat expansions with novel bioinformatic methods in two families of Sri Lankan and Indian ethnicity, hence extending the geographic range of FAME1 further, beyond Japan and China. These bioinformatic tools can be easily added to standard sequencing analysis pipelines to identify putative repeat expansions, performing a simultaneous analysis of all known repeat expansions, substantially decreasing time and effort usually spent on diagnosing repeat expansions, making use of widely available, standard sequencing platforms.  Funding: No funding