Fast and reliable detection of repeat expansions in spinocerebellar ataxia using exomes

Usually, molecular diagnosis of spinocerebellar ataxia is based on a step-by-step approach with targeted sizing of four repeat expansions accounting for most dominant cases, then targeted sequencing of other genes. Nowadays, genome sequencing allows detection of most pathogenic variants in a single step. The ExpansionHunter tool can detect expansions in short-read genome sequencing data. Recent studies have shown that ExpansionHunter can also be used to identify repeat expansions in exome sequencing data. We tested ExpansionHunter on spinocerebellar ataxia exomes in a research context as a second-line analysis, after exclusion of main CAG repeat expansions in half of the probands. First, we confirmed the detection of expansions in seven known expansion carriers and then, after targeted analysis of ATXN1, 2, 3 and 7, CACNA1A, TBP, ATN1, NOP56, AR and HTT in 498 exomes, we found 22 additional pathogenic expansions. Comparison with capillary migration sizing in 247 individuals and confirmation of all expanded alleles detected by ExpansionHunter demonstrated that for these loci, sensitivity and specificity reached 100%. ExpansionHunter detected but underestimated the repeat size for larger expansions, and the normal alleles distribution at each locus should be taken into account to detect expansions. Exome combined with ExpansionHunter is reliable to detect repeat expansions in selected loci as first-line analysis in spinocerebellar ataxia.