Tandem repeat screening by long read single molecule sequencing reveals XLID25 expansion as a candidate XLID allele. Tandem repeat sequencing in X-linked intellectual disability

The etiology of more than half of all patients with X-linked intellectual disability (XLID) remains elusive, despite aCGH, whole exome or genome sequencing. Since short read massive parallel sequencing approaches do not allow the detection of larger tandem repeat expansions, we hypothesized that such expansions could be a hidden cause of XLID. We selectively captured over 1800 tandem repeats on the X chromosome and characterized them by long read single molecule sequencing in 3 idiopathic XLID families. In one family, one repeat expansion co-occurs with down-regulation of the neighboring MIR222 gene. This gene has previously been implicated in ID and, indirectly, leads to FMR1 and NEFH overexpression associated with neurological disorders. This study demonstrates the power of single molecule sequencing to measure tandem repeat lengths and detect expansions, and suggests that TR mutations are a hidden cause of XLID.