Tandem repeat screening by long read single molecule sequencing reveals XLID25 expansion as a candidate XLID allele

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.

尽管已通过阵列比较基因组杂交（array comparative genomic hybridization, aCGH）、全外显子组测序或全基因组测序等技术开展检测，但仍有超过半数的X连锁智力障碍（X-linked intellectual disability, XLID）患者的致病病因尚不明确。由于短读长大规模平行测序技术无法检出较大的串联重复扩张，我们推测此类重复扩张可能是X连锁智力障碍的隐匿致病因素。本研究针对X染色体上的1800余个串联重复序列进行了靶向捕获，并利用长读长单分子测序技术对3个特发性X连锁智力障碍家系的靶标序列进行了特征分析。在其中一个家系中，某一重复扩张与邻近的MIR222基因表达下调共同发生。该基因此前已被证实与智力障碍相关，其间接作用可引发与神经系统疾病相关的FMR1及NEFH基因过表达。本研究证实了单分子测序技术在测定串联重复序列长度、检测重复扩张方面的应用价值，并提示串联重复突变可能是X连锁智力障碍的一类隐匿致病原因。