Certain classes of genetic variation still escape detection in clinical sequencing analysis. One such class is retroelement insertion, which has been reported as a cause of Mendelian diseases and may offer unique therapeutic implications. Here, we conducted retroelement profiling on whole-genome sequencing data from a cohort of 237 individuals with ataxia telangiectasia (A-T). We found 15 individuals carrying retroelement insertions in , all but one of which integrated in noncoding regions. Systematic functional characterization via RNA sequencing, RT-PCR, and/or minigene splicing assays showed that 12 out of 14 intronic insertions led or contributed to ATM loss of function by exon skipping or activating cryptic splice sites. We also present proof-of-concept antisense oligonucleotides that suppress cryptic exonization caused by a deep intronic retroelement insertion. These results provide an initial systematic estimate of the contribution of retroelements to the genetic architecture of recessive Mendelian disorders as ∼2.1%–5.5%. Our study highlights the importance of retroelement insertions as causal variants and therapeutic targets in genetic diseases.

中文翻译：

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逆向元件插入对共济失调毛细血管扩张的贡献和治疗意义

某些类别的遗传变异仍然无法在临床测序分析中检测到。其中一类是逆转录元件插入，据报道它是孟德尔疾病的一个原因，并且可能提供独特的治疗意义。在这里，我们对 237 名毛细血管扩张性共济失调 (AT) 患者的全基因组测序数据进行了逆元件分析。我们发现 15 个个体携带逆转录元件插入，除了一个之外，所有个体都整合在非编码区。通过 RNA 测序、RT-PCR 和/或小基因剪接测定进行的系统功能表征表明，14 个内含子插入中有 12 个通过外显子跳跃或激活隐秘剪接位点导致或促成 ATM 功能丧失。我们还提出了概念验证的反义寡核苷酸，可抑制由深层内含子逆转录元件插入引起的隐秘外显化。这些结果提供了逆转录因子对隐性孟德尔疾病遗传结构贡献的初步系统估计，约为 2.1%–5.5%。我们的研究强调了逆转录元件插入作为遗传疾病的因果变异和治疗靶点的重要性。