The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder. Why the incidence of 22q11.2DS is much greater than that of other genomic disorders remains unknown. Short read sequencing cannot resolve the complex segmental duplicon structure to provide direct confirmation of the hypothesis that the rearrangements are caused by nonallelic homologous recombination between the low copy repeats on Chromosome 22 (LCR22s). To enable haplotype-specific assembly and rearrangement mapping in LCR22 regions, we combined fiber-FISH optical mapping with whole genome (ultra-)long read sequencing or rearrangement-specific long-range PCR on 24 duos (22q11.2DS patient and parent-of-origin) comprising several different LCR22-mediated rearrangements. Unexpectedly, we demonstrate that not only different paralogous segmental duplicon but also palindromic AT-rich repeats (PATRR) are driving 22q11.2 rearrangements. In addition, we show the existence of two different inversion polymorphisms preceding rearrangement, and somatic mosaicism. The existence of different recombination sites and mechanisms in paralogues and PATRRs which are copy number expanding in the human population are a likely explanation for the high 22q11.2DS incidence.

中文翻译：

---

多种旁系同源物和重组机制导致 22q11.2 缺失综合征的高发病率


22q11.2 缺失综合征 （22q11.2DS） 是最常见的微缺失疾病。为什么 22q11.2DS 的发病率远高于其他基因组疾病仍是未知数。短读长测序无法解析复杂的节段双倍体结构，无法直接证实重排是由 22 号染色体 （LCR22） 上低拷贝重复序列之间的非等位基因同源重组引起的假设。为了在 LCR22 区域实现单倍型特异性组装和重排映射，我们将光纤-FISH 光学映射与全基因组（超）长读长测序或重排特异性长程 PCR 相结合，对 24 个二重奏 （22q11.2DS 患者和原源父母） 包含几种不同的 LCR22 介导的重排。出乎意料的是，我们证明不仅不同的旁系同源节段双倍体，而且回文 AT 富集重复序列 （PATRR） 都在驱动 22q11.2 重排。此外，我们还展示了在重排之前存在两种不同的倒置多态性和体细胞嵌合体。在人类群体中拷贝数扩大的旁系同源物和 PATRR 中存在不同的重组位点和机制可能是 22q11.2DS 高发病率的可能解释。