PDF(Pubmed)
Abstract：
Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.
摘要：
结构变体(SV)的检测目前偏向于改变拷贝数的那些。倒位对遗传疾病的相对贡献尚不清楚。在这项研究中,我们分析了来自100,000基因组计划的33,924个罕见疾病家庭的基因组测序数据.从托管超过5亿个SV的数据库中，我们专注于351个基因，其中单倍体功能不全是已确认的疾病机制，并确定了47个超罕见重排，包括倒置（24bp至36.4Mb，20/47从头)。验证使用了许多正交方法，包括回顾性外显子组分析。RNA-seq数据支持六名参与者的各自诊断。表型混合在四个先证中很明显。诊断异常是一个共同的主题(一个人>50年)，和特定基因的有针对性的分析已经进行了30％的这些个体，但没有发现。我们为基因内MSH2反演提供了欧洲创始人的正式确认。对于两个具有涉及MECP2突变热点的复杂SV的个体，使用长读数测序解决了模糊的SV结构，影响临床解释。在一个患有Kantaputra型中膜发育不良的家庭中发现了HOXD11-13的从头倒置。最后,一个复杂的易位干扰APC并涉及9个重排的节段,证实了3个家庭成员的临床诊断,并解决了一个患有单个息肉的兄弟姐妹的难题.总的来说,倒置在罕见疾病中起着很小但值得注意的作用，可能解释了大约1/750个家庭在不同临床队列中的病因。
