Structural Variation (SV) describes a broad class of genetic variation greater than 50bps in size. SVs can cause a wide range of genetic diseases and are prevalent in rare developmental disorders (DD). Patients presenting with DD are often referred for diagnostic testing with chromosomal microarrays (CMA) to identify large copy-number variants (CNVs) and/or with single gene, gene-panel, or exome sequencing (ES) to identify single nucleotide variants, small insertions/deletions, and CNVs. However, patients with pathogenic SVs undetectable by conventional analysis often remain undiagnosed. Consequently, we have developed the novel tool 'InDelible', which interrogates short-read sequencing data for split-read clusters characteristic of SV breakpoints. We applied InDelible to 13,438 probands with severe DD recruited as part of the Deciphering Developmental Disorders (DDD) study and discovered 64 rare, damaging variants in genes previously associated with DD missed by standard SNV, InDel or CNV discovery approaches. Clinical review of these 64 variants determined that about half (30/64) were plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21-500 bps in size, and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.3%. Of particular interest were seven confirmed de novo variants in MECP2 which represent 35.0% of all de novo protein truncating variants in MECP2 among DDD patients. InDelible provides a framework for the discovery of pathogenic SVs that are likely missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES across a broad range of genetic diseases.

中文翻译：

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检测外显子组测序数据中隐秘的临床相关结构变异可提高发育障碍的诊断率

结构变异 (SV) 描述了一大类大于 50bps 的遗传变异。SVs 可导致多种遗传疾病，并且在罕见的发育障碍 (DD) 中很普遍。出现 DD 的患者通常被转诊进行染色体微阵列 (CMA) 诊断测试以识别大拷贝数变异 (CNV) 和/或单基因、基因面板或外显子组测序 (ES) 以识别单核苷酸变异、小插入/删除和 CNV。然而，具有常规分析无法检测到的致病性 SVs 的患者通常仍未确诊。因此，我们开发了新工具“InDelible”，该工具可查询短读长测序数据，以获取具有 SV 断点特征的拆分读长簇。我们将 InDelible 应用于 13，作为破译发育障碍 (DDD) 研究的一部分，招募了 438 名患有严重 DD 的先证者，并在以前与标准 SNV、InDel 或 CNV 发现方法遗漏的 DD 相关的基因中发现了 64 种罕见的破坏性变异。对这 64 种变异的临床审查确定，大约一半 (30/64) 可能具有致病性。InDelible 在确定大小在 21-500 bps 之间的变异方面特别有效，并将 DDD 在该大小范围内鉴定的潜在致病变异的总数增加了 42.3%。特别令人感兴趣的是 MECP2 中的 7 个已确认的 de novo 变异，占 DDD 患者 MECP2 中所有 de novo 蛋白质截短变异的 35.0%。