Structural variation (SV) describes a broad class of genetic variation greater than 50 bp in size. SVs can cause a wide range of genetic diseases and are prevalent in rare developmental disorders (DDs). Individuals presenting with DDs are often referred for diagnostic testing with chromosomal microarrays (CMAs) 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, individuals with pathogenic SVs undetectable by conventional analysis often remain undiagnosed. Consequently, we have developed the 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 DDs recruited as part of the Deciphering Developmental Disorders (DDD) study and discovered 63 rare, damaging variants in genes previously associated with DDs missed by standard SNV, indel, or CNV discovery approaches. Clinical review of these 63 variants determined that about half (30/63) were plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21 and 500 bp in size and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.9%. 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 study participants. InDelible provides a framework for the discovery of pathogenic SVs that are most likely missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES across a broad range of genetic diseases.

结构变异 (SV) 描述了一大类大于 50 bp 的遗传变异。SV 可导致多种遗传疾病，并且在罕见的发育障碍 (DD) 中很普遍。患有 DD 的个体通常被转介进行诊断测试，使用染色体微阵列 (CMA) 来识别大拷贝数变异 (CNV) 和/或使用单基因、基因面板或外显子组测序 (ES) 来识别单核苷酸变异、小的插入/删除和 CNV。然而，具有常规分析无法检测到的致病性 SVs 的个体通常仍未确诊。因此，我们开发了工具 InDelible，该工具可查询短读长测序数据以获取 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 63 种罕见的破坏性变异。对这 63 种变异的临床审查确定，大约一半 (30/63) 可能具有致病性。InDelible 在确定大小在 21 到 500 bp 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 42.9%。特别感兴趣的是七个确认 对这 63 种变异的临床审查确定，大约一半 (30/63) 可能具有致病性。InDelible 在确定大小在 21 到 500 bp 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 42.9%。特别感兴趣的是七个确认 对这 63 种变异的临床审查确定，大约一半 (30/63) 可能具有致病性。InDelible 在确定大小在 21 到 500 bp 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 42.9%。特别感兴趣的是七个确认从头在多个变MECP2，这代表了所有的35.0％从头蛋白质，截断变种MECP2 DDD研究的参与者之一。InDelible 为发现标准分析工作流程最有可能遗漏的致病性 SV 提供了一个框架，并有可能提高 ES 对广泛遗传疾病的诊断率。