BACKGROUND Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. METHODS Of the 101 WES cases, 51 were rare idiopathic disease cases and 50 were postmortem "molecular autopsy" cases of early sudden unexplained death. Variants considered for reporting were prioritized and classified into three groups: (1) diagnostic variants, pathogenic and likely pathogenic variants in genes known to cause the phenotype of interest; (2) possibly diagnostic variants, possibly pathogenic variants in genes known to cause the phenotype of interest or pathogenic variants in genes possibly causing the phenotype of interest; and (3) variants of uncertain diagnostic significance, potentially deleterious variants in genes possibly causing the phenotype of interest. RESULTS Initial analysis revealed diagnostic variants in 13 rare disease cases (25.4%) and 5 sudden death cases (10%). Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%), which increased our molecular diagnostic yield to 31.4% and 12%, respectively. CONCLUSIONS The basis of new findings ranged from improvement in variant classification tools, updated genetic databases, and updated clinical phenotypes. Our findings highlight the potential for re-analysis to reveal diagnostic variants in cases that remain undiagnosed after initial WES.

中文翻译：

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对全外显子组测序数据的重新分析发现了新颖的诊断变异，并提高了猝死和特发性疾病的分子诊断率。

背景技术全外显子测序（WES）已成为可能患有单基因疾病（例如罕见的特发性疾病或突然的无法解释的死亡）的患者的有效诊断测试。然而，许多病例仍未得到诊断。在这里，我们报告了在初次分析后1到7年重新分析的101例WES病例获得的增加的诊断率。方法在101例WES病例中，有51例为特发性特发性疾病，有50例为死因不明的早期“死因分子尸检”。优先考虑考虑用于报告的变体，并将其分为三类：（1）诊断性变体，已知会引起目标表型的基因中的致病性和可能的​​致病性变体；（2）可能是诊断变体，已知会引起目标表型的基因中可能的致病性变体或可能导致目标表型的基因中的致病性变体；（3）具有不确定诊断意义的变体，可能是引起目标表型的基因中潜在有害的变体。结果初步分析显示13例罕见病病例（25.4％）和5例猝死病例（10％）的诊断变异。重新分析后，在3例罕见疾病病例（5.9％）和1例原因不明的猝死病例（2％）中鉴定出了其他诊断变异，这使我们的分子诊断率分别提高到31.4％和12％。结论新发现的基础包括变体分类工具的改进，更新的遗传数据库和更新的临床表型。