PURPOSE Reanalysis of exome sequencing data when results are negative may yield additional diagnoses. We sought to estimate the contribution of clinical geneticists to the interpretation of sequencing data of their patients. METHODS The cohort included 84 probands attending a tertiary genetics institute (2015-2018) with a nondiagnostic result on clinical exome sequencing performed in one of five external laboratories. The raw data were uploaded to the Emedgene bioinformatics and interpretation platform for reanalysis by a team of two clinical geneticists, the geneticist directly involved in the patient's care, and a bioinformatician. RESULTS In ten probands (11.9%), a new definitive diagnosis was reached based on genes that were known to be associated with the phenotype at the time the original report was issued. The main reasons for a negative exome result were incorrect interpretation of the clinical context and absence of OMIM entry. Pathogenic variants in genes with previously unknown gene-disease associations were discovered to be causative in three probands. In total, new diagnoses were established in 13/84 individuals (15.5%). CONCLUSION Direct access to complete clinical data and shortening of time to including gene-phenotype associations in databases can assist the analytics team and reduce the need for additional unnecessary tests.

中文翻译：

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在参与测试个体医疗保健的临床遗传学家重新评估原始数据后，通过外显子组测序改进诊断。

目的 当结果为阴性时，重新分析外显子组测序数据可能会产生额外的诊断。我们试图估计临床遗传学家对其患者测序数据解释的贡献。方法 该队列包括 84 名先证者，他们就读于一家三级遗传学研究所（2015-2018 年），在五个外部实验室之一进行的临床外显子组测序结果未确诊。原始数据被上传到 Emedgene 生物信息学和解释平台，由两名临床遗传学家、直接参与患者护理的遗传学家和一名生物信息学家组成的团队进行重新分析。结果 在 10 名先证者 (11.9%) 中，基于在发布原始报告时已知与表型相关的基因得出了新的明确诊断。阴性外显子组结果的主要原因是对临床背景的错误解释和没有 OMIM 条目。在三个先证者中发现具有先前未知的基因-疾病关联的基因中的致病变异是致病的。总共有 13/84 人（15.5%）建立了新的诊断。结论 直接访问完整的临床数据并缩短将基因-表型关联纳入数据库的时间可以帮助分析团队并减少对额外不必要测试的需求。