Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing
Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing
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DOI：
10.1111/cge.12987
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发表时间：
2017-09-01
影响因子：
3.5
通讯作者：
Boycott, K. M.
中科院分区：
文献类型：
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作者：
Balci, T. B.;Hartley, T.;Boycott, K. M.
背景最近的临床全外显子组测序（WES）队列已经在单个患者中发现了意料之外的多个遗传诊断。然而，在这方面，在加拿大的两个国家研究计划中，我们着手确定先证者及其家庭中多重基因诊断的比率，以供分析。方法我们回顾性分析了过去5年中在FORGE或Care 4 Rare Canada WES计划中提到的802例未确诊先证者的WES结果。先证者中，226例（28.2%）是根据已知疾病基因的突变进行诊断的。8例（3.5%）有两个或更多的基因诊断解释了他们的临床表型，这一比例与大型发表的研究（平均4.3%; 1.4 - 7.2%）保持一致。8个先证者中有7个的家庭成员患有一种或多种分子诊断疾病。血缘关系和多系统疾病出现在一个家庭中的多个遗传diagnosis的可能性增加。ConclusionOur研究结果突出了全面的临床表型的家庭成员，最终提供准确的遗传咨询的重要性。
BackgroundRecent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown.AimsWe set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada.Materials & MethodsWe retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives.ResultsOf the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family.ConclusionOur findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.