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揭穿奥卡姆剃刀原理：通过全外显子组测序诊断家族中的多种遗传疾病。

Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing.

作者信息

Balci T B, Hartley T, Xi Y, Dyment D A, Beaulieu C L, Bernier F P, Dupuis L, Horvath G A, Mendoza-Londono R, Prasad C, Richer J, Yang X-R, Armour C M, Bareke E, Fernandez B A, McMillan H J, Lamont R E, Majewski J, Parboosingh J S, Prasad A N, Rupar C A, Schwartzentruber J, Smith A C, Tétreault M, Innes A M, Boycott K M

机构信息

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.

出版信息

Clin Genet. 2017 Sep;92(3):281-289. doi: 10.1111/cge.12987. Epub 2017 Mar 13.

DOI:10.1111/cge.12987

PMID:28170084

Abstract

BACKGROUND

Recent 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.

AIMS

We 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 & METHODS: We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives.

RESULTS

Of 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.

CONCLUSION

Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.

摘要

背景

近期临床全外显子组测序（WES）队列研究发现，单例患者中存在意料之外的多种基因诊断结果。然而，家庭中出现多种基因诊断结果的频率在很大程度上尚不清楚。

目的

我们旨在确定在加拿大两项国家级研究项目中接受分析的先证者及其家庭中出现多种基因诊断结果的比例。

材料与方法

我们回顾性分析了过去5年中在“FORGE”或“加拿大Care4Rare WES计划”中接受转诊的802例未确诊先证者的WES结果。

结果

在802例先证者中，226例（28.2%）根据已知疾病基因中的突变得到确诊。8例（3.5%）有两种或更多种基因诊断结果可解释其临床表型，这一比例与已发表的大型研究结果一致（平均4.3%；1.4 - 7.2%）。8例先证者中有7例的家庭成员患有一种或多种分子诊断疾病。近亲结婚和多系统疾病似乎会增加家庭中出现多种基因诊断结果的可能性。