Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing

被引：87

作者：

Costain, Gregory ^{[1
]}

Jobling, Rebekah ^{[1
,2
]}

Walker, Susan ^{[3
,4
]}

Reuter, Miriam S. ^{[3
,4
]}

Snell, Meaghan ^{[1
]}

Bowdin, Sarah ^{[1
,5
,6
]}

Cohn, Ronald D. ^{[1
,4
,5
,6
]}

Dupuis, Lucie ^{[1
]}

Hewson, Stacy ^{[1
]}

Mercimek-Andrews, Saadet ^{[1
,4
,6
]}

Shuman, Cheryl ^{[1
,7
]}

Sondheimer, Neal ^{[1
,4
,6
]}

Weksberg, Rosanna ^{[1
,4
,6
]}

Yoon, Grace ^{[1
,6
,8
]}

Meyn, M. Stephen ^{[1
,5
,6
,7
]}

Stavropoulos, Dimitri J. ^{[2
,9
]}

Scherer, Stephen W. ^{[3
,4
,5
,7
]}

Mendoza-Londono, Roberto ^{[1
,5
,6
]}

Marshall, Christian R. ^{[2
,3
,5
,9
]}

机构：

[1] Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON, Canada

[2] Hosp Sick Children, Dept Paediat Lab Med, Genome Diagnost, Toronto, ON, Canada

[3] Hosp Sick Children, Ctr Appl Genom, Toronto, ON, Canada

[4] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON, Canada

[5] Hosp Sick Children, Ctr Genet Med, Toronto, ON, Canada

[6] Univ Toronto, Dept Paediat, Toronto, ON, Canada

[7] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[8] Hosp Sick Children, Div Neurol, Toronto, ON, Canada

[9] Univ Toronto, Lab Med & Pathobiol, Toronto, ON, Canada

来源：

EUROPEAN JOURNAL OF HUMAN GENETICS | 2018年 / 26卷 / 05期

关键词：

OF-FUNCTION MUTATIONS;

D O I：

10.1038/s41431-018-0114-6

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Whole-genome sequencing (WGS) as a first-tier diagnostic test could transform medical genetic assessments, but there are limited data regarding its clinical use. We previously showed that WGS could feasibly be deployed as a single molecular test capable of a higher diagnostic rate than current practices, in a prospectively recruited cohort of 100 children meeting criteria for chromosomal microarray analysis. In this study, we report on the added diagnostic yield with re-annotation and reanalysis of these WGS data similar to 2 years later. Explanatory variants have been discovered in seven (10.9%) of 64 previously undiagnosed cases, in emerging disease genes like HMGA2. No new genetic diagnoses were made by any other method in the interval period as part of ongoing clinical care. The results increase the cumulative diagnostic yield of WGS in the study cohort to 41%. This represents a greater than 5-fold increase over the chromosomal microarrays, and a greater than 3-fold increase over all the clinical genetic testing ordered in practice. These findings highlight periodic reanalysis as yet another advantage of genomic sequencing in heterogeneous disorders. We recommend reanalysis of an individual's genome-wide sequencing data every 1-2 years until diagnosis, or sooner if their phenotype evolves.

引用

页码：740 / 744

页数：5

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