Analytical Validation of Clinical Whole Genome Sequencing for Germline Disease Diagnostics: Best Practices and Performance Standards
Marshall CR, Chowdhury S, Taft RJ, Lebo MS, Buchan JG, Harrison SM, Rowsey R, Klee EW, Liu P, Worthey EA, Jobanputra V, Dimmock D, Kearney HM, Bick D, Kulkarni S, Belmont JW, Stavropoulos DJ, Lennon NJ, on behalf of the Medical Genome Initiative.
Whole-genome sequencing (WGS) has shown promise in becoming a first-tier diagnostic test for patients with rare genetic disorders, however, standards addressing the definition and deployment practice of a best-in-class test are lacking. To address these gaps, the Medical Genome Initiative, a consortium of leading health care and research organizations in the US and Canada, was formed to expand access to high quality clinical WGS by publishing best practices. Here, we present consensus recommendations on clinical WGS analytical validation with a focus on test development, upfront considerations for test design, test validation practices, and metrics to monitor test performance. This work also provides insight into the current state of WGS testing at each member institution, including the utilization of reference and other standards across sites. Importantly, members of this Initiative strongly believe that clinical WGS is an appropriate first-tier test for patients with rare genetic disorders and at minimum is ready to replace chromosomal microarray analysis and whole-exome sequencing. The recommendations presented here should reduce the burden on laboratories introducing WGS into clinical practice and support safe and effective WGS testing for diagnosis of germline disease.
Rare Disease Statistics
Up to 3.5-5.9%
of the population worldwide is affected by a rare disease (RD).1-6
rare diseases have been identified.1,3,6,7
Among rare diseases listed by Orphanet,
~80% are either exclusively genetic or have genetic subtypes.8
Half of Rare Disease cases impact children
and 30% of children affected by a RD will not survive beyond the age of 5 years.3,6
The average diagnostic odyssey lasts approximately
Average healthcare cost per discharge is
in patients with a confirmed genetic diagnosis or other indicators of genetic disease compared to those without.11
For critically ill infants with a Rare Disease, a rapid diagnosis can be critical for timely and appropriate medical intervention.
An early diagnosis can prevent a long, expensive diagnostic journey.12-15
Genetic Testing Approaches for Rare Disease Diagnosis
Current standard of care for rare disease may include single gene testing, multi-gene panel testing, chromosomal microarray (CMA) and/or whole-exome sequencing (WES).
Whole genome sequencing (WGS) is the only test that can detect nearly all types of genetic variants. (Table 1) 16,17
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- Chen, X., Schulz-Trieglaff, O., Shaw, R., et al. Manta: Rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics, 2016;32(8):1220–1222. http://doi.org/10.1093/bioinformatics/btv710
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