As a more efficient test, WGS is poised to replace targeted NGS or WES and chromosomal microarray (CMA), as a first-line laboratory approach in the evaluation of children and adults with a suspected genetic disorder 28, 32, 33. Several studies have demonstrated the advantages of WGS for the identification of clinically relevant variants in a wide range of cohorts 22, 23, 24, 25, 26, and have shown the diagnostic superiority of WGS compared with conventional testing in pediatric patients 27, 28, 29 and critically ill infants 30, 31. Emerging uses of WGS include HLA genotyping 19, pharmacogenetic testing 20, and generation of polygenic risk scores 21. WGS also enables the identification of noncoding variants, such as pathogenic variations disrupting regulatory regions, noncoding RNAs, and mRNA splicing 16, 17, 18. Whole-genome sequencing (WGS) can address many of the technical limitations of other enrichment-based NGS approaches, including improved coverage 13, 14, and sensitivity for the detection of structural and complex variants 15. These approaches, however, have both workflow and test content limitations that may constrain their overall efficacy. Targeted NGS multigene panels have come into widespread use and whole-exome sequencing (WES) is a powerful aid in the diagnosis of patients with nonspecific phenotypic features 6, 7, 8, 9, 10 and critically ill neonates 11, where the differential diagnosis often includes multiple rare genetic disorders 12. 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.Īdvances in next-generation sequencing (NGS) over the past decade have transformed genetic testing by increasing diagnostic yield and decreasing the time to reach a diagnosis 1, 2, 3, 4, 5. 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. 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. Here, we present consensus recommendations on clinical WGS analytical validation for the diagnosis of individuals with suspected germline disease with a focus on test development, upfront considerations for test design, test validation practices, and metrics to monitor test performance. To address these gaps, the Medical Genome Initiative, a consortium of leading healthcare and research organizations in the US and Canada, was formed to expand access to high-quality clinical WGS by publishing best practices. 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. Npj Genomic Medicine volume 5, Article number: 47 ( 2020) Best practices for the analytical validation of clinical whole-genome sequencing intended for the diagnosis of germline disease

Ngs sequence analysis