Whole genome sequencing (WGS) shows promise as 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 convening experts and publishing best practices. Here, we present best practice recommendations for the interpretation and reporting of clinical diagnostic WGS, including discussion of challenges and emerging approaches that will be critical to harness the full potential of this comprehensive test.
BACKGROUND
Genetic testing frequently identifies variants of uncertain significance (VUSs). Providers, however, are often ill-prepared or too time-constrained to manage these findings, and insurers are concerned about impacts on clinical care and cost. Here we compared the contribution of panel-based and genomic (exome and genome) testing to the generation of inconclusive results due to VUSs.
METHODS
Rates of inconclusive results due to VUS and diagnostic yield were determined from over 1.5 million sequencing test results from 19 clinical laboratories in North America from 2020 - 2021.
RESULTS
We found a lower rate of inconclusive test results due to VUSs from genomic tests (22.5%) compared to multi-gene panel tests (32.6%; p<0.001) and a higher diagnostic yield (17.5% vs 10.3%; p<0.001). For panel tests, the rate of inconclusive results correlated with panel size. The use of trios improved yield (19.5% vs 15.2%; p<0.001) and reduced inconclusive rates (18.9% vs 27.6%; p<0.001). The use of genome sequencing compared to exome improved yield (25.1% vs 16.6%; p<0.001) without increasing the rate of inconclusive results (22.2% vs 22.6%).
CONCLUSION
Genomic sequencing demonstrated reduced uncertainty and higher molecular diagnostic yield compared to panel testing. This difference is best explained by obligatory reporting of all VUSs in panel-based testing compared to genomic testing where correlation with phenotype is used to constrain variant reporting. These results may inform future genetic testing practices and heighten appreciation for the professional skills involved in genomic test interpretation.
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