Ascertaining a diagnosis through exome sequencing can provide potential benefits to patients, insurance companies, and the healthcare system. Yet, as diagnostic sequencing is increasingly employed, vast amounts
of human genetic data are produced that need careful curation. We discuss methods for accurately assessing the
clinical validity of gene–disease relationships to interpret
new research findings in a clinical context and increase the
diagnostic rate. The specifics of a gene–disease scoring system adapted for use in a clinical laboratory are described.
In turn, clinical validity scoring of gene–disease relationships can inform exome reporting for the identification of
new or the upgrade of previous, clinically relevant gene
findings. Our retrospective analysis of all reclassification
reports from the first 4 years of diagnostic exome sequencing showed that 78% were due to new gene–disease discoveries published in the literature. Among all exome positive/likely positive findings in characterized genes, 32%
were in genetic etiologies that were discovered after 2010.
Our data underscore the importance and benefits of active
and up-to-date curation of a gene–disease database combined with critical clinical validity scoring and proactive
reanalysis in the clinical genomics era.
