Introduction
Genomic technologies have revolutionized medicine in the post-genome era by offering the promise of personalized, precision healthcare based on DNA sequencing.1 Prior to and immediately after the completion of the human genome project, the primary bottleneck in advancing precision medicine was generating DNA sequencing and genetic variant data. With the advent of massively parallel sequencing technologies, the bottleneck shifted to clinically meaningful variant interpretation that is comprehensive, easily understandable, free from contradictory categorization, curated by experts, and freely available to the public. Guidelines developed by the American College of Medical Genetics and Genomics (ACMG) aid classification using a structured framework that defines 28 evidence codes by which to score a variant. There are 20 rules for combining codes to reach one of five conclusions that predict variant effect: pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), or benign (B).2, 3
The challenging and dynamic process of variant interpretation has spurred the creation of two major variant databases—ClinVar4 and the Human Gene Mutation Database (HGMD)5—to catalog the rapidly increasing volume of reported genetic variants. ClinVar is a freely accessible, public database that archives reports of the relationships between variations and phenotypes with varying degrees of supporting evidence. HGMD, a pay-for-access service, is a comprehensive reference database of published germline mutations that are associated with human inherited diseases based on curation of published literature.6 These databases are invaluable resources but because of their broad all-encompassing design, are not disease specific.
Hearing loss is the most common sensory deficit in humans. It affects an estimated 5% of the world’s population (360 million individuals) and in developed countries is most frequently genetic, segregating in a Mendelian fashion in the case of non-syndromic hearing loss (NSHL) or as a complex genetic disease in the case of age-related hearing loss.7 Its clinical evaluation has been facilitated by the use of comprehensive genetic testing with massively parallel sequencing, which has evolved to become the most informative test in the diagnostic evaluation of the hearing-impaired person. A positive diagnosis is made in more than 40% of persons who undergo this type of testing, and to date more than 6,000 mutations in more than 150 genes have been causally implicated in deafness.8 As the number of genes implicated in NSHL has continued to increase, we sought to provide a freely and continually updated comprehensive database to inform variant classification for deafness.
Called the Deafness Variation Database (DVD, see Web Resources), this resource is collated from major public databases. It provides a single classification for each variant based on collected evidence and is curated by experts in genetic hearing loss to provide a single-source guide to variant interpretation. By capitalizing on the wealth of data the DVD provides to assess the genomic and mutational landscape of deafness, we provide a deeper understanding of hereditary hearing loss and the molecular mechanisms at play.