Gene and Variant Curation Expert Panels for Hearing Loss

Indiana University Indianapolis, Indianapolis IN

Investigators

Abstract

ABSTRACT Hearing loss (HL) is the most common sensory disorder worldwide, with significant genetic, allelic, and phenotypic heterogeneity. Due to its complexity, HL presents many challenges in diagnosis, management, and treatment, with over 220 genes and 16,000 variants implicated in its nonsyndromic and common syndromic forms. The Hearing Loss Clinical Domain Working Group (HL-CDWG) established within the Clinical Genome Resource (ClinGen) has addressed these challenges through the curation of gene-disease relationships (GDRs) and assessment of the pathogenicity of variants associated with HL to enhance the diagnostic accuracy and clinical care of persons with HL. This work is particularly timely, given the rapidly increasing number of genes identified for clinical testing and ongoing clinical trials for genetic HL. The HL-CDWG is an international, multidisciplinary team of over 50 members from 40 institutions across six continents, specializing in the key areas of expertise with representation of research, clinical practice, and diagnostic laboratories. This group consists of HL experts - geneticists, basic research scientists, auditory biologists, otolaryngologists, audiologists, and genetic counselors - along with gene curation framework experts and biocurators ensuring a comprehensive approach to addressing genetic HL. The HL-CDWG is structured into the HL Gene Curation Expert Panel (GCEP) and the HL Variant Curation Expert Panel (VCEP). These panels have collaborated to refine the evidence supporting GDRs and variant classification. In this proposal, we will build upon and expand the activities of the HL-CDWG. In Aim 1, we will thoroughly curate the evidence supporting GDRs and quantify their strength using the ClinGen framework. In Aim 2, we will develop standardized, evidence-based gene-specific variant classification guidelines specifically tailored to each gene's mutational signature and molecular mechanism. We will prioritize genes targeted in gene therapy-based clinical trials and those with pleiotropic effects. This effort enhances the precision of genetic testing and interventions, aligns with successful clinical trials for genetic HL, and marks a pivotal step towards precision medicine. The work of the Hl-GCEP and VCEP will be disseminated through publications, webinars, and workshops at meetings targeted at the clinical and research communities in otolaryngology and the broader genetic community. This strategy ensures the effective implementation of an evidence-based framework and practices to enhance patient care and improve health-related outcomes and aligns perfectly with the 2023-2027 strategic plan of the National Institute on Deafness and Other Communication Disorders.