Expert interpretation of genes and variants in hereditary hearing loss

Abstract

Abstract Background: Hearing loss (HL) is the most common sensory deficit from birth, with at least 50 % due to an underlying genetic etiology. A genetic evaluation is a recommended component to the medical workup for HL, and a genetic diagnosis can impact medical management and provide prognostic and recurrence risk information. The accuracy of a genetic diagnosis relies on the evidence supporting the gene–disease relationship, as well as the evidence supporting individual variant classifications. As such, the ClinGen Hearing Loss Working Group was formed and tasked with curating genes associated with genetic hearing loss and developing specifications of the ACMG/AMP variant interpretation guidelines with the goal of improving the genetic diagnosis of patients with HL. Objectives: To describe the prioritization and expert curation of genes and variants associated with HL performed under the purview of the ClinGen Hearing Loss Gene and Variant Expert Panels (HL GCEP and VCEP). Materials and methods: HL genes were taken from clinical testing panels in the Genetic Testing Registry and prioritized based on a nonsyndromic presentation. Variants were taken from ClinVar and those with diverse data types and medically significant conflicts were prioritized to test the specified variant interpretation guidelines and to resolve classification discrepancies, respectively. Conclusions: The ClinGen HL GCEP has curated 174 gene–disease pairs. The HL VCEP has submitted 77 variants, including the previously controversial p.Met34Thr and p.Val37Ile variants in GJB2, into ClinVar, as an FDA-recognized database. Collaboration across clinics and laboratories were crucial to these curations and highlight the impact that data sharing can have on patient care.