Project Summary Hearing loss is the most common sensory deficit in humans. It affects more than 360 million people worldwide and broadly impacts their quality of life. Although causality is multifactorial, in developed countries a large fraction of hearing loss is genetic and non-syndromic, i.e. not associated with other phenotypes. During the prior granting period (12/01/16-11/20/21), we focused on three specific aims: 1) To optimize phenotype-genotype integration in the analysis of hereditary hearing loss by implementing hierarchical surface clustering and audioprofile surface analysis in AudioGene; 2) To explore physics-based protein modeling as a tool within the Deafness Variation Database; and 3) To determine whether genetic modifiers of specific deafness-causing genes can be predicted by hierarchical surface clustering In this competitive renewal, our overarching goals are to further improve the clinical care of persons with hearing loss and to provide a more robust foundation for gene-specific precision medicine for this population. We will achieve these goals by addressing current knowledge gaps as reflected in the following specific aims: Specific Aim 1. To complete gene-specific natural history studies (NHS) of non-syndromic forms of hearing loss by integrating phenotypic and genotypic data using AudioGene and OtoSCOPE Hypothesis: The natural history of non-syndromic hearing loss is gene specific and can be defined by integrating the hearing loss phenotype (phenome) with the associated genotype (genome) for the various types of non-syndromic hearing loss. Specific Aim 2. To refine ACMG guidelines for hearing loss by making them gene specific and by implementing a combination of deep learning and physics-based protein modeling to improve variant classification Hypothesis: While general guidelines exist for variant classification, guidelines that are disease- specific and even within a disease, gene specific, will facilitate variant annotation. In particular, variant calling for missense variants can be refined by applying deep learning and physics-based modeling to predict free-energy changes associated with missense variants. Specific Aim 3. To identify genetic modifiers of select types of non-syndromic hearing loss Hypothesis: The presence of genetic modifiers is supported by gene-specific differences in ethnically- based population studies and can be validated using murine models of hearing loss. The successful completion of these specific aims will refine our understanding of the biology of hearing and deafness, improve the clinical care of persons with hearing loss, provide a strong foundation for gene- based precision medicine for the hearing impaired, facilitate the design of clinical trials to test novel therapies to treat gene-specific types of hearing loss, and potentially identify new targets for gene therapy for deafness.