Project Description Hearing loss is the most prevalent sensory deficit in humans. Half of all cases of early onset hearing loss in developed countries have a genetic etiology, with single gene mutations in over 100 different loci identified so far. Mutations in the majority of these genes result in nonsyndromic sensorineural hearing loss, where abnormal inner ear function is the only diagnostic feature. In comparison to children, the genetic causes of hearing loss in adults are less well understood. Approximately, 80% of hearing loss cases are diagnosed after the second decade of life and yet, adults are rarely tested for genetic mutations as a possible cause of their condition. To help address this gap in knowledge our research seeks to elucidate the unexplained genetic underpinnings of adult-onset hearing loss, focusing on rare coding variants within established and undiscovered hearing loss genes. Taking advantage of a genome first approach in a hospital-recruited biobank cohort and functional studies in mice we identified ZNF175, and its mouse orthologue Zfp719, as a novel adult onset hearing loss gene. ZNF175/Zfp719 is a member of a large family of Krüppel-associated box zinc-finger proteins that bind DNA and silence target gene expression, including transposable elements and host genes, through the formation of heterochromatin. Our preliminary data indicate that Zfp719 mutant mice exhibit several inner ear pathologies, including synaptopathy, hair cell dysfunction, and hair cell degeneration that progress with age and hearing loss severity in a gene dosage-dependent manner. The overarching goal of experiments in this proposal is to identify the genomic targets of Zfp719 mediated heterochromatin silencing, and determine the pathogenic consequences of their misregulation on ribbon synapses, ion homeostasis, and innate immunity. Importantly, since dysfunction in each of these auditory processes has been implicated in adult onset hearing loss, our studies are likely to provide a better general understanding of this condition. Moreover, the outcome of these efforts may lead to the identification of new drug and gene-based therapies for hearing loss prevention and enable screening of high-risk individuals at an earlier age who might benefit from preventative and restorative treatment options.