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Genetic and epigenomic determinants of hearing loss in Hispanic populations

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ABSTRACT Sensorineural hearing loss (SNHL) is a leading cause of disability and affects ~1.4 billion people globally, including different age groups and ethnicities. Although around 150 genes have been identified for SNHL, the Hispanic population remains understudied for SNHL, with most Hispanic studies focused on a single gene GJB2. A few countries studied ? Chile, Mexico/Hispanic-American, Nicaragua, the Philippines ? have a low prevalence of GJB2 variants, suggesting that SNHL cohorts from these countries have novel genes or variants for discovery. Additionally, Hispanic children are at risk for environmental exposures to chemicals that may lead to epigenetic modifications and cause SNHL. Our overarching hypothesis is that SNHL has a unique, population-specific allelic and epigenetic spectrum in Hispanic-descent populations. We assembled an international group of researchers with complementary expertise in otology, genetics, epigenomics and functional genomics, with previous collaborative experience that signals this project will be highly productive. In our previous studies, we identified novel variants in Hispanic-American and Filipino patients with SNHL, including genetic variants that were associated with temporal bone anomalies and predictive of cochlear implant outcomes. Nicaraguan families were submitted for exome sequencing and were negative for variants; these families likely harbor non-coding variants or have epigenetic mechanisms of SNHL. We have in place efficient pipelines for the identification of novel SNHL genes in families and differentially methylated regions (DMRs) in case-control cohorts, as well as validation methods in animal models and epithelial cells. Our goal is to determine genetic and epigenetic risk factors in Hispanic children with SNHL. For Aim 1, we will identify SNHL variants from next-generation sequence data using a tiered approach, which includes Sanger sequencing, filtering, homozygosity mapping, linkage analysis and transmission disequilibrium tests. We will recruit 500 Hispanic families, including large families sufficient for genome-wide significant linkage, and submit DNA samples to sequencing and analyses. Novel SNHL genes and variants identified in these families will be followed up with protein localization and hearing studies in mouse and zebrafish models and mutation constructs in epithelial cells. For Aim 2, we will perform an epigenome-wide association study by profiling the methylome of a well-powered cohort of 500 SNHL probands and 500 hearing children matched by age, sex and population, in order to identify DMRs that are associated with SNHL. For the top identified DMRs, we will utilize CRISPR-dCas9 technology on epithelial cells to determine if targeting the methylation site will affect gene expression. Integration of methylation profiles and genetic data using methylation quantitative trait locus analysis will aid in understanding genetic vs. environmental contributions to SNHL. Overall this project will impact genetic screening protocols and genetic counseling particularly in Hispanic populations, as well as improve understanding of the hearing mechanism and lead to new targets for the development of treatment of SNHL.
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