Recent advances in molecular technologies have enhanced our ability to identify genetic forms of hearing losses with several important consequences. First, the incorporation of genetic testing into diagnostic algorithms has improved clinical care for deaf/hard-of-hearing persons. As more deafness-associated genes are identified and incorporated into these panels, further improvements in clinical care will follow. Second, because the genetic spectrum of non-syndromic hearing loss (NSHL) has been better defined, epidemiological studies of genetic deafness are possible. These studies can be used to define knowledge gaps in our understanding of genetic hearing loss. Third, the identification of genes required for normal auditory function provides insight into inner ear physiology at the molecular level. This insight is foundational to the development of novel therapies to treat deafness. During the 09/01/2014-08/31/2019 grant period, we built on prior successes to advance our understanding of NSHL by focusing on two specific aims. ? Specific Aim 1: To identify genetic variants in regulatory elements of deafness-associated genes that contribute to NSHL ? Specific Aim 2. To compare simple and complex haplotypes in two well-defined populations ? one with age-related hearing loss (ARHL) and one with normal hearing ? to identify whether common variants in deafness-associated genes contribute to ARHL In this competitive renewal, our overarching goals are to further improve the clinical care of persons with hearing loss and provide a more robust foundation for therapies that target specific types of genetic hearing loss. We will achieve these goals by addressing current knowledge gaps as reflected in the following specific aims: ? Specific Aim 1: We will identify novel deafness-associated genes Hypothesis: By leveraging whole genome sequencing and structured bioinformatic analyses in carefully selected cohorts, we will optimize our ability to identify novel deafness-associated genes. The role of these genes in the biology of hearing and deafness will be validated using animals models of hearing loss. ? Specific Aim 2: We will resolve hidden heritability and complexity in known deafness- associated genes Hypothesis: A wealth of unidentified and unrecognized complexity lies at the variant level in known deafness-associated genes. Examples include the unrecognized effect of missense variants of low predicted pathogenicity, the pathogenicity of synonymous variants, and the pathogenicity of non-coding variants. The completion of these aims will refine our understanding of the biology of hearing and deafness, improve clinical care for persons with hearing loss, provide a better genetic foundation for precision medicine for the hearing impaired, and identify new targets for gene therapy for deafness.
In Specific Aim 1 of this grant, we will leverage the power of whole genome sequencing and structured bioinformatic analysis to identify novel deafness-associated genes in carefully selected patient cohorts. In Specific Aim 2, we will resolve hidden heritability in known deafness-associated genes by targeted analysis of non-coding regions and select missense and synonymous variants. The completion of these two specific aims will improve the clinical care of persons with hearing loss and provide a foundation for gene therapies that target specific types of genetic deafness.
|Booth, K T; Kahrizi, K; Babanejad, M et al. (2018) Variants in CIB2 cause DFNB48 and not USH1J. Clin Genet 93:812-821|
|Booth, Kevin T; Kahrizi, Kimia; Najmabadi, Hossein et al. (2018) Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non-syndromic hearing impairment. J Med Genet 55:555-560|
|Avenarius, Matthew R; Jung, Jae-Yun; Askew, Charles et al. (2018) Grxcr2 is required for stereocilia morphogenesis in the cochlea. PLoS One 13:e0201713|
|Booth, Kevin T; Askew, James W; Talebizadeh, Zohreh et al. (2018) Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37. Genet Med :|
|Azaiez, Hela; Booth, Kevin T; Ephraim, Sean S et al. (2018) Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. Am J Hum Genet 103:484-497|
|Imtiaz, Ayesha; Belyantseva, Inna A; Beirl, Alisha J et al. (2018) CDC14A phosphatase is essential for hearing and male fertility in mouse and human. Hum Mol Genet 27:780-798|
|Booth, Kevin T; Azaiez, Hela; Kahrizi, Kimia et al. (2018) Exonic mutations and exon skipping: Lessons learned from DFNA5. Hum Mutat 39:433-440|
|Michel, Vincent; Booth, Kevin T; Patni, Pranav et al. (2017) CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival. EMBO Mol Med 9:1711-1731|
|Shearer, A Eliot; Eppsteiner, Robert W; Frees, Kathy et al. (2017) Genetic variants in the peripheral auditory system significantly affect adult cochlear implant performance. Hear Res 348:138-142|
|Lansdon, L A; Bernabe, H V; Nidey, N et al. (2017) The Use of Variant Maps to Explore Domain-Specific Mutations of FGFR1. J Dent Res 96:1339-1345|
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