Recent advances in the molecular genetics of deafness have vastly improved our ability to identify heritable hearing losses and have had several important consequences. First, the use of genetic testing to diagnose non-syndromic hearing loss (NSHL) has changed the medical evaluation of the deaf / hard-of-hearing person - after a history, physical examination and audiogram, genetic testing has become the next test ordered in the care of patients with presumed hereditary hearing impairment. Second, the identification of nearly one hundred genes that cause NSHL, coupled with technological advances in sequence capture and deep sequencing, has made robust epidemiological studies of genetic deafness possible for the first time. Third, understanding the genetic basis for normal auditory function is providing insight into inner ear physiology at the molecular level that will lad one day to the development of novel gene-specific and even mutation-specific therapies to treat hearing loss. Over the past granting period, we have focused on the following three specific aims: (1) To identify novel genetic causes of autosomal recessive non-syndromic hearing loss (ARNSHL); (2) To complete mutation screening of the coding sequence of all genes implicated in NSHL; (3) To study the Pendred syndrome / DFNB4 disease spectrum. In this competitive renewal, we will build on these accomplishments by completing the following specific aims:
Specific Aim 1. To identify genetic mutations in regulatory elements that contribute to NSHL Hypothesis. Mutations in regulatory elements contribute to NSHL. These mutations can be identified by: a) studying a carefully selected patient population that is enriched for non-coding disease-causing variants and for whom full phenotypic and clinical data are available; and, b) applying targeted sequence capture and massively parallel sequencing to regulatory regions coupled with integrated analysis of murine ChIP-Seq data, ENCODE data and in silico data.
Specific Aim 2. To compare simple and complex haplotypes in two well-defined populations - one with age-related hearing loss and one with normal hearing. Hypothesis. Custom modifications of the Galaxy pipeline make it possible to reconstruct unphased haplotypes for all NSHL genes included on OtoSCOPE(R). By studying two well-defined populations, one with and the other without age-related hearing loss, we will be able to identify at-risk and protective haplotypes and haplotype combinations that are associated with age-related hearing loss. The successful completion of these aims will have a major impact on our understanding of genetic deafness and offer novel insights into how specific protein-protein interactions contribute to age-related hearing loss.
This competitive renewal is focused on two questions germane to non-syndromic hearing loss: 1) the identification of non-coding deafness-causing mutations in regulatory elements, with a particular focus on promoters; and, 2) the evaluation of simple and complex haplotypes as contributing factors to age-related hearing loss (ARHL). The successful completion of these aims will have a major impact on our understanding of the genetics of hearing loss and offer novel insights into how specific protein-protein interactions contribute to ARHL.
| 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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