Hearing loss is the most common sensory deficit in humans. It is diagnosed in 1 in 500 newborns and affects half of all octogenarians. 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, we implemented and integrated comprehensive genetic testing as a cornerstone in the evaluation of the deaf and hard-of-hearing person. The American College of Medical Genetics has recognized the merit of this approach, and in 2014 included comprehensive genetic testing for the evaluation of deafness in their newest treatment guidelines. In the largest study to date to corroborate this decision, we found an underlying genetic cause for hearing loss in 440 (39%) of 1119 sequentially accrued patients chosen without exclusion criteria. Pathogenic variants were present in 49 genes and included missense variants (49%), copy number changes (18%), indels (18%), nonsense variants (8%), splice-site alterations (6%) and promoter variants (<1%), making comprehensive genetic testing the single best test to order in the diagnosis of hearing loss after an audiogram. In this competitive renewal, we will build on these accomplishments by completing the following aims: ? Specific Aim 1: To optimize phenotype-genotype integration in the analysis of hereditary hearing loss by refining the use of hierarchical surface clustering and audioprofile surface analysis to determine which types of genetic hearing loss are associated with clinically meaningful sub-clusters ? Specific Aim 2: To validate and integrate physics-based protein modeling as a tool within the Deafness Variation Database to predict variant effect and the molecular and patient phenotype ? Specific Aim 3: To identify genetic modifiers of specific deafness-causing genes predicted by hierarchical surface clustering and validated by physics-based potential free-energy modeling The successful completion of this grant will improve the clinical care of persons with hearing loss by enhancing phenome-genome integration and by making variant interpretation more robust. Knowledge gained from this proposal will also lay the foundation for refined studies focused on the identification of genetic modifiers ? both positive and negative ? associated with complex phenotypes such as noise- induced and age-related hearing loss.
This competitive renewal addresses the increasingly daunting challenge of variant interpretation. We will seamlessly integrate AudioGene into the OtoSCOPE pipeline, explore hierarchical surfaces clustering at all loci, enhance the utility of the Deafness Variation Database by adding physics-based potential free-energy modeling, and using these tools, identify genetic modifiers of select types of genetic hearing loss. The completion of these aims will lay the foundation for more refined studies focused on the identification of genetic modifiers ? both positive and negative ? associated with complex hearing loss phenotypes including noise-induced and age-related hearing loss.
|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|
|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|
|Korver, Anna M H; Smith, Richard J H; Van Camp, Guy et al. (2017) Congenital hearing loss. Nat Rev Dis Primers 3:16094|
|Kemerley, Andrew; Sloan, Christina; Pfeifer, Wanda et al. (2017) A novel mutation in ACTG1 causing Baraitser-Winter syndrome with extremely variable expressivity in three generations. Ophthalmic Genet 38:152-156|
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