Hereditary hearing impairment accounts for >50% of severe childhood deafness. It can be associated with other inherited clinical features to form a recognized phenotype or occur in isolation. The latter type is more common and is referred to as non-syndromic hearing loss. Usually inherited in a recessive fashion (autosomal recessive non-syndromic hearing loss, ARNSHL), epidemiological studies strongly implicate monogenic, though heterogeneous, disease loci, the number of which may exceed 100. Paradoxically although the number of genes is numerous, recessive inheritance has severely hampered localization efforts. Large single families suitable for linkage analysis are not common and pooling multiple small families is not feasible. Only seven genes responsible for ARNSHL have been reported, and none has been cloned. Endogamous populations were used in three instances, and small consanguineous families, in four.
The specific aims of this grant are to localize ARNSHL genes by homozygosity mapping in multiplex consanguineous families, to identify candidate ARNSHL genes by direct cDNA selection, to demonstrate mutations in candidate genes, and to offer genetic counseling to families. By localizing many of the relevant ARNSHL genes and cloning the more common ones, this research will lead to a better understanding of hereditary hearing impairment in the United States. Appropriate mouse mutants will be identified, permitting studies in development, gene-gene interactions, and ultimately, therapeutic intervention.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Hearing Research Study Section (HAR)
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University of Iowa
Schools of Medicine
Iowa City
United States
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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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