Hearing loss (HL) affects at least 30% of the population at some time in their lives. While HL has both genetic and environmental underpinnings, the genetic causes of hearing loss are estimated to account for 68% of cases expressed at birth and 55% of those expressed by the age of four. The identification of many genes for HL has dramatically improved the clinical diagnosis and management of deaf and hard-of-hearing families. However, current strategies for genetic testing for deafness are inadequate. Genetic testing currently focuses on testing only a few of the known genes and so in many cases, the genetic cause is never determined. The identification of numerous genes causing NSHL along with recent technological advances in "target-enrichment" methods and next generation sequencing (NGS) is now making possible molecular epidemiological studies of genetic deafness and a new wave of discoveries of the remaining genes for genetic diseases. The translation of this knowledge to patient care is, however, lagging behind. Currently, few available databases have useful evidence-based information concerning the clinical validity and clinical utility of genetic information for deafness patient management. There is an urgent need to bring comprehensive genomic information of individual patients into the "real world" clinical environment. We have collected a unique cohort of multiplex families derived from three unique sources from USA, China and Turkey, suitable for determination of molecular epidemiology of hereditary deafness and for new gene identification. We have established the Miami Otogenetic Program including the Molecular Genetic Laboratory and the Hereditary Hearing Loss Clinic. Importantly, as shown in our preliminary studies, we have shown that it is possible to analyze all deafness genes simultaneously on a single platform, excluded known causes of HL in 40% of the probands in our pilot studies and successfully identified three new genes in these small multiplex families using whole exome sequencing. Building on these preliminary data in this translational proposal we will complete three specific aims. 1: To determine molecular epidemiology of deafness-causing mutations in known NSHL genes by completing mutation screening of all genes causing NSHL in a large cohort of probands from different ethnic populations. 2: To identify new genes for non-syndromic hearing loss in those multiplex families found to be negative for all known deafness genes by whole exome sequence. 3: To create Genomic Deafness Database (GDD) and Personalized Sequence Profile (PSP) for care of deafness patients.

Public Health Relevance

Completion of the proposed aims will to 1) determine molecular epidemiology of NSHL, 2) lead toward enhanced clinical diagnostics, a biological understanding of a comprehensive list of proteins involved in auditory function, and a potential for development of therapeutics for deafness. PUBLIC HEALTH RELEVANCE: We will develop a comprehensive genetic testing platform and genomic deafness database for clinical care of deaf individuals to: 1) improve the clinical care of deaf and hard of hearing persons;and 2) determine the epidemiology of hereditary hearing loss in the United States. The successful completion of the proposed aims will significantly improve our ability to provide genetic counseling for affected patients/families and to expand our knowledge on the genomic basis of hereditary hearing.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC012115-02
Application #
8634091
Study Section
Special Emphasis Panel (ZDC1-SRB-L (46))
Program Officer
Watson, Bracie
Project Start
2013-03-08
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$613,833
Indirect Cost
$213,942
Name
University of Miami School of Medicine
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Qing, Jie; Yan, Denise; Zhou, Yuan et al. (2014) Whole-exome sequencing to decipher the genetic heterogeneity of hearing loss in a Chinese family with deaf by deaf mating. PLoS One 9:e109178
Mittal, Rahul; Grati, M'hamed; Gerring, Robert et al. (2014) In vitro interaction of Pseudomonas aeruginosa with human middle ear epithelial cells. PLoS One 9:e91885
Vivero, Richard J; Ouyang, Xiaomei; Kim, Yeunjung Grant et al. (2013) Audiologic and genetic features of the A3243G mtDNA mutation. Genet Test Mol Biomarkers 17:383-9
Yan, Denise; Tekin, Mustafa; Blanton, Susan H et al. (2013) Next-generation sequencing in genetic hearing loss. Genet Test Mol Biomarkers 17:581-7