Sensorineural hearing loss (SNHL) is the most prevalent congenital sensory deficit. In over 50% of cases, the cause is genetic. Genetic testing plays an important role in caring for patients with SNHL, as early intervention programs can significantly improve development and quality of life. More than 64 genes have been causally implicated in SNHL without other defects, termed non-syndromic hearing loss (NSHL). Genetic testing currently focuses on testing only a few of these genes and so in many cases, the genetic cause is never determined. This gap in genetic testing is a result of three factors: 1) the relative contribution of these genes to deafness in the United States is not known;2) a large number of 'deafness'genes have not yet been discovered;3) until recently, sequencing technology has been too costly and time-consuming to permit mutation screening of large numbers of genes on a per-person basis. In this study, we propose to address these issues, thereby improving genetic testing for NSHL. In order to address the need for an efficient and comprehensive genetic testing platform for NSHL we are developing a low-cost diagnostic platform in which high-throughput genomic enrichment is paired with next-generation sequencing to interrogate all genes implicated in NSHL in persons with SNHL. In additional to filling a clinical need, this platform will provide epidemiological data on genetic deafness in the USA, which is currently not available. To increase the rate of discovery of new genes important in the biology of hearing and deafness, we will link the diagnostic platform with a gene discovery platform based on protein expression data from hair bundles. In addition, we propose to use functional studies to gain a better understanding of a known deafness gene, TECTA. We will use AudioGene audio profiling to further define genotype-phenotype correlations in DFNA8/12 and determine if this type of deafness is common in the US population. We will clarify, in part, the functional relationship of 1-tectorin with one of its interacting partners, CEACAM16, to improve our understanding of the molecular mechanisms underlying deafness. Completion of the goals of this project will improve the diagnosis for hereditary hearing loss and provide a greater understanding of the genes involved in hearing.
We will develop a comprehensive genetic testing platform using high throughput sequencing technologies 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. We will optimize novel gene discovery using similar technologies, and study in-depth a known deafness-causing gene to provide a better understanding of the molecular mechanisms of deafness and hearing.
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| Ephraim, Sean S; Anand, Nikhil; DeLuca, Adam P et al. (2014) Cordova: web-based management of genetic variation data. Bioinformatics 30:3438-9 |
| Shearer, A Eliot; Eppsteiner, Robert W; Booth, Kevin T et al. (2014) Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am J Hum Genet 95:445-53 |
| Shearer, A Eliot; Black-Ziegelbein, E Ann; Hildebrand, Michael S et al. (2013) Advancing genetic testing for deafness with genomic technology. J Med Genet 50:627-34 |
| Taylor, Kyle R; Deluca, Adam P; Shearer, A Eliot et al. (2013) AudioGene: predicting hearing loss genotypes from phenotypes to guide genetic screening. Hum Mutat 34:539-45 |
| Shearer, Aiden Eliot; Hildebrand, Michael S; Smith, Richard J H (2012) Solution-based targeted genomic enrichment for precious DNA samples. BMC Biotechnol 12:20 |
| Eppsteiner, Robert W; Shearer, A Eliot; Hildebrand, Michael S et al. (2012) Using the phenome and genome to improve genetic diagnosis for deafness. Otolaryngol Head Neck Surg 147:975-7 |
| Eppsteiner, Robert W; Shearer, A Eliot; Hildebrand, Michael S et al. (2012) Prediction of cochlear implant performance by genetic mutation: the spiral ganglion hypothesis. Hear Res 292:51-8 |
| Fattahi, Zohreh; Shearer, A Eliot; Babanejad, Mojgan et al. (2012) Screening for MYO15A gene mutations in autosomal recessive nonsyndromic, GJB2 negative Iranian deaf population. Am J Med Genet A 158A:1857-64 |
| Shearer, A Eliot; Hildebrand, Michael S; Ravi, Harini et al. (2012) Pre-capture multiplexing improves efficiency and cost-effectiveness of targeted genomic enrichment. BMC Genomics 13:618 |
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