More than 60% of prelingual deafness is genetic in origin, and of these up to 93% are monogenic autosomal recessive traits. Some forms of genetic deafness can be recognized by their associated syndromic features, but in most cases, hearing loss is the only abnormality. While causal mutations have been identified in one of 31 different genes in a subset of patients with non-syndromic autosomal recessive sensorineural hearing loss, at least 40% of families do not have an identifiable mutation nor do they demonstrate linkage to any known gene. Moreover, the distribution of recognized genetic causes in different populations as well as mutation specific phenotypes remains unknown. Recent advances in molecular technologies provide unprecedented opportunities to genotype dense arrays of SNP markers throughout the genome and to sequence large segments of the human genome with ease. Turkey provides a very valuable resource for the identification of new genes for deafness because it has been continually inhabited since ancient times and much of the population still lives in about 40,000 small villages throughout the country, where consanguinity is the cultural norm. There is also a high level of assortative mating among the deaf and a very long history of the use of sign language in specific areas of Turkey. All of these factors are known to have a profound influence on the survival, expression and spread of new mutations for deafness. We have ascertained 247 inbred multiplex Turkish families with autosomal recessive non-syndromic hearing loss. We will recruit >100 additional families with the same characteristics which will lead to creation of an excellent repository that can be used to identify many of the remaining genes for autosomal recessive non-syndromic deafness. After exclusion of common known genes, we will have ~150 families to discover and confirm new genes for deafness. We will use genome wide dense SNP arrays to find new loci for deafness and identify causative mutations with either traditional or next-generation sequencing. We have already discovered a new deafness gene in one family using the proposed strategy, clearly demonstrating the utility of this invaluable resource. The Repository will be made available to external investigators upon completion of this proposal.
This project is a collaborative study of genetic deafness involving investigators from the United States and Turkey. The goals of the project are to identify new loci and new genes for non-syndromic deafness and to establish a resource for research on genetic deafness including biological samples and clinical data from large numbers of families in Turkey. The outcome of this proposal will expand the scientific knowledge on the genomic basis of hereditary deafness.
|Tekin, D; Tutar, E; Ozturkmen Akay, H et al. (2015) Comprehensive genetic testing can save lives in hereditary hearing loss. Clin Genet 87:190-1|
|Lasisi, Akeem O; Bademci, Guney; Foster 2nd, Joseph et al. (2014) Common genes for non-syndromic deafness are uncommon in sub-Saharan Africa: a report from Nigeria. Int J Pediatr Otorhinolaryngol 78:1870-3|
|Oonk, Anne M M; Leijendeckers, Joop M; Huygen, Patrick L M et al. (2014) Similar phenotypes caused by mutations in OTOG and OTOGL. Ear Hear 35:e84-91|
|Bademci, Guney; Diaz-Horta, Oscar; Guo, Shengru et al. (2014) Identification of copy number variants through whole-exome sequencing in autosomal recessive nonsyndromic hearing loss. Genet Test Mol Biomarkers 18:658-61|
|Diaz-Horta, Oscar; Subasioglu-Uzak, Asli; Grati, M'hamed et al. (2014) FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing. Proc Natl Acad Sci U S A 111:9864-8|
|Yildirim-Baylan, Muzeyyen; Bademci, Guney; Duman, Duygu et al. (2014) Evidence for genotype-phenotype correlation for OTOF mutations. Int J Pediatr Otorhinolaryngol 78:950-3|
|Yan, Denise; Zhu, Yan; Walsh, Tom et al. (2013) Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise. Proc Natl Acad Sci U S A 110:2228-33|
|Tekin, Mustafa; Chioza, Barry A; Matsumoto, Yoshifumi et al. (2013) SLITRK6 mutations cause myopia and deafness in humans and mice. J Clin Invest 123:2094-102|
|Subasioglu Uzak, Asli; Cakar, Nilgun; Comak, Elif et al. (2013) ATP6V1B1 mutations in distal renal tubular acidosis and sensorineural hearing loss: clinical and genetic spectrum of five families. Ren Fail 35:1281-4|
|Uzak, Asli Subasioglu; Tokgoz, Bulent; Dundar, Munis et al. (2013) A novel COL4A3 mutation causes autosomal-recessive Alport syndrome in a large Turkish family. Genet Test Mol Biomarkers 17:260-4|
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