Mehdi Dianatpour1, Emily Smith2, Seyed Basir Hashemi3, Mohammad A Farazifard4, Navid Nezafat5, Vahid Razban6, Arya Mani7. 1. Department of Medical Genetic, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. 2. Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, School of Medicine, New Haven, CT, United States. Electronic address: emily.smith@yale.edu. 3. Department of Otolaryngology, Shiraz University of Medical Sciences, Shiraz, Iran. 4. Department of Medical Genetic, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. 5. Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. 6. Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran. 7. Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, School of Medicine, New Haven, CT, United States. Electronic address: arya.mani@yale.edu.
Abstract
BACKGROUND: Hearing loss is the most common sensory disorder worldwide, affecting about 1 out of every 1000 newborns. The disease has major genetic components, and can be inherited as a single gene disorder either in autosomal dominant or recessive fashions. Due to the high rate of consanguineous unions, Iran has one of the highest prevalence of autosomal recessive nonsyndromic deafness (ARNSD) in the world. METHODS: We carried out a genetic screening of ten Iranian kindreds with more than one offspring affected by ARNSD caused by consanguineous unions. Sanger sequencing and whole exome sequencing together with in silico 3D structure modeling and protein stability prediction were used to identify the underlying disease causing genes. CONCLUSION: We identified the causes of deafness in all 10 kindred. In six kindreds homozygous mutations were identified in GJB2 gene by Sanger sequencing. By using whole exome sequencing (WES), a homozygous missense mutation was identified in ESRRB gene as the first ever reported disease gene in Iran. Also two novel homozygous frameshift and missense mutations were identified in MYO15A gene and one previously reported mutation in TMC1 gene in three independent kindred. Our study shows the efficacy of WES for unraveling new pathogenic mutations in ARNSD patients and expands the spectrum of genes contributing to ARNSD in the Iranian population. The findings of our study can facilitate future genetic screening of patients with ARNSD , early screening and optimal design of novel therapeutics.
BACKGROUND: Hearing loss is the most common sensory disorder worldwide, affecting about 1 out of every 1000 newborns. The disease has major genetic components, and can be inherited as a single gene disorder either in autosomal dominant or recessive fashions. Due to the high rate of consanguineous unions, Iran has one of the highest prevalence of autosomal recessive nonsyndromic deafness (ARNSD) in the world. METHODS: We carried out a genetic screening of ten Iranian kindreds with more than one offspring affected by ARNSD caused by consanguineous unions. Sanger sequencing and whole exome sequencing together with in silico 3D structure modeling and protein stability prediction were used to identify the underlying disease causing genes. CONCLUSION: We identified the causes of deafness in all 10 kindred. In six kindreds homozygous mutations were identified in GJB2 gene by Sanger sequencing. By using whole exome sequencing (WES), a homozygous missense mutation was identified in ESRRB gene as the first ever reported disease gene in Iran. Also two novel homozygous frameshift and missense mutations were identified in MYO15A gene and one previously reported mutation in TMC1 gene in three independent kindred. Our study shows the efficacy of WES for unraveling new pathogenic mutations in ARNSD patients and expands the spectrum of genes contributing to ARNSD in the Iranian population. The findings of our study can facilitate future genetic screening of patients with ARNSD , early screening and optimal design of novel therapeutics.
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