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A Novel Pathologic Variant in Otof in an Iranian Family Segregating Hereditary Hearing Loss Publisher Pubmed



Tabatabaiefar MA1, 2 ; Pourreza MR1 ; Tahmasebi P3 ; Saki N4 ; Hashemzadeh Chaleshtori M5 ; Salehi R1 ; Mohammadiasl J6
Authors
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Authors Affiliations
  1. 1. Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
  3. 3. Department of Biology, Faculty of Science, Ilam University, Ilam, Iran
  4. 4. Department of Otolaryngology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
  5. 5. Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
  6. 6. Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

Source: Otolaryngology - Head and Neck Surgery (United States) Published:2018


Abstract

Objective: Hearing loss (HL) is the most common sensory-neural defect and the most heterogeneous trait in humans, with the involvement of >100 genes, which make a molecular diagnosis problematic. Next-generation sequencing (NGS) is a new strategy that can overcome this problem. Study Design: Descriptive experimental study. Setting: Diagnostic laboratory. Subjects and Methods: A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in a family with multiple individuals with HL. As the first tier, GJB2 was sequenced, and genetic linkage analysis of DFNB1A/B was performed to rule out the most common cause of the disease. Targeted NGS was used to unravel the molecular etiology of the disease in the HL-associated genes in the proband. Two homozygous variants remained in OTOF after proper filtration. Cosegregation and in silico analysis were done. Preimplantation genetic diagnosis (PGD) was accomplished via linkage analysis and direct sequencing of the pathogenic variant. Results: Clinical evaluations suggested autosomal recessive nonsyndromic HL. Two homozygous variants, c.367G>A (p.Gly123Ser) and c.1392+1G>A, were identified in cis status. c.1392+1G>A met the criteria for being pathogenic according to the variant interpretation guideline of the American College of Medical Genetics and Genomics. PGD was successfully performed to prevent the recurrence of the disease in the related family. Conclusion: A novel OTOF mutation causing HL was identified. Here, we report the effectiveness of the combined application of targeted NGS and PGD in diagnosis and prevention of hereditary HL. © 2018, © American Academy of Otolaryngology–Head and Neck Surgery Foundation 2018.
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