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Identification of Novel Likely Pathogenic Variant in Cdh23 Causing Non-Syndromic Hearing Loss, and a Novel Variant in Otogl in an Extended Iranian Family Publisher



Mohammadi A1, 2 ; Hoseinzadeh M1, 3 ; Narrei S3 ; Pourreza MR4 ; Mohammadi Y3 ; Norouzi M1 ; Sadeghian L5 ; Tabatabaiefar MA1, 3, 6
Authors
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Authors Affiliations
  1. 1. Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Department of Research and Development, Baran Pathobiology Lab, Kangavar, Kermanshah, Iran
  3. 3. Department of Research and Development, Harmonic Medical Genetics Lab, Isfahan, Iran
  4. 4. Core Research Facilities, Isfahan University of Medical Sciences, Isfahan, Iran
  5. 5. Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
  6. 6. Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

Source: Egyptian Journal of Medical Human Genetics Published:2024


Abstract

Background: Sensorineural hearing loss (SNHL) is a clinically and genetically heterogeneous group of disorders of the auditory system. SNHL can occur as a symptom in more than 400 syndromes, and mutations in more than 150 genes can lead to SNHL. Mutations in the GJB2 and GJB6 genes are among the most common causes of SNHL worldwide. Mutations in Cadherin 23 (CDH23) can cause Usher syndrome and/or non-syndromic hearing loss (NSHL). Material and methods: In this study, the Whole Exome Sequencing (WES) was used to detect the cause of hearing loss in a large consanguineous Iranian family with two patients. All family members underwent a thorough Genotype–phenotype correlation assessment and co-segregation analysis to understand the inheritance pattern within the family. The candidate variants were further confirmed by Sanger sequencing. In addition, in silico analysis was performed to predict the functional impact of the variants; the interpretation of the variants was performed in accordance with the American College of Medical Genetics (ACMG) guidelines. Results: WES results identified two novel variants, a homozygous missense variant in CDH23 (c.2961T > G) and a heterozygous splice site variant in OTOGL that was compatible with the autosomal recessive pattern of inheritance. Bioinformatics studies confirmed the pathogenic effects of novel variants. The c.2961T > G variant was classified as likely pathogenic. Conclusions: The novel identified variant in the CDH23 was the cause of congenital profound progressive form of HL. Samples were not available from the second family to distinguish which variant is responsible for the molecular pathology of the disease. Further studies and functional examinations are suggested for investigating the role of OTOGL: c. 1863-1G > T in deafness. © The Author(s) 2024.
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