Identification of homozygous mutations for hearing loss.

TitleIdentification of homozygous mutations for hearing loss.
Publication TypeJournal Article
Year of Publication2021
AuthorsDianatpour, M, Smith, E, Hashemi, SBasir, Farazifard, MA, Nezafat, N, Razban, V, Mani, A
Date Published2021 Apr 30
KeywordsConnexin 26, Consanguinity, Female, Frameshift Mutation, Genetic Predisposition to Disease, Hearing Loss, Homozygote, Humans, Iran, Male, Membrane Proteins, Models, Molecular, Mutation, Missense, Myosins, Pedigree, Protein Stability, Receptors, Estrogen, Whole Exome Sequencing

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.

Alternate JournalGene
PubMed ID33524517
PubMed Central IDPMC7987747
Grant ListR01 HL122830 / HL / NHLBI NIH HHS / United States
R35 HL135767 / HL / NHLBI NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States