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.
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, School of Medicine, New Haven, CT, United States.
Gene. 2021 Apr 30;778:145464. doi: 10.1016/j.gene.2021.145464. Epub 2021 Jan 29.
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.
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.
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.
听力损失是全球最常见的感觉障碍，影响到每 1000 名新生儿中的 1 名。该疾病具有主要的遗传成分，并且可以作为常染色体显性或隐性方式的单一基因疾病遗传。由于近亲结婚率高，伊朗是世界上常染色体隐性非综合征性耳聋（ARNSD）发病率最高的国家之一。
我们对 10 个有多个受近亲结婚引起的 ARNSD 影响的后代的伊朗家族进行了遗传筛查。桑格测序和全外显子组测序，以及计算机 3D 结构建模和蛋白质稳定性预测，用于鉴定潜在的致病基因。
我们确定了这 10 个家族的耳聋原因。在 6 个家族中，桑格测序鉴定出 GJB2 基因的纯合突变。通过全外显子组测序（WES），在 ESRRB 基因中鉴定出纯合错义突变，这是伊朗首例报道的疾病基因。在另外三个独立的家族中，我们还在 MYO15A 基因中鉴定出两个新的纯合移码和错义突变，以及 TMC1 基因中一个先前报道的突变。我们的研究表明，WES 可有效揭示 ARNSD 患者的新致病突变，并扩展伊朗人群中导致 ARNSD 的基因谱。我们研究的结果可以为 ARNSD 患者的未来遗传筛查、早期筛查和新型治疗药物的优化设计提供便利。
