Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Clin Genet. 2021 Jul;100(1):59-78. doi: 10.1111/cge.13956. Epub 2021 Mar 24.
Hearing loss (HL) is one of the most common sensory defects affecting more than 466 million individuals worldwide. It is clinically and genetically heterogeneous with over 120 genes causing non-syndromic HL identified to date. Here, we performed exome sequencing (ES) on a cohort of Iranian families with no disease-causing variants in known deafness-associated genes after screening with a targeted gene panel. We identified likely causal variants in 20 out of 71 families screened. Fifteen families segregated variants in known deafness-associated genes. Eight families segregated variants in novel candidate genes for HL: DBH, TOP3A, COX18, USP31, TCF19, SCP2, TENM1, and CARMIL1. In the three of these families, intrafamilial locus heterogeneity was observed with variants in both known and novel candidate genes. In aggregate, we were able to identify the underlying genetic cause of HL in nearly 30% of our study cohort using ES. This study corroborates the observation that high-throughput DNA sequencing in populations with high rates of consanguineous marriages represents a more appropriate strategy to elucidate the genetic etiology of heterogeneous conditions such as HL.
听力损失（HL）是影响全球超过 4.66 亿人最常见的感觉缺陷之一。它在临床上和遗传上具有异质性，迄今为止已经确定了超过 120 个导致非综合征性 HL 的基因。在这里，我们对一个伊朗家系进行了外显子组测序（ES），这些家系在经过靶向基因panel 筛查后，没有发现已知耳聋相关基因中的致病变异。我们在 71 个筛查的家系中发现了 20 个可能的致病变异。15 个家系中的变异位于已知的耳聋相关基因中。8 个家系中的变异位于 HL 的新候选基因中：DBH、TOP3A、COX18、USP31、TCF19、SCP2、TENM1 和 CARMIL1。在其中的三个家系中，观察到了已知和新候选基因中的变异在家族内的遗传异质性。总的来说，我们能够通过 ES 确定我们研究队列中近 30%的 HL 的潜在遗传原因。这项研究证实了这样一种观察结果，即在高近亲结婚率的人群中进行高通量 DNA 测序代表了一种更合适的策略，可以阐明 HL 等异质性疾病的遗传病因。
