Sang Shushan, Ling Jie, Liu Xuezhong, Mei Lingyun, Cai Xinzhang, Li Taoxi, Li Wu, Li Meng, Wen Jie, Liu Xianlin, Liu Jing, Liu Yalan, Chen Hongsheng, He Chufeng, Feng Yong
Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, China.
Key Laboratory of Otolaryngology Major Diseases Research of Hunan Province, Changsha, China.
Front Genet. 2019 Jul 17;10:639. doi: 10.3389/fgene.2019.00639. eCollection 2019.
Autosomal recessive non-syndromic hearing loss (ARNSHL) is a highly heterogeneous disease involving more than 70 pathogenic genes. However, most ARNSHL families have small-sized pedigrees with limited genetic information, rendering challenges for the molecular diagnosis of these patients. Therefore, we attempted to establish a strategy for identifying deleterious variants associated with ARNSHL by applying proband whole-exome sequencing (proband-WES). Aside from desiring to improve molecular diagnostic rates, we also aimed to search for novel deafness genes shared by patients with similar phenotype, making up for the deficiency of small ARNSHL families. In this study, 48.5% (16/33) families were detected the pathogenic variants in eight known deafness genes, including 10 novel variants identified in (MIM 605551), (MIM 602666), (MIM 606706), (MIM 602851), and (MIM 603317). Apart from six novel variants with a truncating effect (nonsense, deletion, insertion, and splice-site), four novel missense variants were not found in 200 unrelated control population by using Sanger sequencing. It is important to note that none of novel genes were shared across different pedigrees, indicating that a larger sample size might be needed. Proband-WES is a cost-effective and precise way of identifying causative variants in nuclear families with ARNSHL. This economical strategy may be appropriated as a clinical application to provide molecular diagnostics, genetic counseling, and individualized health maintenance measures for patients with ARNSHL at hearing clinics.
常染色体隐性非综合征性听力损失（ARNSHL）是一种高度异质性疾病，涉及70多个致病基因。然而，大多数ARNSHL家系规模较小，遗传信息有限，给这些患者的分子诊断带来了挑战。因此，我们试图通过应用先证者全外显子测序（proband-WES）建立一种识别与ARNSHL相关的有害变异的策略。除了希望提高分子诊断率外，我们还旨在寻找具有相似表型的患者共有的新型耳聋基因，以弥补小型ARNSHL家系的不足。在本研究中，48.5%（16/33）的家系在8个已知耳聋基因中检测到致病变异，包括在（MIM 605551）、（MIM 602666）、（MIM 606706）、（MIM 602851）和（MIM 603317）中鉴定出的10个新变异。除了6个具有截断效应的新变异（无义、缺失、插入和剪接位点）外，通过Sanger测序在200名无关对照人群中未发现4个新的错义变异。需要注意的是，不同家系之间没有共享新基因，这表明可能需要更大的样本量。先证者全外显子测序是一种经济有效的方法，可用于识别ARNSHL核心家系中的致病变异。这种经济策略可作为一种临床应用，为听力诊所的ARNSHL患者提供分子诊断、遗传咨询和个性化的健康维护措施。
