Whole exome sequencing of six Chinese families with hereditary non-syndromic hearing loss
Whole exome sequencing of six Chinese families with hereditary non-syndromic hearing loss
复制标题
六个中国遗传性非综合征性听力损失家庭的全外显子组测序。
DOI：
10.1016/j.ijporl.2021.110817
复制
发表时间：
2021-07-13
影响因子：
1.5
通讯作者：
Zha, Dingjun
中科院分区：
文献类型：
--
作者：
Liang, Pengfei;Chen, Fengping;Zha, Dingjun
目的：遗传性非综合征性听力损失（NSHL）具有高度的遗传异质性，约有152个基因被确定为相关的分子原因。本研究的目的是从6个无关的中国家系中检测耳聋先证者可能的损害性变异。研究方法：在排除最常见基因GJB 2和SLC 26 A4中的致病/可能致病变异后，通过全外显子组测序（WES）评估了12例常染色体隐性遗传的语前聋先证者。通过桑格测序在所有患者及其父母中验证所有候选变体。结果：所有耳聋患者均存在双等位基因变异。在这6个家系中，在3个不同的肥胖相关常染色体隐性（DFNB）基因（MYO 15 A，COL 11 A2和CDH 23）中鉴定出10个潜在致病变异，包括3个已报道的变异和7个新变异。这些新的变异体被认为是致病的或可能致病的，因为它们对蛋白质的预测损伤功能，同时与耳聋表型共分离。MYO 15 A基因变异频率较高，候选变异占7/10。结论：新一代测序技术（NGS）在分析大规模基因时比传统的基于聚合酶链反应的桑格测序（Sanger sequencing）更具成本效益和效率，后者通常用于筛选常见的遗传相关基因。本研究结果进一步扩展了中国人群中听力损失的致病/可能致病变异谱，对遗传咨询具有积极意义。
Objectives: Hereditary non-syndromic hearing loss (NSHL) has a high genetic heterogeneity with about 152 genes identified as associated molecular causes. The present study aimed to detect the possible damaging variants of the deaf probands from six unrelated Chinese families. Methods: After excluding the pathogenic/likely pathogenic variants in the most common genes, GJB2 and SLC26A4, 12 probands with prelingual deafness and autosomal recessive inheritance were evaluated by wholeexome sequencing (WES). All the candidate variants were verified by Sanger sequencing in all patients and their parents. Results: Biallelic variants were identified in all deaf patients. Among these six families, 10 potentially causative variants, including 3 reported and 7 novel variants, in 3 different deafness-associated autosomal recessive (DFNB) genes (MYO15A, COL11A2, and CDH23) were identified. These novel variants are thought to be pathogenic or likely pathogenic for theirs predicted damage function upon the protein as while as cosegregated with the deafness phenotype. The variants in MYO15A were frequent with 7/10 candidate ones. Conclusion: Next-generation sequencing (NGS) approach becomes more cost-effective and efficient when analyzing large-scale genes compared to the conventional polymerase chain reaction-based Sanger sequencing, which is often used to screen common deafness-related genes. The current findings further extend the pathogenic/likely pathogenic variants spectrum of hearing loss in the Chinese population, which has a positive significance for genetic counseling.