Xiang Yan-Bao, Tang Shao-Hua, Li Huan-Zheng, Xu Chen-Yang, Chen Chong, Xu Yun-Zhi, Ding Li-Rong, Xu Xue-Qin
Key Laboratory of Birth Defects, Department of Genetics, Wenzhou Central Hospital, Wenzhou, China.
Key Laboratory of Birth Defects, Department of Genetics, Wenzhou Central Hospital, Wenzhou, China; Key Laboratory of Medical Genetic, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China.
Int J Pediatr Otorhinolaryngol. 2019 Jul;122:185-190. doi: 10.1016/j.ijporl.2019.04.024. Epub 2019 Apr 21.
The frequency and spectrum of mutations in deafness-causing genes differs significantly according to the ethnic population and region under investigation. The molecular etiology of nonsyndromic hearing loss (NSHL) in Wenzhou, China, has not yet been systematically elucidated. To provide accurate genetic testing and counseling in this area, we investigated the molecular etiology of NSHL in a deaf population from Wenzhou.
A total 506 unrelated patients with NSHL were enrolled in this study. Nine hotspot mutations in four major deafness genes were investigated by sequencing (Group I: 187 patients enrolled between 2011 and 2015) or allele-specific PCR-based universal array (Group II: 319 patients enrolled between 2016 and 2017). The investigated genes included GJB2 (c.35delG, c.176_191del16, c.235delC, c.299-300delAT), SLC26A4 (c.2168A > G, c.919-2A > G), mtDNA 12SrRNA (m.1555A > G, m.1494C > T), and GJB3 (c.538C > T). Furthermore, whole coding region sequencing or improved multiplex ligation detection reaction (IMLDR) were performed for patients who carried mono-allelic variants of GJB2 and SLC26A4, in order to detect other mutations among these patients.
GJB2 mutations were detected in 22.92% (116/506) of the entire cohort and SLC26A4 mutations were found in 6.52% (33/506) of the cohort. GJB3 mutations were detected in 0.79% (4/506) of the cohort. The mutation rate of mitochondrial DNA 12SrRNA in our patients was 17.40% (88/506), including 17.00% (86/506) with the m.1555A > G mutation and 0.40% (2/506) with the m.1494C > T mutation. The allelic frequency of the c.235delC mutation was 14.62% (148/1012), which is significantly higher than that of c.109G > A (33/1012, 3.26%), c.299_300delAT (13/1012, 1.28%), and c.176_191del16 (6/1012, 0.59%). The most common pathogenic mutation of SLC26A4 was the c.919-2A > G mutation (37/1012, 3.66%), followed by c.2168A > G (6/1012, 0.59%), and c.1229C > T (4/1012, 0.40%). Moreover, five rare pathogenic variants of GJB2 and eight rare pathogenic variants of SLC26A4 were identified.
GJB2 is the primary deafness-causing gene in deaf patients from Wenzhou, China; this is consistent with what is observed in most Chinese populations. However, the surprisingly high rate of the m.1555A > G mutation (17.00%) in patients from Wenzhou was significantly higher than in other populations in China. These findings highlight the specificity of the common deafness-causing gene mutation spectrum in the Wenzhou area. This information may be of benefit for genetic counseling and risk assessment for deaf patients from this area.
致聋基因的突变频率和谱在不同种族人群及所研究地区之间存在显著差异。中国温州非综合征性听力损失（NSHL）的分子病因尚未得到系统阐明。为在该地区提供准确的基因检测和咨询服务，我们对温州耳聋人群中NSHL的分子病因进行了研究。
本研究共纳入506例无亲缘关系的NSHL患者。通过测序（第一组：2011年至2015年纳入的187例患者）或基于等位基因特异性PCR的通用芯片技术（第二组：2016年至2017年纳入的319例患者）检测四个主要致聋基因中的九个热点突变。所检测的基因包括GJB2（c.35delG、c.176_191del16、c.235delC、c.299 - 300delAT）、SLC26A4（c.2168A > G、c.919 - 2A > G）、线粒体DNA 12SrRNA（m.1555A > G、m.1494C > T）和GJB3（c.538C > T）。此外，对携带GJB2和SLC26A4单等位基因突变的患者进行全编码区测序或改进的多重连接检测反应（IMLDR），以检测这些患者中的其他突变。
在整个队列中，22.92%（116/506）的患者检测到GJB2突变，6.52%（33/506）的患者检测到SLC26A4突变。0.79%（4/506）的患者检测到GJB3突变。我们患者中线粒体DNA 12SrRNA的突变率为17.40%（88/506），其中m.1555A > G突变为17.00%（86/506），m.1494C > T突变为0.40%（2/506）。c.235delC突变的等位基因频率为14.62%（148/1012），显著高于c.109G > A（33/1012，3.26%）、c.299_300delAT（13/1012，1.28%）和c.176_191del16（6/1012，0.59%）。SLC26A4最常见的致病突变为c.919 - 2A > G突变（37/1012，3.66%），其次是c.2168A > G（6/
