Tang Fengzhu, Ma Dengke, Wang Yulan, Qiu Yuecai, Liu Fei, Wang Qingqing, Lu Qiutian, Shi Min, Xu Liang, Liu Min, Liang Jianping
Department of Otolaryngology, The People's Hospital of Guangxi Zhuang Autonomous Region, 6 Taoyuan Road, Nanning, 530021, China.
CapitalBio Technology Co., Ltd., Building C, Block 88 Kechuang 6th Street, Yizhuang Biomedical Park, Beijing Economic- Technological Development Area, Beijing, 101111, China.
BMC Med Genet. 2017 Mar 23;18(1):35. doi: 10.1186/s12881-017-0400-0.
Many hearing-loss diseases are demonstrated to have Mendelian inheritance caused by mutations in single gene. However, many deaf individuals have diseases that remain genetically unexplained. Auditory neuropathy is a sensorineural deafness in which sounds are able to be transferred into the inner ear normally but the transmission of the signals from inner ear to auditory nerve and brain is injured, also known as auditory neuropathy spectrum disorder (ANSD). The pathogenic mutations of the genes responsible for the Chinese ANSD population remain poorly understood.
A total of 127 patients with non-syndromic hearing loss (NSHL) were enrolled in Guangxi Zhuang Autonomous Region. A hereditary deafness gene mutation screening was performed to identify the mutation sites in four deafness-related genes (GJB2, GJB3, 12S rRNA, and SLC26A4). In addition, whole-exome sequencing (WES) was applied to explore unappreciated mutation sites in the cases with the singularity of its phenotype.
Well-characterized mutations were found in only 8.7% (11/127) of the patients. Interestingly, two mutations in the OTOF gene were identified in two affected siblings with ANSD from a Chinese family, including one nonsense mutation c.1273C > T (p.R425X) and one missense mutation c.4994 T > C (p.L1665P). Furthermore, we employed Sanger sequencing to confirm the mutations in each subject. Two compound heterozygous mutations in the OTOF gene were observed in the two affected siblings, whereas the two parents and unaffected sister were heterozygous carriers of c.1273C > T (father and sister) and c.4994 T > C (mother). The nonsense mutation p.R425X, contributes to a premature stop codon, may result in a truncated polypeptide, which strongly suggests its pathogenicity for ANSD. The missense mutation p.L1665P results in a single amino acid substitution in a highly conserved region.
Two mutations in the OTOF gene in the Chinese deaf population were recognized for the first time. These findings not only extend the OTOF gene mutation spectrum for ANSD but also indicate that whole-exome sequencing is an effective approach to clarify the genetic characteristics in non-syndromic ANSD patients.
许多听力损失疾病被证明是由单基因突变引起的孟德尔遗传。然而，许多耳聋患者的疾病在基因方面仍无法解释。听觉神经病是一种感音神经性耳聋，声音能够正常传入内耳，但从内耳到听神经和大脑的信号传递受损，也称为听觉神经病谱系障碍（ANSD）。对于中国ANSD人群中致病基因的突变情况仍知之甚少。
共纳入广西壮族自治区127例非综合征性听力损失（NSHL）患者。进行遗传性耳聋基因突变筛查，以确定四个耳聋相关基因（GJB2、GJB3、12S rRNA和SLC26A4）中的突变位点。此外，应用全外显子组测序（WES）来探索表型独特病例中未被发现的突变位点。
仅在8.7%（11/127）的患者中发现了明确的突变。有趣的是，在中国一个家庭的两名患有ANSD的患病兄弟姐妹中鉴定出OTOF基因的两个突变，包括一个无义突变c.1273C>T（p.R425X）和一个错义突变c.4994 T>C（p.L1665P）。此外，我们采用桑格测序法确认每个受试者的突变。在两名患病兄弟姐妹中观察到OTOF基因的两个复合杂合突变，而父母和未患病的妹妹分别是c.1273C>T（父亲和妹妹）和c.4994 T>C（母亲）的杂合携带者。无义突变p.R425X导致提前终止密码子，可能产生截短的多肽，这强烈提示其对ANSD具有致病性。错义突变p.L1665P导致在一个高度保守区域发生单个氨基酸替换。
首次在中国耳聋人群中识别出OTOF基因的两个突变。这些发现不仅扩展了ANSD的OTOF基因突变谱，还表明全外显子组测序是阐明非综合征性ANSD患者遗传特征的有效方法。
