Difference of SLC26A4 gene mutation frequency between patients with large vestibular aqueduct syndrome and/or Mondini dysplasia
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摘要: 目的 评估SLC26A4基因在大前庭水管综合征(EVAS)和/或Mondini畸形(MD)患儿中的突变频率, 为临床耳聋的分子诊断提供证据。方法 对74例患儿行颞骨薄层CT检查, 并进行二代测序, 分析SLC26A4基因编码的外显子。结果 共发现EVAS合并MD(E+M)37例, 单独EVAS(E)28例, 单独MD(M)9例。74例患儿中66例(89.2%)发现突变, 其中双等位基因突变64例(86.5%), 单等位基因突变2例(2.7%)。不同组的SLC26A4突变检出率差异有统计学意义(P < 0.001), M组突变发生率明显低于E组、E+M组(P < 0.001)。E组28例中发现SLC26A4双等位基因27例(96.4%), 单等位基因1例(3.6%); E+M组37例中发现SLC26A4双等位基因37例(100%); M组9例中只发现1例(11.1%)携带SLC26A4单杂合突变。结论 EVAS合并MD、单独EVAS与单独MD有着完全不同的发病机制, 早期EVAS和/或MD患儿的临床遗传学诊断有助于提供听力损失遗传原因的精确信息和遗传咨询, 从而实施适当的疾病控制和预防措施, 下一代测序技术在耳聋的分子诊断中发挥愈加重要的作用。Abstract: Objective The purpose of this study was to evaluate the mutation frequency of SLC26A4 gene in patients with enlarged vestibular aqueduct syndrome(EVAS) and/or Mondini dysplasia(MD), so as to provide evidence for molecular diagnosis of deafness.Methods In total, 74 patients with sensorineural hearing loss were included in this study. All patients underwent thin-layer CT examination of temporal bone. The coding exons of SLC26A4 were analyzed by second-generation sequencing in all subjects.Results Among them, 37 patients with EVAS and MD(E+M group), 28 patients with EVAS and without MD(E group), and 9 patients with isolated MD(M group) were identified. In 74 cases, 66 cases(89.2%) were found to have mutation, including 64 cases(86.5%) of biallelic mutation and two cases(2.7%) of single allele mutation. The detection rate of SLC26A4 in different groups was statistically significant(P < 0.001). The mutation rate in group M was significantly lower than that in Group E and E+M(P < 0.001). In Group E, 27 cases(96.4%) had SLC26A4 biallelic mutations and one case(3.6%) had SLC26A4 single allele mutation, respectively; in Group E+M, 37 cases(100%) had SLC26A4 biallelic mutations; in group M, only one patient(11.1%) carried monoallelic mutations of the SLC26A4 gene.Conclusion There are totally different pathogenesis in Chinese EVAS patients with or without MD, or isolated MD. Early clinical genetic diagnosis of patients with EVAS and/or MD helps to provide accurate information about the genetic causes of hearing loss, provide genetic counseling, and implement appropriate disease control and prevention measures. Next generation sequencing technology plays an increasingly important role in molecular diagnosis of deafness.
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表 2 SLC26A4基因的突变谱和发生频率
畸形 基因型 氨基酸 发生频率/例(%) 单独EVAS c.919-2A>G/c.919-2A>G 剪切位点 9(32.1) c.919-2A>G/c.2168A>G 剪切位点/H723R 4(14.3) c.919-2A>G/c.1174A>T 剪切位点/N392Y 2(7.1) c.919-2A>G/c.ivs15+5G>A 剪切位点 1(3.6) c.919-2A>G/c.1079C>T 剪切位点/A360V 1(3.6) c.919-2A>G/c.1226G>A 剪切位点/R409H 1(3.6) c.919-2A>G/c.1229C>T 剪切位点/T410M 1(3.6) c.919-2A>G/589G>A 剪切位点/G197R 1(3.6) c.919-2 A>G/c.1586T>G 剪切位点/I529S 1(3.6) c.919-2 A>G/c.1262A>C 剪切位点/Q421P 1(3.6) c.919-2 A>G/c.1318A>T 剪切位点/K440X 1(3.6) c.919-2 A>G/c.1975G>C 剪切位点/V659L 1(3.6) c.2168A>G/c.2168A>G H723R /H723R 1(3.6) c.1174A>T/c.1343C>T N392Y/S448X 1(3.6) c.919-2A>G/ 剪切位点 1(3.6) EVAS合并MD c.919-2A>G/c.919-2A>G 剪切位点 14(37.8) c.919-2A>G/c.2168A>G 剪切位点/H723R 4(10.8) c.919-2A>G/589G>A 剪切位点/G197R 2(5.4) c.919-2A>G/c.1229C>T 剪切位点/T410M 2(5.4) c.919-2A>G/c.1174A>T 剪切位点/N392Y 1(2.7) c.919-2A>G/c.414delT 剪切位点/移码 1(2.7) c.919-2A>G/c.1586T>G 剪切位点/I529S 1(2.7) c.919-2A>G/c.1548insC 剪切位点/移码 1(2.7) c.919-2A>G/c.1079C>T 剪切位点/A360V 1(2.7) c.919-2A>G/ivs15+5G>A 剪切位点 1(2.7) c.919-2A>G/c.1825delG 剪切位点/移码 1(2.7) c.919-2A>G/c.1829C>A 剪切位点/S610X 1(2.7) c.919-2A>G/c.1991C>T 剪切位点/A664V 1(2.7) c.919-2A>G/c.2027T>A 剪切位点/L676Q 1(2.7) c.919-2A>G/c.ivs18-1G>A H723R/S532R 1(2.7) c.1174A>T/c.754T>C 剪切位点 1(2.7) c.2168A>G /1594A>C N392Y/S252P 1(2.7) c.2168A>G/1673A>T H723R/N558I 1(2.7) c.1124A>G/c.1409G>A Y375C/R470H 1(2.7) 单独MD c.919-2A>G/ 剪切位点 1(11.1) 
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