GJB2和SLC26A4基因部分罕见变异的致病性研究

目的通过对听力正常的耳聋人群亲属的基因筛查，对隐性遗传性耳聋基因部分罕见错义序列变异的致病性提出一种简单而有效的排查方法。方法收集800例具有不同程度听力障碍患者的DNA样本，通过多聚酶链反应（PCR）扩增GJB2和/或SLC26A4基因片段（包括编码外显子和邻近的侧翼区域），并对PCR产物进行Sanger测序和序列分析。当先证者含有明确致病突变时，在取得同意的情况下进一步对其听力正常的亲属进行相应基因的突变检测。结果在3个携带GJB2或者SLC26A4基因突变的先证者亲属中，一些正常听力者以复合杂合的形式同时携带GJB2或者SLC26A4基因的一个致病性明确突变和一个致病性不明确的罕见序列变异，包括GJB2基因p.T123N/c.235delC突变(2例)和SLC26A4基因 p.A434T/c.919-2A>G突变(1例)。结论GJB2基因p.T123N和SLC26A4基因p.A434T可基本排除为外显率较高的致病性突变的可能性。以上关于隐性遗传性耳聋基因疑似突变致病性的排除方法相对简便易行，通过大样本量的基因筛查可以为临床遗传性耳聋基因诊断和遗传咨询提供更可靠、明确的依据。

Study on pathogenicity of some rare sequence variants in GJB2 and SLC26A4 genes

Abstract:ObjectiveTo determine the pathogenicity of rare, missense variants in known causative recessive deafness genes by sequencing of unaffected family members of the deaf patients.MethodsA total of 800 probands with hearing impairment were collected to screen the deafness causing genes GJB2 and/or SLC26A4 by PCR and Sanger sequencing, including the coding exons and flanking sequences. When probands harbored the pathogenic mutations and if possible, some unaffected family members of probands were recruited to further analyze the mutations in the corresponding genes.ResultsTwo rare missense variants were found in three unaffected family members in different families, including p.T123N (n=2) in GJB2 and p.A434T (n=1) in SLC26A4, with the opposite allele to a known pathogenic recessive mutation.Conclusionp.T123N in GJB2 and p.A434T in SLC26A4 are rare but benign variants for deafness. Sequencing of unaffected family members of the affected patients may be an efficient approach to clarify the pathogenicity of some rare variants for recessive genetic disorders with high penetrance. More reliable data will be provided for deafness causing gene diagnosis and counseling through screening plentiful samples.