大前庭水管综合征第二致病因子的鉴定及致病机制研究

大前庭水管综合征是伴有内耳畸形的最常见遗传性耳聋之一，SLC26A4基因是其主要致病因子。在中国患者人群中，通过SLC26A4基因一代序列分析双等位基因突变检出率达89.15%，远超其他种族，但仍有10.85%的患者分子病因不明。本课题组近期基因组生物信息学分析提示该病存在第二致病因子。其中SLC26A4基因拷贝数变异（CNVs）和致病新的突变形式或新基因的鉴定可能是解决上述科学问题的关键。本研究以前期建立的1,668例大前庭水管综合征资源库为基础，对目前分子病因不明的病例首先进行SLC26A4基因全序列（外显子和内含子）捕获、二代测序鉴定致病CNVs，分析断裂点，绘制详细的CNVs谱；然后对CNVs研究仍未明确病因的患者群采用全外显子组或全基因组测序鉴定致病新突变或新基因；进而对重要的CNVs及新基因构建动物模型进行功能研究，填补大前庭水管综合征致病机制研究中的空白点，建立更为精准的预防

Enlarged Vestibular Aqueduct Syndrome(EVAS) is one of the most common genetic deafness associated with inner ear malformations. The detection rate of double allelic mutation in SLC26A4 gene is 89.15% in the patients of China, which is far more than other races. However, clear molcular etiology can’t be determined in about 10.85% of Chinese EVAS patient. Our recent genome bioinformatics analysis suggested that there are second pathogenic factors with this disease. Genomic structural abnormalities, such as copy number variations (CNVs), are increasingly associated with monogenic diseases. Identification of SLC26A4 gene copy number variations and new pathogenic genes may be the key to solve the problems. Based on the 1668 cases of EVAS genetic resource bank, gene whole sequence capture (including exons and introns) and next generation sequencing will be performed for cases with unknown molecular etiology to identify the pathogenic CNVs, and analyze the breakpoint and draw the detailed CNVs spectrum. Identification of pathogenic new genes was performed by whole exon groups sequencing or whole genome sequencing in patients without CNVs. Then construct animal models of important CNVs and new genes to carry out the functional studies, which will fill the gaps in the study of pathogenesis of EVAS and establish a more precise prevention intervention strategy.