Abstract:

In order to detect the common inherited disorders of hyperbilirubinemia and cholestasis syndrome in Chinese population more quickly， accurately， at lower cost and in higher throughput， the SNPs/CNVs of all exons and introns of ten susceptible genes were selected， and a targeted capture sequencing method based on next-generation sequencing （NGS） technology was established. The accuracy of this method was verified by six samples of known mutation sites， and the accuracy rate was 100%. The 39 patients with inherited disorders of hyperbilirubinemia and cholestasis syndrome were collected from Beijing Friendship Hospital， Capital Medical University. A total of 58 mutations were detected. The test results were compared with HGMD， ClinVar and OMIM mutation databases. The unreported mutations were compared using the international genome sample resource and according to the Hardy-Weinberg equilibrium （HWE_P>0.05） and chi-square test. 19 new mutations were identified. The different mutation types detected effectively reveal the genetic diversity of this disease. The establishment and application of NGS method provides a new technical means for clinical diagnosis.

Key words: inherited disorders of hyperbilirubinemia, cholestasis, next-generation sequencing technology, targeted capture

摘要：

为快速准确、低成本、高通量地检测我国人群常见的遗传性胆红素代谢障碍及胆汁淤积综合征，选择了10个易感基因的全部外显子及内含子剪切区的SNP/CNV，建立了基于二代测序技术（next generation sequencing, NGS）的靶向捕获测序方法。通过6例已知突变位点的样本对该方法的准确性进行验证，准确率为100%。收集首都医科大学附属北京友谊医院遗传性胆红素代谢障碍及胆汁淤积综合征患者39例进行检测，共检测到58种突变。检测结果与HGMD、ClinVar、OMIM突变数据库比较，未报道的突变通过千人基因组数据集对比并按照哈温平衡检验（HWE_P＞0.05）和χ^２ 检验确定新突变19种。检测到的不同突变类型有效地揭示了该类疾病的遗传多样性。NGS方法的建立及应用为临床诊断提供了新的技术手段。

关键词: 遗传性胆红素代谢障碍, 胆汁淤积, 二代测序技术, 靶向捕获