Department of Cardiology, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
Department of Cardiology, Chinese Academy of Medical College and Peking Union Medical College Hospital; Peking Union Medical College Hospital, Beijing, 100730, China.
Sci Rep. 2019 Mar 14;9(1):4456. doi: 10.1038/s41598-019-38898-9.
This study was aimed to identify the potentially pathogenic gene variants that contribute to the etiology of the tuberous sclerosis complex. A Chinese pedigree with tuberous sclerosis complex was collected and the exomes of two affected individuals were sequenced using the whole exome sequencing technology. The resulting variants from whole exome sequencing were filtered by basic and advanced biological information analysis and the candidate mutation was verified as heterozygous by sanger sequencing. After basic and advanced biological information analysis, a total of 9 single nucleotide variants were identified, which were all follow the dominant inheritance pattern. Among which, the intron heterozygous mutation c.600-145 C > T transition in TSC2 was identified and validated in the two affected individuals. In silico analysis with human splicing finder (HSF) predicted the effect of the c.600-145 C > T mutations on TSC2 mRNA splicing, and detected the creation of a new exonic cryptic donor site, which would result in a frame-shift, and finally premature termination codon. Our results reported the novel intron heterozygous mutation c.600-145 C > T in TSC2 may contribute to TSC, expanding our understanding of the causally relevant genes for this disorder.
本研究旨在鉴定导致结节性硬化症发病的潜在致病性基因突变。收集了一个中国结节性硬化症家系，使用全外显子组测序技术对两个受影响个体的外显子组进行测序。通过基本和高级生物信息分析对全外显子组测序产生的变异进行筛选，通过桑格测序验证候选突变是杂合的。经过基本和高级生物信息分析，共鉴定出 9 个单核苷酸变异，均符合显性遗传模式。其中，在 TSC2 中鉴定并验证了第 600-145 位核苷酸 C>T 转换的内含子杂合突变。通过人类剪接预测器（HSF）的计算机分析预测了 c.600-145C>T 突变对 TSC2mRNA 剪接的影响，并检测到一个新的外显子隐匿供体位点的产生，这将导致移码，最终导致提前终止密码子。我们的结果报告了 TSC2 中新型内含子杂合突变 c.600-145C>T，可能导致 TSC，扩展了我们对该疾病相关致病基因的理解。
