全外显子组测序证实家族性肺动脉高压骨形成蛋白受体2基因新突变的研究

Whole Exome Sequencing Reveals A Novel Frameshift Mutation in the BMPR2 Gene in A Chinese Family With Pulmonary Arterial Hypertension

目的:探讨一个中国汉族肺动脉高压(PAH)家系的致病基因及其位点。方法:对该PAH家系中的2例PAH患者与2名正常者作对照进行全外显子组测序,利用生物信息学分析和组间比较,筛选出患者特有的变异,并对筛选出的变异使用Sanger测序法验证,同时在100名健康志愿者中进行测序验证。结果:共纳入该家系成员8例,有2位已确诊为PAH,其中男性1例(先证者),女性1例,为母子关系。先证者表现为活动后胸闷、气喘,右心导管测量肺动脉平均压77 mmHg(1 mmHg=0.133 kPa),心输出量4.92 L/min,肺小动脉阻力13.4 Wood units。本家系中母子患病符合常染色体显性遗传模式特征。经外显子组测序、数据分析和Sanger测序验证后发现骨形成蛋白受体2(BMPR2)基因6号外显子747位点发生插入杂合突变(c.747_748ins CCTTTG ATGGAACATGA:p.V250fs)。另外,在100名健康志愿者中,Sanger测序没有发现该位点杂合突变。结论:发现了BMPR2基因的一个新的突变位点,扩大了BMPR2致病基因位点谱。

Objectives： To investigate the genetic mutation in a Chinese family with Pulmonary Arterial Hypertension（PAH）. Methods： Whole exome sequencing was performed in two patients and two healthy family members in the PAH pedigree. Patient-specific variations were screened by bioinformatics methods and compared between groups. To further identify the association between these variations and PAH, Sanger sequencing was used to analyze the genotype of PAH patients and 100 healthy controls. Results： Two affected persons were found among the eight family members. The patients was presented as dyspnea after exercise, and right-heart catheterization was performed to measure the mean pulmonary arterial pressure（m PAP, 77 mmHg）, cardiac output（CO, 4.92 L/min）, and pulmonary vascular resistance（PVR, 13.4 Wood units）. The hereditary characteristic in this family presented in mother and child, suggesting an autosomal dominant patter. Exome sequencing,mutation detection and sanger variants validation revealed a novel heterozygous frameshift mutation（c.747_748 ins CCTTTGATGGAACATGA：p.V250 fs） in the BMPR2 gene. Meanwhile, this heterozygous insertion mutation was absent in 100 ethnically matched control samples screened by direct sanger sequencing. Conclusions： Our study revealed a novel heterozygous frameshift mutation in the BMPR2 gene, expanding the BMPR2 mutation spectrums.