家族性胸主动脉瘤-夹层致病基因鉴定及表型特征研究

The research of causative genes and phenotypic features in Chinese families with thoracic aortic aneurysm and dissec- tion

目的对两个汉族家族性胸主动脉瘤-夹层家系进行致病基因筛查，同时总结家系临床表型特征。方法使用全外显子捕获＋高通量测序对家系成员进行致病基因鉴定。临床表型检查参照马方综合征和家族性胸主动脉瘤-夹层已报道的表型特征，由心外科医师和遗传学专家共同实施。结果TAA01家系检测分析后得到4个已知可能致病的变异位点：FBNl（rs140598），MYH11（rs185661462），MYLK3（rs77620762），TGFBRl（rs111426349）。Sanger法证实TGFBRl（C．1459C〉T）与该家系胸主动脉疾病呈共分离。早发的主动脉窦部扩张是该家系内一显著特征，家系内6位主动脉窦瘤／扩张患者平均发病年龄为23．2岁。TAA02家系致病基因为ACTA2（C．445C〉T），伴皮肤网状青斑改变。结论TGFBRl（C．1459C〉T）和ACTA2（C．445C〉T）分别为两胸主动脉瘤一夹层家系致病基因。对于TGFBRl突变（C．1459C〉T）导致的FTAAD，早发的主动脉窦部扩张较为显著。ACTA2基因突变伴发的网状青斑样改变得到证实。

Objective This study aimed at exploring the causative genes and summarizing the clinical characteristics in two Chinese families with thoracic aortic aneurysm and dissection （TAAD）. Methods The whole exome capture and high throughput sequencing were applied to identify the causative gene. Family members were examined for features of syndromic ge- netic diseases by clinician and geneticist. Results Four known TAAD candidate genes were identified in family TAA01 ： rs140598 （ FBN1 ）, rs185661462 （ MYHll ）, rs77620762 （ MYLK3 ）, and rsl 11426349 （ TGFBR1 ）. The TGFBR1 mutation （c. 1459C 〉 T） had been confirmed to co-segregate with the TAAD phenotype in all affected family members. Early onset of aortic root dilatation was significant in this family, and the average age at diagnosis of aortic root dilatation or aneurysm was23. 2 years. ACTA2（c. 445C 〉T） was proved in family TAA02, and livedo retieularis was confirmed. Conclusion The causa- tive genes were identified via whole exome capture and high throughput sequencing in two TAAD families. Early onset of aortic root aneurysm was proved in TAA01, while livedo retieularis was found in TAA02.