226例中国南方人群散发性主动脉疾病的基因-临床表型相关性分析  

Gene-phenotype correlation analysis of 226 cases of sporadic thoracic aortic diseases in southern China

作　　者：李莹 方妙弦[2] 于长江[1] 张创文 王秋吉 杨珏[1] 李欣[1] 孙图成 范瑞新[1] Li Ying;Fang Miaoxian;Yu Changjiang;Zhang Chuangwen;Wang Qiuji;Yang Jue;Li Xin;Sun Tucheng;Fan Ruixin(Department of Cardiovascular Surgery,Guangdong Cardiovascular Institute,Guangdong Provincial People’s Hospital,Guangdong Academy of Medical Sciences,Guangzhou 510080,China;Department of Intensive Care Unit of Cardiovascular Surgery,Guangdong Cardiovascular Institute,Guangdong Provincial People’s Hospital,Guangdong Academy of Medical Sciences,Guangzhou 510080,China;Department of Cardiovascular Surgery,Guangdong Cardiovascular Institute,Guangdong Provincial People’s Hospital,Guangdong Academy of Medical Sciences,Southern Medical University,Guangzhou 510080,China)

机构地区：[1]广东省人民医院广东省心血管病研究所广东省医学科学院心外科,广州510080 [2]广东省人民医院广东省心血管病研究所广东省医学科学院心外重症监护室,广州510080 [3]广东省心血管病研究所广东省人民医院广东省医学科学院南方医科大学心外科,广州510080

出　　处：《中华胸心血管外科杂志》2022年第6期348-356,共9页Chinese Journal of Thoracic and Cardiovascular Surgery

基　　金：国家重点研发计划(2017YFC1308003);广州市科技计划项目(202002020037)。

摘　　要：目的鉴定中国南方人群散发性胸主动脉瘤/主动脉夹层的致病基因,并分析其与临床表型的相关性。方法利用二代测序技术分析226例无明确家族史的胸主动脉瘤/主动脉夹层患者的11个主动脉相关基因,并对其近亲属进行一代验证。收集先证者的临床资料,包括发病年龄、综合征表型、累及主动脉根部、主动脉最大直径、D-二聚体浓度等,利用统计学软件分析临床表型与基因型的相关性。结果在226例先证者中共检测到106个突变位点,基因阳性率44.69%(101/226)。明确致病性突变16个,可能致病性突变18个,意义未明性突变71个。超过一半的突变位点来自非综合征型主动脉人群,其中FBN1基因仍是最常见的致病基因。致病性突变携带者发病年龄较小、女性比例较高、主动脉直径更大,易表现为Stanford B型夹层及重度主动脉瓣反流。意义未明性突变携带者更易出现胸主动脉瘤。具有综合征、夹层伴有动脉瘤表型会增加基因突变携带的可能性,而D-二聚体浓度及累及主动脉根部无明显影响。结论中国南方人群散发性主动脉疾病具有明显的遗传异质性,其临床表型与突变基因、致病等级之间均存在一定的相关性,非综合征型患者中尤为显著。发病年龄越早,越易携带FBN1、ACTA2基因,胸主动脉直径越大,越易携带致病性突变。Objective To identify the causative genes of sporadic thoracic aortic aneurysm or dissection(TAAD)and their correlation with clinical phenotype in the southern Chinese.Methods We analyzed 11 core genes of TAAD probands without specific family history of 226 cases by next-generation sequencing technology,and performed sanger sequencing for their close relatives.Clinical data of each patient,including age of onset,syndromic phenotypes,involvement of aortic root,aortic maximum diameter and D-dimer were collected.And statistical software SPSS was used to evaluate the correlation between clinical phenotypes and gene mutations.Results A total of 106 variants were detected in 226 probands with gene-positive frequency of 44.69%,consist of 16 pathogenic(P)variants,18 likely pathogenic(LP)variants and 71 variants of uncertain significance(VUS).More than half of the mutations were from the non-syndromic TAAD,in which the FBN1 still was the most common causative gene.Earlier age of onset,an increase of women,larger diameter of aorta,Stanford B dissection and severe aortic regurgitation were likely to occur on carriers of P/LP,while thoracic aortic aneurysm occurs on carriers of VUS.Phenotype of both syndrome and dissection with aneurysm could increase the likelihood of carrying gene mutation,but D-dimer and involvement of aortic root couldn’t.Conclusion Patients with sporadic aortic diseases in southern China have significant genetic heterogeneity and specific correlation between their clinical phenotype and gene mutation,especially in non-syndromic population.Earlier age of onset in carriers of FBN1 or ACTA2 genes,and larger maximum diameters of aorta in carrier of P/LP.

关 键 词：主动脉夹层 胸主动脉瘤 基因突变 表型 

分 类 号：R543.1[医药卫生—心血管疾病]