背景:胸主动脉瘤(TAA)与显著的发病率和死亡率相关。尽管有TAA家族史的个体经常接受临床分子遗传学检测,患有非综合征性TAA的成年人通常不进行遗传原因评估.我们试图了解在单个中心具有非综合征性TAA的成年个体队列中种系和体细胞镶嵌变异的遗传贡献。
结果:在马萨诸塞州总医院接受非综合征性TAA治疗的一百八十一名60岁以下的连续患者对与TAA及其相关功能通路相关的114个候选基因进行了深度(>500倍)靶向测序。来自354个年龄和性别匹配的没有TAA的个体的样本也进行了测序,2:1匹配。我们发现种系显著富集(比值比[OR],2.44,P=4.6×10-6[95%CI,1.67-3.58])以及体细胞花叶病变(OR,4.71,P=0.026[95%CI,1.20-18.43])在有和没有TAA的个体之间。可能的遗传原因存在于24%的非综合征性TAA,其中21%来自种系变异,3%来自体细胞花叶病等位基因。我们队列中最常见的3个突变基因是FLNA(编码FilaminA),NOTCH3(编码Notch受体3),和FBN1(编码纤溶蛋白-1)。在TAA个体中,错义和功能变异丧失的频率增加。
结论:在近四分之一的TAA非综合征成年人中发现了可能的显性作用遗传变异。我们的发现表明TAA的遗传结构比预期的更广泛,并且基因检测可以改善非综合征性TAA成人的护理和临床管理。
BACKGROUND: Thoracic aortic aneurysm (TAA) is associated with significant morbidity and mortality. Although individuals with family histories of TAA often undergo clinical molecular genetic testing, adults with nonsyndromic TAA are not typically evaluated for genetic causes. We sought to understand the genetic contribution of both germline and somatic mosaic variants in a cohort of adult individuals with nonsyndromic TAA at a single center.
RESULTS: One hundred eighty-one consecutive patients <60 years who presented with nonsyndromic TAA at the Massachusetts General Hospital underwent deep (>500×) targeted sequencing across 114 candidate genes associated with TAA and its related functional pathways. Samples from 354 age- and sex-matched individuals without TAA were also sequenced, with a 2:1 matching. We found significant enrichments for germline (odds ratio [OR], 2.44, P=4.6×10-6 [95% CI, 1.67-3.58]) and also somatic mosaic variants (OR, 4.71, P=0.026 [95% CI, 1.20-18.43]) between individuals with and without TAA. Likely genetic causes were present in 24% with nonsyndromic TAA, of which 21% arose from germline variants and 3% from somatic mosaic alleles. The 3 most frequently mutated genes in our cohort were FLNA (encoding Filamin A), NOTCH3 (encoding Notch receptor 3), and FBN1 (encoding Fibrillin-1). There was increased frequency of both missense and loss of function variants in TAA individuals.
CONCLUSIONS: Likely contributory dominant acting genetic variants were found in almost one quarter of nonsyndromic adults with TAA. Our findings suggest a more extensive genetic architecture to TAA than expected and that genetic testing may improve the care and clinical management of adults with nonsyndromic TAA.