Mapping of familial thoracic aortic aneurysm/dissection with patent ductus arteriosus to 16p12.2-p13.13
Mapping of familial thoracic aortic aneurysm/dissection with patent ductus arteriosus to 16p12.2-p13.13
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DOI：
10.1161/circulationaha.104.506345
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发表时间：
2005-07-12
期刊：
影响因子：
37.8
通讯作者：
Jeunemaitre, X
中科院分区：
文献类型：
--
作者：
Van Kien, PK;Mathieu, F;Jeunemaitre, X
背景-三个基因座已被证明与非综合征性家族性胸主动脉瘤（TAAs）和主动脉夹层（ADs）有关。我们最近描述了一个大家族，其中TAA/AD与动脉导管未闭（PDA）有关，并为一种独特的病理生理实体提供了遗传学论据。方法和结果-对这个大谱系中属于3代的40名受试者进行了全基因组扫描。以7例TAA/AD病例为例，我们观察到16p染色体相邻标记的2点LOD评分为阳性，在theta=0时LOD评分最大值为2.73，当包括5例PDA病例时，LOD评分值增加到3.56。多点连锁分析结果显示，D16S3103附近的LOD评分最高，为4.14。精细的定位可以观察到重组单倍型，在16p12.2-p13.13之间划分了一个临界的20厘米间隔。电影MRI自动测定主动脉顺应性显示，所有患有该疾病单倍型的受试者，即使无症状，主动脉顺应性和扩张性水平都很低。主动脉僵硬与疾病单倍型密切相关，年龄影响显著，提示该疾病有亚临床和早期表现。结论：该家族的遗传分析在染色体16p12.2-p13.13上发现了一个独特的位点，负责TAA/AD和PDA，主动脉僵硬是该疾病的早期标志。TAA/AD合并PDA是TAA/AD遗传异质性群体中一种新的单基因实体。
Background - Three loci have been shown to be responsible for nonsyndromic familial thoracic aortic aneurysms (TAAs) and aortic dissections (ADs). We recently described a large family in which TAA/AD associates with patent ductus arteriosus (PDA) and provided genetic arguments for a unique pathophysiological entity.Methods and Results - Genome-wide scan was performed in 40 subjects belonging to 3 generations in this large pedigree. Using the 7 TAA/AD cases as affected, we observed positive 2-point LOD scores on adjacent markers at chromosome 16p, with a maximum LOD score value of 2.73 at theta=0, a value that increased to 3.56 when 5 PDA cases were included. Multipoint linkage analysis yielded a maximum LOD score of 4.14 in the vicinity of marker D16S3103. Fine mapping allowed the observation of recombinant haplotypes that delimited a critical 20-cM interval at 16p12.2-p13.13. Automatic determination of aortic compliance with cine MRI showed that all subjects bearing the disease haplotype, even asymptomatic, displayed a very low level of aortic compliance and distensibility. Aortic stiffness was strongly associated with disease haplotype with a marked effect of age, indicating subclinical and early manifestation of the disease.Conclusions - Genetic analysis of this family identified a unique locus responsible for both TAA/AD and PDA at chromosome 16p12.2-p13.13 with aortic stiffness as an early hallmark of the disease. TAA/AD with PDA is a new monogenic entity among the genetically heterogeneous group of TAA/AD disease.