The non-syndromic familial thoracic aortic aneurysms and dissections maps to 15q21 locus.
The non-syndromic familial thoracic aortic aneurysms and dissections maps to 15q21 locus.
复制标题
DOI：
10.1186/1471-2350-11-143
复制
发表时间：
2010-10-11
影响因子：
--
通讯作者：
Mani A
中科院分区：
文献类型：
--
作者：
Keramati AR;Sadeghpour A;Farahani MM;Chandok G;Mani A
胸主动脉瘤和夹层（TAAD）是一种严重的疾病，通常未被诊断出致命的后果。虽然大多数病例是散发性的，但超过20%是作为单基因疾病遗传的。最常见的家族性TAA是马凡氏综合征（MFS），其主要是由BFN-1（FBN 1）基因突变引起。与其他具有相似尺寸动脉瘤的患者相比，FBN 1突变患者的夹层风险更高。15个家庭成员的基因分型使用Affytron-10 K基因芯片。全基因组关联研究采用常染色体显性不完全遗传模型进行。通过直接测序对FBN 1基因的所有外显子和外显子-内含子边界进行突变筛查，这些外显子和内含子边界位于峰值Lod评分附近。索引病例出现胸骨下疼痛，经胸超声心动图发现TAAD。3名TAA一级亲属的家族史意义重大。另外9名家庭成员通过超声心动图检查诊断为TAA。受影响的个人没有症状特征。全基因组连锁分析将该疾病基因定位于染色体15 q21上的单个位点，其中在FBN 1基因位点处的峰值Lod评分为3.6（优势比> 4000：1，有利于连锁），强烈表明FBN 1是致病基因。FBN 1基因外显子和外显子-内含子边界未发现与疾病分离的突变。单倍型分析确定了额外的突变携带者，他们以前由于升主动脉边缘扩张而状态未知。家族性非综合征性TAAD与FBN 1基因位点密切相关，并且在MFS患者中常见恶性病程。这一发现表明获得详细的家族史和超声心动图筛查非综合征型TAAD患者的远亲以改善预后的重要性。此外，非综合征型TAAD与马凡氏病基因位点的相关性提出了一个问题，即用于马凡氏综合征患者的二级预防策略是否应适用于所有家族性TAAD患者。
Thoracic aortic aneurysms and dissections (TAAD) is a critical condition that often goes undiagnosed with fatal consequences. While majority of the cases are sporadic, more than 20% are inherited as a single gene disorder. The most common familial TAA is Marfan syndrome (MFS), which is primarily caused by mutations in fibrillin-1 (FBN1) gene. Patients with FBN1 mutations are at higher risk for dissection compared to other patients with similar size aneurysms. Fifteen family members were genotyped using Affymetrix-10K genechips. A genome-wide association study was carried out using an autosomal dominant model of inheritance with incomplete penetrance. Mutation screening of all exons and exon-intron boundaries of FBN1 gene which reside near the peak Lod score was carried out by direct sequencing. The index case presented with agonizing substernal pain and was found to have TAAD by transthoracic echocardiogram. The family history was significant for 3 first degree relatives with TAA. Nine additional family members were diagnosed with TAA by echocardiography examinations. The affected individuals had no syndromic features. A genome-wide analysis of linkage mapped the disease gene to a single locus on chromosome 15q21 with a peak Lod score of 3.6 at fibrillin-1 (FBN1) gene locus (odds ratio > 4000:1 in favour of linkage), strongly suggesting that FBN1 is the causative gene. No mutation was identified within the exons and exon-intron boundaries of FBN1 gene that segregated with the disease. Haplotype analysis identified additional mutation carriers who had previously unknown status due to borderline dilation of the ascending aorta. A familial non-syndromic TAAD is strongly associated with the FBN1 gene locus and has a malignant disease course often seen in MFS patients. This finding indicates the importance of obtaining detailed family history and echocardiographic screening of extended relatives of patients with non-syndromic TAAD to improve the outcome. In addition, association of non-syndromic TAAD with the Marfan disease gene locus poses the question whether secondary prevention strategies employed for Marfan syndrome patients should be applied to all patients with familial TAAD.