Whole exome sequencing for the identification of a new mutation in TGFB2 involved in a familial case of non-syndromic aortic disease
Whole exome sequencing for the identification of a new mutation in TGFB2 involved in a familial case of non-syndromic aortic disease
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DOI：
10.1016/j.cca.2014.07.016
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发表时间：
2014-11-01
影响因子：
5
通讯作者：
Brion, Maria
中科院分区：
文献类型：
--
作者：
Gago-Diaz, Marina;Blanco-Verea, Alejandro;Brion, Maria
背景：非综合征性主动脉疾病(NSAD)是一种常见的无症状但具有潜在致命性的疾病，其特征是有家族性的胸主动脉瘤和夹层。这种单基因但遗传异质性的疾病主要遗传为低外显性和可变表达的常染色体显性遗传病。方法：通过5500 Solid(TM)系统对一个西班牙非典型肺炎患者家族中两个远亲和受累成员的外显子全外显子进行分析，以确定共同的和可能的致病变异。结果：在最近发现的与NSAD相关的进化高度保守区域(ChR1：218,519,577-218,617,961)的TGFB2中发现了一个新的突变，命名为c.C1042T：p.R348C(NM_001135599.2)。用毛细管测序对其他家系成员的分析证实了该突变与疾病及其不完全穿透的共分离。结论：TGFB2基因在胸主动脉瘤和夹层的发生发展中的反复暗示提示在该病的基因诊断中应考虑该基因。对受影响的个人和其他处于危险中的家庭成员进行准确的诊断，可以进行个性化和更有效的基于基因的后续和治疗。最后，在TGFB2突变患者中反复出现常见的肌肉骨骼和颅面部的附加特征，表明存在一种新的但尚未明确的结缔组织综合征，不仅导致主动脉扩张，而且还导致受影响患者的其他心外改变。(C)2014爱思唯尔B.V.保留所有权利。
Background: Non-syndromic aortic disease (NSAD) is a frequently asymptomatic but potentially lethal disease characterised by familial cases of thoracic aortic aneurysms and dissections. This monogenic but genetically heterogeneous condition is primarily inherited as an autosomal dominant disorder with low penetrance and variable expression. Mutations in ACTA2, TGFBR1, TGFBR2, MYH11, SMAD3, MYLK, and FBN1 genes have been described but still, there are many unresolved familial cases.Methods: The whole exome of two distantly related and affected members of a Spanish family with multiple cases of NSAD was analysed through 5500 SOLiD (TM) System for the identification of shared and putative pathogenic variants.Results: A new mutation termed c.C1042T:p.R348C (NM_001135599.2) was identified in TGFB2, a gene located in an evolutionary highly conserved region (Chr1: 218,519,577-218,617,961) that has been recently connected to this disease. The analysis of other family members using capillary sequencing confirmed cosegregation of the mutation with the disease and its incomplete penetrance.Conclusions: The repeated implication of TGFB2 in the development of thoracic aortic aneurysms and dissections suggests that this gene should be considered during genetic diagnosis of this disease. An accurate diagnosis of affected individuals and additional family members at risk allows for a personalised and more efficient gene-based follow-up and treatment. Finally, the reiterative presence of common musculoskeletal and craniofacial additional features in patients with TGFB2 mutations suggests the existence of a new yet undefined connective tissue syndrome responsible for not only aortic dilation, but also for the other extracardiac alterations present in the affected patients. (C) 2014 Elsevier B.V. All rights reserved.