Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.
Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.
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DOI：
10.1161/circresaha.111.248161
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发表时间：
2011-09-02
影响因子：
20.1
通讯作者：
Milewicz DM
中科院分区：
文献类型：
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作者：
Regalado ES;Guo DC;Villamizar C;Avidan N;Gilchrist D;McGillivray B;Clarke L;Bernier F;Santos-Cortez RL;Leal SM;Bertoli-Avella AM;Shendure J;Rieder MJ;Nickerson DA;NHLBI GO Exome Sequencing Project;Milewicz DM
胸主动脉瘤导致急性主动脉夹层（TAAD）可以遗传常染色体显性方式的家庭。作为家族性TAAD临床异质性谱的一部分，我们最近描述了有多个成员患有TAAD和颅内动脉瘤或TAAD和颅内及腹主动脉瘤以常染色体显性遗传方式遗传的家族。通过对两个远亲TAAD患者进行外显子组测序并鉴定共享的罕见变异，确定常染色体显性遗传TAAD颅内和腹主动脉瘤大家族的致病突变。在SMAD3基因中发现了一个新的框架移位突变p. N218fs (c.652delA)，并与该家族的血管疾病分离，LOD评分为2.52。对家族性TAAD的181个先证进行测序，在4个家族中发现了另外3个SMAD3突变，p.R279K (c.836G>A), p.E239K （c.715G>A）和p.A112V (c.235C>T)，导致LOD评分为5.21。这四个突变在2300个对照外显子组中明显缺失。最近在动脉瘤性骨关节炎综合征患者中发现了SMAD3突变，并且在我们的队列中发现了该综合征的一些特征，但这些特征在许多SMAD3突变携带者中明显缺失。SMAD3突变占家族性TAAD的2%。突变存在于TAAD家族中，也存在于TAAD家族中，颅内动脉瘤、主动脉动脉瘤和双侧髂动脉瘤以常染色体显性方式分离。
Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in families in an autosomal dominant manner. As part of the spectrum of clinical heterogeneity of familial TAAD, we recently described families with multiple members that had TAAD and intracranial aneurysms or TAAD and intracranial and abdominal aortic aneurysms inherited in an autosomal dominant manner. To identify the causative mutation in a large family with autosomal dominant inheritance of TAAD with intracranial and abdominal aortic aneurysms by performing exome sequencing of two distantly related individuals with TAAD and identifying shared rare variants. A novel frame shift mutation, p. N218fs (c.652delA), was identified in the SMAD3 gene and segregated with the vascular diseases in this family with a LOD score of 2.52. Sequencing of 181 probands with familial TAAD identified three additional SMAD3 mutations in 4 families, p.R279K (c.836G>A), p.E239K (c.715G>A), and p.A112V (c.235C>T) resulting in a combined LOD score of 5.21. These four mutations were notably absent in 2300 control exomes. SMAD3 mutations were recently described in patients with Aneurysms Osteoarthritis Syndrome and some of the features of this syndrome were identified in individuals in our cohort, but these features were notably absent in many SMAD3 mutation carriers. SMAD3 mutations are responsible for 2% of familial TAAD. Mutations are found in families with TAAD alone, along with families with TAAD, intracranial aneurysms, aortic and bilateral iliac aneurysms segregating in an autosomal dominant manner.