Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations:: An international study
Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations:: An international study
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DOI：
10.1086/520125
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发表时间：
2007-09-01
影响因子：
9.8
通讯作者：
Boileau, C.
中科院分区：
文献类型：
--
作者：
Faivre, L.;Collod-Beroud, G.;Boileau, C.
纤维蛋白1 （FBN1）基因突变导致马凡氏综合征（MFS），并与多种重叠表型相关。临床护理因发病年龄不同和主动脉特征严重程度不同而复杂。调节表型严重程度的因素，无论是家庭之间还是家庭内部，仍有待确定。国际FBNI突变通用突变数据库（UMD-FBN1）的可用性使我们能够进行有史以来最大的合作研究，以调查FBNI基因型与临床表型的性质和严重程度之间的相关性。对1013例致病性FBNI突变先证者的不同突变类型（类型和位置）进行了一系列定性和定量临床参数（骨骼、心血管、眼科、皮肤、肺部和硬脑膜）的比较。与其他错义突变相比，替换或产生半胱氨酸的错义突变患者发生异位透镜的可能性更高。具有FBN1过早终止密码子的患者比具有框架内突变的患者具有更严重的骨骼和皮肤表型。外显子24-32的突变与更严重和完整的表型相关，包括诊断为I型纤原性病变时年龄更小，发生异位晶状体、升主动脉扩张、主动脉手术、二尖瓣异常、脊柱侧凸的概率更高，生存期更短；即使排除了新生儿MFS病例，这些结果中的大多数也是重复的。不同突变类型与临床表现之间的相关性可能由不同的潜在遗传机制（显性阴性与单倍不全）和纤颤蛋白-1的两种主要生理功能（结构与TGF β信号传导介质）来解释。外显子24-32突变定义了所有年龄段与严重预后相关的心脏表现的高危人群。
Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBNI mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBNI genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBNI mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.