Novel FBN1 gene mutation and maternal germinal mosaicism as the cause of neonatal form of Marfan syndrome
Novel FBN1 gene mutation and maternal germinal mosaicism as the cause of neonatal form of Marfan syndrome
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DOI：
10.1002/ajmg.a.36480
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发表时间：
2014-06-01
影响因子：
2
通讯作者：
Freiberger, Tomas
中科院分区：
文献类型：
--
作者：
Sipek, Antonin, Jr.;Grodecka, Lucie;Freiberger, Tomas
马凡综合征(MFS)是一种常染色体显性遗传病，由纤维蛋白1基因(FBN1)突变引起。新生儿形式的MFS是罕见的，并与严重的表型和预后不良有关。我们报告一名患有新生儿MFS的新生女婴，在出生第一天就表现出发紫和呼吸困难。主要临床表现为二尖瓣和三尖瓣关闭不全、主动脉根部扩张、蛛网膜炎和皮肤松弛。尽管存在严重的无法手术的心脏异常，但经对症治疗后，女孩的情况相当稳定，并活到了7个月大时，她因心肺衰竭去世。分子遗传学研究揭示了FBN1基因中一个新的内含子c.4211-32-13del突变。随后的体外剪接分析表明，该突变导致外显子35跳过，推测导致42个氨基酸的缺失(p.Leu1405_Asp1446del)。有趣的是，这种突变位于外显子24-32区域之外，该外显子的突变导致了绝大多数新生儿MFS病例。虽然MFS的家族史为阴性，但随后的分子遗传学检查发现母体血细胞中存在相同突变的嵌合体(占基因组DNA的10%-25%)，详细的临床检查显示为单侧晶状体异位。(C)2014年威利期刊公司。
Marfan syndrome (MFS) is an autosomal dominant disorder caused by mutations in the fibrillin 1 gene (FBN1). Neonatal form of MFS is rare and is associated with severe phenotype and a poor prognosis. We report on a newborn girl with neonatal MFS who displayed cyanosis and dyspnea on the first day of life. The main clinical features included mitral and tricuspid valve insufficiency, aortic root dilatation, arachnodactyly, and loose skin. Despite the presence of severe and inoperable heart anomalies, the girl was quite stable on symptomatic treatment and lived up to the 7th month of age when she died due to cardiorespiratory failure. Molecular-genetic studies revealed a novel intronic c.4211-32_-13del mutation in the FBN1 gene. Subsequent in vitro splicing analysis showed this mutation led to exon 35 skipping, presumably resulting in a deletion of 42 amino acids (p.Leu1405_Asp1446del). Interestingly, this mutation is localized outside the region of exons 24-32, whose mutation is responsible for the substantial majority of cases of neonatal MFS. Although the family history of MFS was negative, the subsequent molecular genetic examination documented a mosaicism of the same mutation in the maternal blood cells (10-25% of genomic DNA) and the detailed clinical examination showed unilateral lens ectopy. (c) 2014 Wiley Periodicals, Inc.