Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Key Lab. of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, China.
Clin Chim Acta. 2016 Sep 1;460:102-6. doi: 10.1016/j.cca.2016.06.031. Epub 2016 Jun 25.
Previous studies demonstrated that patients with different FBN1 mutations often present more considerable phenotypic variation compared to different members of the related family carrying a same mutation. The purpose of our study was to identify pathogenic mutation and provide more information about genotype-phenotypic correlations in a large Chinese family with Marfan syndrome.
15 related family members from a Chinese 4-generation pedigree with Marfan syndrome underwent physical, ophthalmologic, radiological and cardiovascular examinations. The propositus has De Bakey III aortic dissection and didn't fulfill the revised Ghent criteria for Marfan syndrome. Nine family members have ectopia lentis and their echocardiogram was normal. Five other family members have no evidence of Marfan syndrome. Genomic DNA was isolated from blood leukocytes. The exome sequencing was employed on the propositus, then the Sanger sequencing was conducted for mutation verification in other 14 participants of this family.
The causative mutation in FBN1 discovered in the propositus was a known heterozygous missense mutation, c.1633T>G (p.R545C), in exon 14 (NM 000138). This same mutation was also identified in all 9 ectopia lentis patients and one unaffected 8-year-old girl. However, the same mutation was not discovered in other 4 unaffected family members.
Our data enhance the information of genotype-phenotype correlation owing to FBN1 mutations. To our current knowledge, we firstly reported that the same FBN1 mutation, c. 1633C>T (Arg545Cys), was detected simultaneously in three different cardinal phenotypes (ectopia lentis, aortic dissection and unaffected) within one family. The unaffected girl with FBN1 mutation may presumably represent a rare case of nonpenetrance.
先前的研究表明，与携带相同突变的不同家族成员相比，患有不同 FBN1 突变的患者通常表现出更为显著的表型变异。本研究的目的是在一个大型的中国马凡综合征家系中鉴定致病性突变，并提供更多关于基因型-表型相关性的信息。
15 名来自一个有马凡综合征的中国 4 代家系的相关家族成员接受了体格、眼科、放射学和心血管检查。先证者患有 De Bakey III 型主动脉夹层，不符合马凡综合征的修订 Ghent 标准。9 名家族成员有晶状体异位，其超声心动图正常。另外 5 名家族成员没有马凡综合征的证据。从血液白细胞中提取基因组 DNA。对先证者进行外显子组测序，然后对该家系的其他 14 名参与者进行 Sanger 测序进行突变验证。
在先证者中发现的 FBN1 致病突变是一个已知的杂合错义突变，c.1633T>G（p.R545C），位于 14 号外显子（NM 000138）。这同样的突变也在所有 9 名晶状体异位患者和一名 8 岁的未受影响女孩中被发现。然而，在其他 4 名未受影响的家族成员中没有发现同样的突变。
我们的数据增加了由于 FBN1 突变导致的基因型-表型相关性的信息。就我们目前所知，我们首次报道了同一 FBN1 突变，c.1633C>T（Arg545Cys），同时在一个家族中的三种不同的主要表型（晶状体异位、主动脉夹层和未受影响）中被检测到。携带 FBN1 突变的未受影响的女孩可能代表了一种罕见的非外显率病例。
