Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype–phenotype correlations in 76 patients with Marfan syndrome

✍ Scribed by Kathrin Rommel; Matthias Karck; Axel Haverich; Yskert von Kodolitsch; Meike Rybczynski; Götz Müller; Krishna K. Singh; Jörg Schmidtke; Mine Arslan-Kirchner

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 180 KB
• Volume: 26
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.20239

✦ Synopsis

Communicated by Jurgen Horst

Marfan syndrome (MFS) is an autosomal-dominant disorder of the fibrous connective tissue that is typically caused by mutations in the gene coding for fibrillin-1 (FBN1), a major component of extracellular microfibrils. The clinical spectrum of MFS is highly variable and includes involvement of the cardiovascular, skeletal, ocular, and other organ systems; however, the genotype-phenotype correlations have not been well developed. Various screening methods have led to the identification of about 600 different mutations (FBN1-UMD database; www.umd.be). In this study we performed SSCP and/or direct sequencing to analyze all 65 exons of the FBN1 gene in 116 patients presenting with classic MFS or related phenotypes. Twenty-nine novel and nine recurrent mutations were identified in 38 of the analyzed patients. The mutations comprised 18 missense (47%), eight nonsense (21%), and five splice site (13%) mutations. Seven further mutations (18%) resulted from deletion, insertion, or duplication events, six of which led to a frameshift and subsequent premature termination. Additionally, we describe new polymorphisms and sequence variants.

On the basis of the data presented here and in a previous study, we were able to establish highly significant correlations between the FBN1 mutation type and the MFS phenotype in a group of 76 mutationpositive patients for whom comprehensive clinical data were available. Most strikingly, there was a significantly lower incidence of ectopia lentis in patients who carried a mutation that led to a premature termination codon (PTC) or a missense mutation without cysteine involvement in FBN1, as compared to patients whose mutations involved a cysteine substitution or splice site alteration.