TGGE screening of the entireFBN1coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies

Abstract

Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome (MFS), an autosomal dominant heritable disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. FBN1 mutations have also been identified in a series of related disorders of connective tissue collectively termed type-1 fibrillinopathies. We have developed temperature-gradient gel electrophoresis (TGGE) assays for all 65 FBN1 exons, screened 126 individuals with MFS, other type-1 fibrillinopathies, and other potentially related disorders of connective tissue for FBN1 mutations, and identified a total of 53 mutations, of which 33 are described here for the first time. Several mutations were identified in individuals with fibrillinopathies other than classic Marfan syndrome, including aneurysm of the ascending aorta with only minor skeletal anomalies, and several individuals with only skeletal and ocular involvement. The mutation detection rate in this study was 42% overall, but was only 12% in individuals not fulfilling the diagnostic criteria for MFS, suggesting that clinical overdiagnosis is one reason for the low detection rate observed for FBN1 mutation analysis.

Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies

“…Among the published mutations, R62C was associated with isolated ectopia lentis in one 31-year-old man with a de novo mutation but with manifestations of classic MFS in two other unrelated individuals with the identical, recurrent mutation [Katzke et al, 2002]. S115C was found in an individual with ectopia lentis and skeletal involvement but not aortic dilatation [Katzke et al, 2002].…”

Recent progress in genetics of Marfan syndrome and Marfan-associated disorders

“…More than 600 FBN1 mutations are registered in the UMD-FBN1 database for MFS and its associated disorders (http:// www.umd.be:2030/) . The mutation detection rate of FBN1 in MFS varies among studies, ranging from 9% to 91% (Katzke et al 2002;Loeys et al 2004;Tynan et al 1993). This variability could be explained, in part, by the different techniques used, but the most significant influencing factor is likely to be sample bias.…”

A Novel Fibrillin 1 Gene Mutation Leading to Marfan Syndrome with Minimal Cardiac Features

“…Cysteine substitutions in the vicinity of C538P on exon 13 (this study) such as C570R on exon 14 (previously 13) [Schrijver et al, 1999], or C587Y on exon 15 (previously 14) [Booms et al, 1997] both result in ectopia lentis with some skeletal and integument features, but no cardiac symptoms. Likewise, more distant substitutions such as C776G [Katzke et al, 2002], or C1782R [Adés et al, 2004] have been also shown to have little cardiac effect.…”