Clustering of mutations associated with mild Marfan-like phenotypes in the3 ' region of FBN1 suggests a potential genotype-phenotype correlation

Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, a domin antly inherited disorder of connective tissue that primarily involves the c ardiovascular, ocular, and skeletal systems. There is a remarkable degree o f variability both within and between families with Marfan syndrome, and FB N1 mutations have also been found in a range of other related connective ti ssue disorders collectively termed type-1 fibrillinopathies. FBN1 mutations have been found in almost all of the 65 exons of the FBN1 gene and for the most part have been unique to one affected patient or family. Aside from t he "hot spots" for the neonatal Marfan syndrome in exons 24-27 and 31-32, g enotype-phenotype correlations have been slow to emerge. Here we present th e results of temperature-gradient gel electrophoresis analysis of FBN1 exon s 59-65. Six mutations were identified, only one of which had been previous ly reported. Two of the six mutations were found in patients with mild phen otypes. Taken together with other published reports, our results suggest th at a sizable subset (ca. 40%) of mutations in this region is associated wit h mild phenotypes characterized by the lack of significant aortic pathology , compared with about 7% in the rest of the gene. In two cases, mutations a ffecting analogous positions within one of the 43 cbEGF modules of FBN1 are associated with mild phenotypes when found in one of the 6 C-terminal modu les (encoded by exons 59-63), but are associated with classic or severe phe notypes when found in cbEGF modules elsewhere in the gene. (C) 2000 Wiley-L iss, Inc.