Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24-40

Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, an auto somal dominant disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. There is a remarkable d egree of clinical variability both within and between families with Marfan syndrome as well as in individuals with related disorders of connective tis sue caused by FBN1 mutations and collectively termed type-1 fibrillinopathi es. The so-called neonatal region in FBN1 exons 24-32 comprises one of the few generally accepted genotype-phenotype correlations described to date. I n this work, we report 12 FBN1 mutations identified by temperature-gradient gel electrophoresis screening of exons 24-40 in 127 individuals with Marfa n syndrome or related disorders. The data reported here, together with othe r published reports, document a significant clustering of mutations in exon s 24-32. Although all reported mutations associated with neonatal Marfan sy ndrome and the majority of point mutations associated with atypically sever e presentations have been found in exons 24-32 mutations associated with cl assic Marfan syndrome occur in this region as well. It is not possible to p redict whether a given mutation in exons 24-32 will be associated with clas sic, atypically severe, or neonatal Marfan syndrome.