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 autosomal dominant disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. There is a remarkable degree of clinical variability both within and between families with Marfan syndrome as well as in individuals with related disorders of connective tissue caused by FBN1 mutations and collectively termed type-1 fibrillinopathies. The so-called neonatal region in FBN1 exons 24-32 comprises one of the few generally accepted genotype-phenotype correlations described to date. In this work, we report 12 FBN1 mutations identified by temperature-gradient gel electrophoresis screening of exons 24-40 in 127 individuals with Marfan syndrome or related disorders. The data reported here, together with other published reports, document a significant clustering of mutations in exons 24-32. Although all reported mutations associated with neonatal Marfan syndrome and the majority of point mutations associated with atypically severe presentations have been found in exons 24-32, mutations associated with classic Marfan syndrome occur in this region as well. It is not possible to predict whether a given mutation in exons 24-32 will be associated with classic, atypically severe, or neonatal Marfan syndrome.

Novel exon skipping mutation in the fibrillin-1 gene: two 'hot spots' for the neonatal Marfan syndrome.

The Marfan syndrome is an autosomal dominant heritable disorder of connective tissue that involves principally the skeletal, ocular, and cardiovascular systems. The most severe end of the phenotypic spectrum, the neonatal Marfan syndrome (nMFS), is characterized by pronounced atrioventricular valve dysfunction, and death often occurs within the first year of life due to congestive heart failure. Mutations in the gene coding for fibrillin-1, FBN1, are known to cause Marfan syndrome, and have been identified in almost all exons of FBN1. Here, we describe a novel mutation affecting the invariant + 1 position of the splice donor site in intron 31, associated with skipping of exon 31, in a patient with nMFS. Published reports of nMFS are reviewed and a strict definition for nMFS is suggested. If this definition is used, all nMFS mutations reported to date lie in one of two hot spots, comprising mainly missense mutations in FBN1 exons 24-27 and mutations causing skipping of exon 31 or 32.