The Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue. Variable and pleiotropic clinical features are observed in the skeletal, ocular, and cardiovascular systems. The most severe end of the phenotypic spectrum of this disorder comprises a group of patients usually diagnosed at birth, who have a life expectancy of little more than a year. To distinguish this group of patients from those with classical MFS, we refer to them as neonatal Marfan syndrome (nMFS). These infants usually die of congestive heart failure rather than aortic aneurysmal disease, the most frequent cause of morbidity and mortality in classical MFS. Defects in fibrillin, an elastin-associated microfibrillar glycoprotein, are now known to cause both the classical and neonatal forms of MFS. Here we report the recurrent mis-splicing of fibrillin (FBN1) exon 32, a precursor EGF-like calcium binding domain, in two unrelated infants with nMFS. The mis-splicing, in one patient, was due to an A-->T transversion at the -2 position of the consensus acceptor splice site; while that in the second patient was caused by a G-->A transition at the +1 position of the donor splice site. Characterization of FBN1 mutations in individuals at the most severe end of the Marfan syndrome spectrum should provide greater understanding of the multiple domains and regions of fibrillin.

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The Marfan syndrome (MFS) is a heritable connective tissue disorder characterized by skeletal, ocular, and cardiovascular abnormalities. Defects in fibrillin, an elastin-associated microfibrillar protein, are now known to cause MFS. Since the discovery of fibrillin as the gene responsible for MFS, requests for prenatal and presymptomatic diagnosis have become common-place. Here we report the use of the polymerase chain reaction (PCR), using fluorescence labelled primers and an automated sequencer, to establish linkage data for 'molecular diagnosis'. The mistaken clinical diagnosis of MFS based on the appearance of a common cardiovascular manifestation, mitral valve prolapse, and a positive family history is also discussed.

The recent identification of numerous matrix genes and gene products has allowed a detailed examination of their roles in development. Two of these extracellular matrix proteins, fibrillin-1 and fibrillin-2, are components of the elastin-associated microfibrils. Given what is known about the distribution of the fibrillins in normal tissues and the abnormalities that result when mutations occur, a basic hypothesis has emerged: fibrillin-1 is primarily responsible for load bearing and providing structural integrity, whereas fibrillin-2 may be a director of elastogenesis. Nevertheless, examination of phenotypes in disorders caused by mutations in fibrillin-1 or fibrillin-2 suggests some common functions. To better understand these similar and diverse roles, it would be helpful to examine these proteins during chick development. To accomplish this goal, it is first necessary to characterize the chick homologs of the known fibrillins. In this study, the partial chick FBN1 cDNA was identified by polymerase chain reaction-aided cloning as a first step toward elucidating these goals. Sequence analysis indicated that there is striking conservation between chick and mammalian fibrillin-1 at the DNA and protein levels. Antisense and sense riboprobes were synthesized and used in in situ hybridization in stage 14 chick embryos and high levels of FBN1 transcripts were observed in the heart.

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