Marfan Syndrome (MfS) is an autosomal dominant inherited connective tissue 
disorder with variable phenotypic expression of cardiovascular, skeletal and 
ocular manifestations. Cardiovascular complications, such as aortic aneurysm and 
dissection drastically reduce life expectancy of individuals with MfS, whereas 
preventive surgery substantially improves the prognosis of these patients. A 
number of mutations in the fibrillin 1 (FBN1) gene associated with MfS have been 
identified to date, demonstrating considerable molecular heterogeneity. One 
region, however, located around exon 24, exhibits a striking clustering of 
mutations, which are associated with a severe, socalled neonatal form of MfS. 
Here we report the first mutation (G2950A) in exon 24 of the neonatal region of 
the FBN1 gene, associated with a classic MfS phenotype. The mutation leads to 
the subsitution of valin by isoleucin (V984I), both uncharged amino acids, which 
only differ in a single methyl group. This defect was identified in a proband 
with cardiovascular manifestations of MfS by SSCP analysis of PCR-amplified 
genomic DNA, direct PCR sequencing and RFLP analysis. The substitution was 
neither detected in the unaffected 4-year old daughter of the proband, nor in 3 
of his healthy family members nor in 108 allels from control individuals, 
suggesting that this mutation is causative for MfS in the patient. Since no 
other family member of the proband is affected by MfS, the defect described is 
sporadic. In summary, we identified a novel defect in exon 24 of the neonatal 
region of the FBN1 gene in a patient with a classic phenotype of MfS, suggesting 
that conservative substitutions in this region may lead to a less severe 
phenotype of the disease. This finding further demonstrates the remarkable 
phenotypic heterogeneity associated with FBN1 mutations and stresses the 
significance of modifying genes and individual alterations in protein function 
for the pheontypic expression of the disease.