Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have 
been associated with a wide range of overlapping phenotypes. Clinical care is 
complicated by variable age at onset and the wide range of severity of aortic 
features. The factors that modulate phenotypical severity, both among and within 
families, remain to be determined. The availability of international FBN1 
mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the 
largest collaborative study ever reported, to investigate the correlation 
between the FBN1 genotype and the nature and severity of the clinical phenotype. 
A range of qualitative and quantitative clinical parameters (skeletal, 
cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for 
different classes of mutation (types and locations) in 1,013 probands with a 
pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for 
patients with a missense mutation substituting or producing a cysteine, when 
compared with other missense mutations. Patients with an FBN1 premature 
termination codon had a more severe skeletal and skin phenotype than did 
patients with an inframe mutation. Mutations in exons 24-32 were associated with 
a more severe and complete phenotype, including younger age at diagnosis of type 
I fibrillinopathy and higher probability of developing ectopia lentis, ascending 
aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and 
shorter survival; the majority of these results were replicated even when cases 
of neonatal MFS were excluded. These correlations, found between different 
mutation types and clinical manifestations, might be explained by different 
underlying genetic mechanisms (dominant negative versus haploinsufficiency) and 
by consideration of the two main physiological functions of fibrillin-1 
(structural versus mediator of TGF beta signalling). Exon 24-32 mutations define 
a high-risk group for cardiac manifestations associated with severe prognosis at 
all ages.