BACKGROUND: The fibrillin gene encodes a protein in the extracellular matrix, 
and this protein is widely distributed in elastic tissues. The fibrillin gene is 
the site of mutations causing Marfan's syndrome. This disorder shows a high 
degree of clinical variability both between and within families. Each family 
appears to have a unique mutation in the fibrillin gene, which precludes the 
routine use of mutation screening for presymptomatic diagnosis of the disorder. 
The goal of this study was to develop a widely applicable method of molecular 
diagnosis.
METHODS: We used three newly characterized intragenic sites of normal DNA 
repeat-sequence variation (i.e., polymorphisms) as markers to follow the 
inheritance pattern of specific copies (alleles) of the fibrillin gene in 
multiple kindreds with various clinical features of Marfan's syndrome.
RESULTS: The polymorphic markers allowed identification of the particular copy 
of the fibrillin gene that cosegregated with Marfan's syndrome in 13 of the 14 
families tested. In 11 families a definite presymptomatic diagnosis of Marfan's 
syndrome could be made in family members who had only equivocal manifestations 
of the disorder. In two other families, some family members demonstrated either 
classic Marfan's syndrome or a milder but closely related phenotype. The copy of 
the fibrillin gene that cosegregated with classic Marfan's syndrome was not 
inherited by family members with the latter, atypical, form of the disease. 
These milder phenotypes, previously diagnosed as Marfan's syndrome, were not 
associated with aortic involvement.
CONCLUSIONS: These results document the usefulness of novel polymorphic DNA 
repeat sequences in the presymptomatic diagnosis of Marfan's syndrome. Our 
findings also demonstrate that the various clinical phenotypes seen in selected 
families may be due not to single fibrillin mutations, but rather to different 
genetic alterations. These findings underscore the need for a modification of 
the current diagnostic criteria for Marfan's syndrome in order to achieve 
accurate risk assessment.