A MOLECULAR APPROACH TO THE STRATIFICATION OF CARDIOVASCULAR RISK IN FAMILIES WITH MARFANS-SYNDROME

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. Th is disorder shows a high degree of clinical variability both between a nd within families. Each family appears to have a unique mutation in t he fibrillin gene, which precludes the routine use of mutation screeni ng for presymptomatic diagnosis of the disorder. The goal of this stud y was to develop a widely applicable method of molecular diagnosis. Me thods. We used three newly characterized intragenic sites of normal DN A 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 t he 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 Marfa n's syndrome or a milder but closely related phenotype. The copy of th e 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 sy ndrome, were not associated with aortic involvement. Conclusions, Thes e results document the usefulness of novel polymorphic DNA repeat sequ ences in the presymptomatic diagnosis of Marfan's syndrome. Our findin gs also demonstrate that the various clinical phenotypes seen in selec ted families may be due not to single fibrillin mutations, but rather to different genetic alterations. These findings underscore the need f or a modification of the current diagnostic criteria for Marfan's synd rome in order to achieve accurate risk assessment.