Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome.

BACKGROUND Marfan syndrome (MFS) is an underrecognized heritable connective tissue disorder resulting from mutations in the gene for fibrillin-1 (FBN1). Affected patients are at risk for aortic dissection and/or severe ocular and orthopedic problems. The diagnosis is primarily based on a set of well-defined clinical criteria (Ghent nosology). The age-related nature of some clinical manifestations and variable phenotypic expression may hinder the diagnosis, particularly in children. Molecular analysis may be helpful to identify at-risk individuals early and start prophylactic medical treatment. FBN1 mutations have also been reported in patients with Marfan-related conditions, but it is unknown what proportion of all FBN1 mutation carriers they represent. METHODS We reviewed the clinical and molecular data of 171 consecutive patients referred for FBN1 analysis because either MFS was diagnosed or they had signs suggestive of MFS. We compared the incidence of mutations in patients who fulfilled the clinical diagnostic criteria for MFS with those who did not. RESULTS Diagnostic criteria for MFS were fulfilled in 94 patients, 62 (66%) of whom had an FBN1 mutation. A significantly higher incidence of ectopia lentis was found in the patients with MFS with an FBN1 mutation vs those without (P=.04). Among the 77 patients who did not meet the criteria, an FBN1 mutation was found in 9 patients (12%). No correlation was found between the severity of the phenotype and the position and nature of the FBN1 mutation. CONCLUSIONS This study showed a significant difference in the number of FBN1 mutations between patients fulfilling and those not fulfilling the diagnostic criteria for MFS, which seems to be a good predictor of the presence of an FBN1 mutation. A comprehensive clinical evaluation is mandatory before establishing a definitive diagnosis. An FBN1 mutation analysis is helpful to identify individuals at high risk for MFS who need careful follow-up, particularly in families displaying phenotypic variability and in children.