Prenatal and Presymptomatic Diagnosis of Marfan Syndrome Using Fluorescence PCR and an Automated Sequencer

The Marfan syndrome (MFS) is an autosomal dominant heritable connective tissue disorder characterized by variable and pleiotropic manifestations primarily in the skeletal, ocular, and cardiovascular systems (1 ). Molecular defects in fibrillin-1, a 350 kDa glycoprotein, encoded by the FBN1 gene located on chromosome 15 are now well documented in individuals and families with MFS (see ref. 2 for a review). The variability in phenotypic expression of MFS is significant not only between families, but also within a family, while the effective treatment of patients with MFS relies heavily on early and accurate diagnosis. It, therefore, seems likely that prenatal and presymptomatic molecular genetic analysis would prove a valuable adjunct to clinical diagnosis for purposes of risk assessment (3 –5 ). Mutations have been found along the entire 10 kb coding region of fibrillin and in most of its 65 exons. In addition, most families appear to have unique mutations. Therefore, the routine use of mutation screening for prenatal and presymptomatic diagnosis is impractical in this disorder. We have used intragenic polymorphic markers in FBN-1 (4 ) to perform linkage analyses in MFS families. We have adapted a “one-step” or “two-step” fluorescence PCR and automated sequencer to accurately, reproducibly, and rapidly perform prenatal or presymptomatic diagnosis of MFS in informative families.