Novel approach to the molecular diagnosis of Marfan syndrome: Application to sporadic cases and in prenatal diagnosis

Marfan syndrome is an autosomal dominant disorder affecting the skeletal, o cular, and cardiovascular systems. Defects in the gene that encodes fibrill in-1 (FBN1), the main structural component of the elastin-associated microf ibrils, are responsible for the disorder. Molecular diagnosis in families w ith Marfan syndrome can be undertaken by using intragenic FBN1 gene markers to identify and track the disease allele However, in sporadic cases, which constitute up to 30% of the total, DNA-based diagnosis cannot be performed using linked markers but rather requires the identification of the specifi c FBN1 gene mutation, Due to the size and complexity of the FBN1 gene, iden tification of a causative Marfan syndrome mutation is not a trivial underta king. Herein, we describe a comprehensive approach to the molecular diagnos is of Marfan syndrome that relies on the direct analysis of the FBN1 gene a t the cDNA level and detects both coding sequence mutations and those leadi ng to exon-skipping, which are often missed by analysis at the genomic DNA level, The ability to consistently determine the specific FBN1 gene mutatio n responsible for a particular case of Marfan syndrome allows both prenatal and pre-implantation diagnosis, even in sporadic instances of the disease. (C) 2001 Wiley-Liss, Inc.