15 NOVEL FBN1 MUTATIONS CAUSING MARFAN-SYNDROME DETECTED BY HETERODUPLEX ANALYSIS OF GENOMIC AMPLICONS

Mutations in the gene encoding fibrillin-1 (FBN1), a component of the extracellular microfibril, cause the Marfan syndrome (MFS). This state ment is supported by the observations that the classic Marfan phenotyp e cosegregates with intragenic and/or flanking marker alleles in all f amilies tested and that a significant number of FBN1 mutations have be en identified in affected individuals. We have now devised a method to screen the entire coding sequence and flanking splice junctions of FB N1. On completion for a panel of nine probands with classic MFS, six n ew mutations were identified that accounted for disease in seven (78%) of nine patients. Nine additional new mutations have been characteriz ed in the early stages of a larger screening project. These 15 mutatio ns were equally distributed throughout the gene and, with one exceptio n, were specific to single families. One-third of mutations created pr emature termination codons, and 6 of 15 substituted residues with puta tive significance for calcium binding to epidermal growth factor (EGF) -like domains. Mutations causing severe and rapidly progressive diseas e that presents in the neonatal period can occur in a larger region of the gene than previously demonstrated, and the nature of the mutation is as important a determinant as its location, in predisposing to thi s phenotype.