Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome

Am J Hum Genet. 1998 Dec;63(6):1703-11. doi: 10.1086/302144.


Mutations in the FBN1 gene, which encodes fibrillin-1, cause Marfan syndrome (MFS) and have been associated with a wide range of milder, overlap phenotypes. The factors that modulate phenotypic severity, both between and within families, remain to be determined. This study examines the relationship between the FBN1 genotype and phenotype in families with extremely mild phenotypes and in those that show striking clinical variation among apparently affected individuals. In one family, clinically similar but etiologically distinct disorders are segregating independently. In another, somatic mosaicism for a mutant FBN1 allele is associated with subdiagnostic manifestations, whereas germ-line transmission of the identical mutation causes severe and rapidly progressive disease. A third family cosegregates mild mitral valve prolapse syndrome with a mutation in FBN1 that can be functionally distinguished from those associated with the classic MFS phenotype. These data have immediate relevance for the diagnostic and prognostic counseling of patients and their family members.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Alleles
  • Cells, Cultured
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Female
  • Fibrillin-1
  • Fibrillins
  • Genetic Linkage
  • Genetic Variation
  • Genotype
  • Haplotypes / genetics
  • Heteroduplex Analysis
  • Humans
  • Male
  • Marfan Syndrome / diagnosis
  • Marfan Syndrome / genetics*
  • Marfan Syndrome / pathology
  • Microfilament Proteins / genetics*
  • Microfilament Proteins / metabolism
  • Middle Aged
  • Mitral Valve Prolapse
  • Mosaicism / genetics
  • Mutation*
  • Pedigree
  • Phenotype


  • FBN1 protein, human
  • Fibrillin-1
  • Fibrillins
  • Microfilament Proteins