Abstract for presentation at 11th International Congress of Human Genetics

Homozygosity for FBN1 missense mutation: clinical and molecular evidence for recessive Marfan syndrome

  • Ben Hamel, Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • Gerard Pals, Department of Clinical Genetics, Free University medical center, Amsterdam, The Netherlands
  • Johan Waelkens, Department of Paediatrics, Catharina Hospital, Eindhoven, The Netherlands
  • Bert de Vries, Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    • Marfan syndrome is an autosomal dominant connective tissue disorder with very variable expressivity and complete, age-dependent penetrance. In the large majority of cases it is caused by hardly recurring heterozygous mutations in the FBN1 gene. Although OMIM online states that there is no evidence for a recessive form of Marfan syndrome, there are a few references to recessive (Fried & Krakowsky, 1977; Sun et al., 1990; Alvarez-Arratia et al., 1992) and to homozygous Marfan syndrome (Chemke et al., 1984), while there is one description of a FBN1 compound-heterozygous lethal Marfan syndrome patient (Karttunnen et al., 1994). We report on 2 cousins from a consanguineous family with a homozygous c.1453C>T FBN1 mutation (p.Arg485Cys). The 1st patient is a 22 years old male with ectopia lentis ODS, aortic dilatation and dissection, pneumothorax and some skeletal features who therefore fulfills the Ghent criteria for Marfan syndrome. The 2nd patient is his 13 years old female cousin with ectopia lentis ODS, high palate and some facial Marfan features, who does not fulfill the Ghent criteria. The parents of these 2 patients are first cousins and 2 by 2 siblings. So far, none of these 4 parents fulfills the Ghent criteria for Marfan syndrome (for the parents of patient 1 cardiologic examination will follow). The c.1453C>T FBN1 exon 11 mutation is a new mutation that was not found in 200 control chromosomes and leads to the substitution of the highly conserved amino acid arginine in an “EFG-like” domain of the protein into a cysteine which may have an effect on the function and/or structure of the protein. A new cysteine will probably interfere with S-S bridge formation or cause interchain crosslinks. The current clinical and molecular data support the diagnosis of recessive Marfan syndrome with minor features in some carriers.

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