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Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome
  1. Pauline Arnaud1,2,
  2. Nadine Hanna1,3,
  3. Mélodie Aubart3,
  4. Bruno Leheup4,
  5. Sophie Dupuis-Girod5,
  6. Sophie Naudion6,
  7. Didier Lacombe6,
  8. Olivier Milleron7,
  9. Sylvie Odent8,
  10. Laurence Faivre9,
  11. Laurence Bal10,
  12. Thomas Edouard11,
  13. Gwenaëlle Collod-Beroud12,
  14. Maud Langeois7,
  15. Myrtille Spentchian7,
  16. Laurent Gouya7,
  17. Guillaume Jondeau2,7,
  18. Catherine Boileau1,2
  1. 1Département de Génétique et Centre de Référence Maladies Rares Syndrome de Marfan et pathologies apparentées, Assistance Publique—Hôpitaux de Paris, Hôpital Bichat, Paris, France
  2. 2LVTS, INSERM U1148, Université Paris Diderot, Hôpital Bichat, Paris, France
  3. 3LVTS, INSERM U1148, Hôpital Bichat, Paris, France
  4. 4Hôpital de Brabois, Service de Génétique Clinique, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-lès-Nancy, France
  5. 5Hôpital Femme-Mère-Enfant, Service de Génétique Clinique, Centre Hospitalier Universitaire de Lyon, Bron, France
  6. 6GH Pellegrin, Service de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
  7. 7Hôpital Bichat, Centre de Référence Maladies Rares, Syndrome de Marfan et pathologies apparentéés, Assistance Publique—Hôpitaux de Paris, Paris, France
  8. 8Hôpital Sud, Service de Génétique Clinique, Centre Hospitalier Universitaire de Rennes, Rennes, France
  9. 9Hôpital François Mitterrand, Centre de Génétique-Dijon, Centre Hospitalier Universitaire Dijon, Dijon, France
  10. 10Hôpital Timone Adultes, Service de Chirurgie vasculaire, Assistance Publique—Hôpitaux de Marseille, Marseille, France
  11. 11Centre Hospitalier Universitaire de Toulouse, Hôpital des Enfants, Service de Cardiologie, Toulouse, France
  12. 12Aix Marseille Univ, INSERM, GMGF, Marseille, France
  13. 13Faculté de Médecine, Aix-Marseille Université, Marseille, France
  1. Correspondence to Professor Catherine Boileau, Département de Génétique, Hôpital Bichat, 46 rue Henri Huchard, Paris 75018, France; catherine.boileau{at}


Background Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation.

Objectives Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases.

Methods and results In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands.

Conclusion Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided.

  • Marfan syndrome
  • Genetic heterogeneity
  • FBN1 gene
  • Homozygosity

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