title: Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome.
abstract: 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.
  
  
  
  Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases.
  
  
  
  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.
  
  
  
  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.
authors: Département de Génétique et Centre de Référence Maladies Rares Syndrome de Marfan et pathologies apparentées, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France.|LVTS, INSERM U1148, Université Paris Diderot, Hôpital Bichat, Paris, France.
authors: Pauline
authors: P
authors: Arnaud
authors: Département de Génétique et Centre de Référence Maladies Rares Syndrome de Marfan et pathologies apparentées, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France.|LVTS, INSERM U1148, Hôpital Bichat, Paris, France.
authors: Nadine
authors: N
authors: Hanna
authors: LVTS, INSERM U1148, Hôpital Bichat, Paris, France.
authors: Mélodie
authors: M
authors: Aubart
authors: Hôpital de Brabois, Service de Génétique Clinique, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-lès-Nancy, France.
authors: Bruno
authors: B
authors: Leheup
authors: Hôpital Femme-Mère-Enfant, Service de Génétique Clinique, Centre Hospitalier Universitaire de Lyon, Bron, France.
authors: Sophie
authors: S
authors: Dupuis-Girod
authors: GH Pellegrin, Service de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors: Sophie
authors: S
authors: Naudion
authors: GH Pellegrin, Service de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors: Didier
authors: D
authors: Lacombe
authors: Hôpital Bichat, Centre de Référence Maladies Rares, Syndrome de Marfan et pathologies apparentéés, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors: Olivier
authors: O
authors: Milleron
authors: Hôpital Sud, Service de Génétique Clinique, Centre Hospitalier Universitaire de Rennes, Rennes, France.
authors: Sylvie
authors: S
authors: Odent
authors: Hôpital François Mitterrand, Centre de Génétique-Dijon, Centre Hospitalier Universitaire Dijon, Dijon, France.
authors: Laurence
authors: L
authors: Faivre
authors: Hôpital Timone Adultes, Service de Chirurgie vasculaire, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
authors: Laurence
authors: L
authors: Bal
authors: Centre Hospitalier Universitaire de Toulouse, Hôpital des Enfants, Service de Cardiologie, Toulouse, France.
authors: Thomas
authors: T
authors: Edouard
authors: Aix Marseille Univ, INSERM, GMGF, Marseille, France.
authors: Gwenaëlle
authors: G
authors: Collod-Beroud
authors: Hôpital Bichat, Centre de Référence Maladies Rares, Syndrome de Marfan et pathologies apparentéés, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors: Maud
authors: M
authors: Langeois
authors: Hôpital Bichat, Centre de Référence Maladies Rares, Syndrome de Marfan et pathologies apparentéés, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors: Myrtille
authors: M
authors: Spentchian
authors: Hôpital Bichat, Centre de Référence Maladies Rares, Syndrome de Marfan et pathologies apparentéés, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors: Laurent
authors: L
authors: Gouya
authors: LVTS, INSERM U1148, Université Paris Diderot, Hôpital Bichat, Paris, France.|Hôpital Bichat, Centre de Référence Maladies Rares, Syndrome de Marfan et pathologies apparentéés, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors: Guillaume
authors: G
authors: Jondeau
authors: Département de Génétique et Centre de Référence Maladies Rares Syndrome de Marfan et pathologies apparentées, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France.|LVTS, INSERM U1148, Université Paris Diderot, Hôpital Bichat, Paris, France.
authors: Catherine
authors: C
authors: Boileau
mesh_terms: D000483:Alleles; D018389:Codon, Nonsense; D005260:Female; D000071838:Fibrillin-1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D057089:Pathology, Molecular; D010375:Pedigree; D054392:Adipokines
chemical_list: D018389:Codon, Nonsense; D000071838:Fibrillin-1; C000605722:FBN1 protein, human; D054392:Adipokines
keywords: FBN1 gene; Genetic heterogeneity; Homozygosity; Marfan syndrome