Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation.

Laurence Faivre; Gwenaëlle Collod-Beroud; Bert Callewaert; Anne Child; Christine Binquet; Elodie Gautier; Bart Loeys; Eloisa Arbustini; Karin Mayer; Mine Arslan-Kirchner; Chantal Stheneur; Anatoli Kiotsekoglou; Paolo Comeglio; Nicola Marziliano; Jean-Eric Wolf; Olivier Bouchot; Philippe Khau-Van-Kien; Christophe Béroud; Mireille Claustres; Claire Bonithon-Kopp; Peter Robinson; Lesley Adès; Julie De Backer; Paul Coucke; Uta Francke; Anne De Paepe; Guillaume Jondeau; Catherine Boileau

doi:10.1038/ejhg.2008.207

Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation.

Laurence Faivre ^{1, 2, *} Gwenaëlle Collod-Beroud ³ Bert Callewaert ⁴ Anne Child ⁵ Christine Binquet ¹ Elodie Gautier ¹ Bart Loeys ^{4, 6} Eloisa Arbustini ⁷ Karin Mayer ⁸ Mine Arslan-Kirchner ⁹ Chantal Stheneur ¹⁰ Anatoli Kiotsekoglou ⁵ Paolo Comeglio ⁵ Nicola Marziliano ⁷ Jean-Eric Wolf ^{11, 12} Olivier Bouchot ¹³ Philippe Khau-Van-Kien ³ Christophe Béroud ³ Mireille Claustres ³ Claire Bonithon-Kopp ¹ Peter Robinson ¹⁴ Lesley Adès ^{15, 16, 17} Julie De Backer ⁴ Paul Coucke ⁴ Uta Francke ¹⁸ Anne De Paepe ⁴ Guillaume Jondeau ¹⁹ Catherine Boileau ^{20, 21, 22}

* Auteur correspondant

1 CIC-EC - Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques

2 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)

3 Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques

4 Center for Medical Genetics [Ghent]

5 Department of Cardiological Sciences

6 Institute of Genetic Medicine and the Howard Hughes Medical Institute

7 Centre for Inherited Cardiovacular Diseases

8 Center for Human Genetics and Laboratory Medicine

9 Institut für Humagenetik

10 Service de pédiatrie, urgences enfants

11 Le2i - Laboratoire Electronique, Informatique et Image

12 Service de Cardiologie II, Centre Hospitalier Universitaire

13 Service de chirurgie cardio-vasculaire

14 Institut für Medizinische Genetik

15 Discipline of Paediatrics and Child Health

16 Marfan Research Group

17 Department of Clinical Genetics

18 Department of Genetics and Pediatrics

19 Centre de reference national pour le syndrome de Marfan et apparentés

20 Service de biochimie, d'hormonologie et de génétique moléculaire

21 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement

22 UFR P.I.F.O

Abstract : Mutations in the FBN1 gene cause Marfan syndrome (MFS) and a wide range of overlapping phenotypes. The severe end of the spectrum is represented by neonatal MFS, the vast majority of probands carrying a mutation within exons 24-32. We previously showed that a mutation in exons 24-32 is predictive of a severe cardiovascular phenotype even in non-neonatal cases, and that mutations leading to premature truncation codons are under-represented in this region. To describe patients carrying a mutation in this so-called 'neonatal' region, we studied the clinical and molecular characteristics of 198 probands with a mutation in exons 24-32 from a series of 1013 probands with a FBN1 mutation (20%). When comparing patients with mutations leading to a premature termination codon (PTC) within exons 24-32 to patients with an in-frame mutation within the same region, a significantly higher probability of developing ectopia lentis and mitral insufficiency were found in the second group. Patients with a PTC within exons 24-32 rarely displayed a neonatal or severe MFS presentation. We also found a higher probability of neonatal presentations associated with exon 25 mutations, as well as a higher probability of cardiovascular manifestations. A high phenotypic heterogeneity could be described for recurrent mutations, ranging from neonatal to classical MFS phenotype. In conclusion, even if the exons 24-32 location appears as a major cause of the severity of the phenotype in patients with a mutation in this region, other factors such as the type of mutation or modifier genes might also be relevant.

Keywords : Marfan syndrome Neonatal Marfan syndrome FBN1 mutations exons 24–32 clinical and mutation-type analysis

Type de document :

Article dans une revue

European Journal of Human Genetics, Nature Publishing Group, 2009, 17 (4), pp.491-501. 〈10.1038/ejhg.2008.207〉

Domaine :

Sciences du Vivant [q-bio] / Génétique

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http://www.hal.inserm.fr/inserm-00343925
Contributeur : Gwenaëlle Collod-Beroud <>
Soumis le : mercredi 20 décembre 2017 - 18:03:12
Dernière modification le : mardi 10 avril 2018 - 12:34:01

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