Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study.

Laurence Faivre; Gwenaëlle Collod-Beroud; Bart Loeys; Anne Child; Christine Binquet; Elodie Gautier; Bert Callewaert; Eloisa Arbustini; Karin Mayer; Mine Arslan-Kirchner; Anatoli Kiotsekoglou; Paolo Comeglio; Nicola Marziliano; Harry Dietz; Dorothy Halliday; Christophe Béroud; Claire Bonithon-Kopp; Mireille Claustres; Christine Muti; Henri Plauchu; Peter Robinson; Lesley Adès; Andrew Biggin; Bruce Benetts; Maggie Brett; Katherine Holman; Julie De Backer; Paul Coucke; Uta Francke; Anne De Paepe; Guillaume Jondeau; Catherine Boileau

doi:10.1086/520125

Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study.

Laurence Faivre ^{1, 2} Gwenaëlle Collod-Beroud ^{3, *} Bart Loeys ^{4, 5} Anne Child ⁶ Christine Binquet ² Elodie Gautier ² Bert Callewaert ⁴ Eloisa Arbustini ⁷ Karin Mayer ⁸ Mine Arslan-Kirchner ⁹ Anatoli Kiotsekoglou ⁶ Paolo Comeglio ⁶ Nicola Marziliano ⁷ Harry Dietz ⁵ Dorothy Halliday ¹⁰ Christophe Béroud ² Claire Bonithon-Kopp ² Mireille Claustres ³ Christine Muti ¹¹ Henri Plauchu ¹² Peter Robinson ¹³ Lesley Adès ^{14, 15, 16} Andrew Biggin ^{14, 17} Bruce Benetts ^{14, 17} Maggie Brett ^{14, 17} Katherine Holman ^{14, 17} Julie De Backer ⁴ Paul Coucke ⁴ Uta Francke ¹⁸ Anne De Paepe ^{4, 19} Guillaume Jondeau ^{11, 20} Catherine Boileau ^{11, 21}

* Auteur correspondant

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

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

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

4 Center for Medical Genetics [Ghent]

5 Institute of Genetic Medicine and the Howard Hugues Medical Institute

6 Sonalee Laboratory for Marfan syndrome and related disorders, Department of Cardiological Sciences

7 Centre for Inherited Cardiovacular Diseases

8 Center for Human Genetics and Laboratory Medicine

9 Institut für Humagenetik

10 Department of Biochemistry [Oxford]

11 Consultation Marfan

12 Service de Génétique

13 Institut für Medizinische Genetik

14 Marfan Research Group

15 Department of Clinical Genetics

16 Discipline of Paediatrics and Child Health

17 Department of Molecular Genetics

18 Department of Genetics and Pediatrics

19 Cardiological Sciences

20 Service de cardiologie

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

Abstract : Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

Type de document :

Article dans une revue

American Journal of Human Genetics, Elsevier (Cell Press), 2007, 81 (3), pp.454-66. 〈10.1086/520125〉

Domaine :

Sciences du Vivant [q-bio] / Génétique

Liste complète des métadonnées

Littérature citée [48 références] Voir Masquer Télécharger

http://www.hal.inserm.fr/inserm-00344134
Contributeur : Gwenaëlle Collod-Beroud <>
Soumis le : mercredi 20 décembre 2017 - 19:02:05
Dernière modification le : vendredi 8 juin 2018 - 14:50:10

Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study.

Fichier

Accès restreint

Identifiants

Collections

Citation

Exporter

Métriques

257

Contact

Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study.

Fichier

Accès restreint

Identifiants

Collections

Citation

Exporter

Partager

Métriques

257

Contact