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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
* Corresponding author
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 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques
4 Center for Medical Genetics [Ghent]
5 HHMI - Howard Hughes 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 [Stanford]
19 Cardiological Sciences
20 Service de cardiologie
21 Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré]
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.
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INSERM | UNIV-BOURGOGNE | UNIV-PARIS7 | USPC | BS | UNIV-MONTPELLIER | UNIV-PARIS

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Laurence Faivre, Gwenaëlle Collod-Beroud, Bart Loeys, Anne Child, Christine Binquet, et al.. 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.. American Journal of Human Genetics, Elsevier (Cell Press), 2007, 81 (3), pp.454-66. ⟨10.1086/520125⟩. ⟨inserm-00344134⟩

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