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Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands.

Laurence Faivre 1, 2 Gwenaëlle Collod-Beroud 3 Anne Child 4 Bert Callewaert 5 Bart Loeys 5, 6 Christine Binquet 2 Elodie Gautier 2 Eloisa Arbustini 7 Karin Mayer 8 Mine Arslan-Kirchner 9 Chantal Stheneur 10, 11 Anatoli Kiotsekoglou 4 Paolo Comeglio 4 Nicola Marziliano 7 Dorothy Halliday 12 Christophe Béroud 3 Claire Bonithon-Kopp 2 Mireille Claustres 3 Henri Plauchu 13 Peter Robinson 14 Lesley Adès 15, 16, 17 Julie de Backer 5 Paul Coucke 5 Uta Francke 18 Anne de Paepe 5 Catherine Boileau 19 Guillaume Jondeau 11
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 Department of Cardiological Sciences
5 Center for Medical Genetics [Ghent]
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 [CHU Ambroise-Paré]
11 Consultation Marfan
12 Department of Biochemistry [Oxford]
13 Service de Génétique
14 Institut für Medizinische Genetik
15 Marfan Research Group
16 Department of Clinical Genetics
17 Discipline of Paediatrics and Child Health
18 Department of Genetics [Stanford]
19 Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré]
Abstract : BACKGROUND: The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. METHODS: Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the "clinical" international criteria. RESULTS: Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled "clinical criteria" when compared to the Marfan syndrome group (44% vs 73% at 40 years, p<0.001), but the lifelong risk for ascending aortic dissection or surgery was not significantly different in both groups. CONCLUSIONS: Because of its implications for aortic follow-up, FBN1 molecular analysis is recommended in newly suspected MFS when two systems are involved with at least one major system affected. This is of utmost importance in patients without aortic dilatation and in children.
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INSERM | UNIV-BOURGOGNE | BS | UNIV-MONTPELLIER

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Laurence Faivre, Gwenaëlle Collod-Beroud, Anne Child, Bert Callewaert, Bart Loeys, et al.. Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands.. Journal of Medical Genetics, BMJ Publishing Group, 2008, 45 (6), pp.384-90. ⟨10.1136/jmg.2007.056382⟩. ⟨inserm-00343946⟩

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