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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 L. Callewaert 4 Anne H. Child 5 Christine Binquet 1 Elodie Gautier 1 Bart L. 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 N. Robinson 14 Lesley C. 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 
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.
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Laurence Faivre, Gwenaëlle Collod-Beroud, Bert L. Callewaert, Anne H. Child, Christine Binquet, et al.. Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation.. European Journal of Human Genetics, Nature Publishing Group, 2009, 17 (4), pp.491-501. ⟨10.1038/ejhg.2008.207⟩. ⟨inserm-00343925v2⟩



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