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NF1 Molecular Characterization and Neurofibromatosis Type I Genotype–Phenotype Correlation: The French Experience |
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| Authors: | Audrey Sabbagh Eric Pasmant Apolline Imbard Armelle Luscan Magali Soares Hélène Blanché Ingrid Laurendeau Salah Ferkal Michel Vidaud Stéphane Pinson Christine Bellanné‐Chantelot Dominique Vidaud the members of the NF France Network Béatrice Parfait Pierre Wolkenstein |
| Affiliation: | 1. UMR745 INSERM, PRES Sorbonne Paris Cité, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, , Paris, France;2. IRD, UMR216, Mère et enfant face aux infections tropicales, , Paris, France;3. PRES Sorbonne Paris Cité, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, , Paris, France;4. Service de Biochimie et de Génétique Moléculaire, H?pital Cochin, AP‐HP, , Paris, France;5. Service de Biochimie‐Hormonologie, H?pital Robert Debré, , Paris, France;6. Fondation Jean‐Dausset‐Centre d'Etude du Polymorphisme Humain (CEPH), Institut de Génétique Moléculaire, , Paris, France;7. INSERM, Centre d'Investigation Clinique 006, AP‐HP, Groupe hospitalier Henri Mondor‐Albert Chenevier, , Créteil, France;8. Service de Génétique moléculaire, H?pital Edouard‐Herriot, , Lyon, France;9. Département de Génétique, H?pital de la Pitié‐Salpêtrière, Université Pierre et Marie Curie, APHP, , Paris, France;10. Département de Dermatologie, Centre de référence des neurofibromatoses, H?pital Henri‐Mondor, AP‐HP and EA 4393 LIC, Université Paris Est Créteil (UPEC), , Créteil, France |
| Abstract: | Neurofibromatosis type 1 (NF1) affects about one in 3,500 people in all ethnic groups. Most NF1 patients have private loss‐of‐function mutations scattered along the NF1 gene. Here, we present an original NF1 investigation strategy and report a comprehensive mutation analysis of 565 unrelated patients from the NF‐France Network. A NF1 mutation was identified in 546 of the 565 patients, giving a mutation detection rate of 97%. The combined cDNA/DNA approach showed that a significant proportion of NF1 missense mutations (30%) were deleterious by affecting pre‐mRNA splicing. Multiplex ligation‐dependent probe amplification allowed the identification of restricted rearrangements that would have been missed if only sequencing or microsatellite analysis had been performed. In four unrelated families, we identified two distinct NF1 mutations within the same family. This fortuitous association points out the need to perform an exhaustive NF1 screening in the case of molecular discordant‐related patients. A genotype–phenotype study was performed in patients harboring a truncating (N = 368), in‐frame splicing (N = 36), or missense (N = 35) mutation. The association analysis of these mutation types with 12 common NF1 clinical features confirmed a weak contribution of the allelic heterogeneity of the NF1 mutation to the NF1 variable expressivity. |
| Keywords: | neurofibromatosis type 1 NF1 genotype– phenotype correlation mutation database |