title: NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience.
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.
authors.affiliation: UMR745 INSERM, PRES Sorbonne Paris Cité, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France; IRD, UMR216, Mère et enfant face aux infections tropicales, Paris, France; PRES Sorbonne Paris Cité, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Sabbagh
authors.forename: Eric
authors.initials: E
authors.lastname: Pasmant
authors.forename: Apolline
authors.initials: A
authors.lastname: Imbard
authors.forename: Armelle
authors.initials: A
authors.lastname: Luscan
authors.forename: Magali
authors.initials: M
authors.lastname: Soares
authors.forename: Hélène
authors.initials: H
authors.lastname: Blanché
authors.forename: Ingrid
authors.initials: I
authors.lastname: Laurendeau
authors.forename: Salah
authors.initials: S
authors.lastname: Ferkal
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pinson
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: Dominique
authors.initials: D
authors.lastname: Vidaud
authors.forename: Béatrice
authors.initials: B
authors.lastname: Parfait
authors.forename: Pierre
authors.initials: P
authors.lastname: Wolkenstein
mesh_terms: D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D005260:Female; D005602:France; D018628:Gene Dosage; D016514:Genes, Neurofibromatosis 1; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009456:Neurofibromatosis 1 / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult
keywords: NF1; genotype-phenotype correlation; mutation database; neurofibromatosis type 1