Journal
HUMAN MUTATION
Volume 34, Issue 11, Pages 1510-1518Publisher
WILEY
DOI: 10.1002/humu.22392
Keywords
neurofibromatosis type 1; NF1; genotype-phenotype correlation; mutation database
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Funding
- Association Neurofibromatoses et Recklinghausen
- Ligue Francaise Contre les Neurofibromatoses
- French Clinical Research program (PHRC)
- INSERM (Nf1GeneModif project)
- Ministere de l'Enseignement Superieur et de la Recherche
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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.
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