• neurofibromatosis type 1
• NF1
• recurrent mutation
• splicing defect

Neurofibromatosis type 1 (NF1) is one of the commonest autosomal dominant disorders in man, affecting 1 in 3500 people. Consensus clinical criteria were defined in 1987¹ and revised and updated in 1997.² Café au lait spots, axillary freckling, dermal neurofibromas, and Lisch nodules of the iris are the most common manifestations of this disorder. Most of the clinical symptoms of the disease are age dependent and considerable phenotypic variability has been described both between and within families.^3,4 This genetic disorder is caused by mutations in the NF1 gene, one of the largest human genes, composed of 60 exons and spanning more than 300 kb of genomic DNA.⁵ The determination of the NF1 mutational spectrum has been complex owing to the large number of coding exons and the considerable mutational heterogeneity. Until recently, most diagnostic laboratories just offered linkage analysis for NF1 patients, which excluded diagnosis of the 50% of de novo cases. The use of techniques based on the analysis of NF1 mRNA greatly facilitated the number of mutations identified and NF1 screening efficiency, depicting a mutational NF1 spectrum.^6–8 These studies highlighted the importance of splicing defects in molecular NF1 pathology and, despite most patients bearing unique mutations, they suggested the recurrence of several mutations.

Here we present our experience with the direct analysis of the whole NF1 coding region in 474 unrelated subjects suspected of having NF1. Mutations have been identified in 189 patients, 85 of them bearing recurrent mutations.