NOVEL RECURRENT NONSENSE MUTATION CAUSING NEUROFIBROMATOSIS TYPE-1 (NF1) IN A FAMILY SEGREGATING BOTH NF1 AND NOONAN-SYNDROME

Neurofibromatosis type 1 (NF1), a genetic disorder with neuroectoderma l involvement, demonstrates phenotypic overlap in some patients with N oonan syndrome CNS), ultimately resulting in the so-called neurofibrom atosis-Noonan syndrome (NF-NS). A strong association of the two phenot ypic traits was recently illustrated by a four-generation family, alth ough NF1 and NS were eventually demonstrated to segregate independentl y on the basis of polymorphic DNA markers [Bahuau et al., 1996: Am J M ed Genet 66:347-355]. Identification of the causal NF1 mutation seemed a prerequisite to further dissecting this singular familial associati on. Using the protein truncation assay, a nonsense mutation (C2446T--> R816X) of the neurofibromin gene was evidenced. This mutation occurred on a CpG dinucleotide within exon 16 and 5' to the GAP domain-specify ing region of the gene. R816X creates a recognition site for endonucle ase HphI, absent in 2 individuals with NS only. Screening 184 unrelate d NF1 patients, three novel occurrences of the mutation were found in individuals diagnosed with classical NF1. Based on the assumption of g enotype-phenotype correlation in these individuals, clinical and molec ular analyses of this four-generation family demonstrated that the NF- NS phenotype was additive, being the result of both classical NF1 and NS. This particular observation also suggests the presence of an NS lo cus on 17q, which might be of interest for further linkage studies. (C ) 1998 Wiley-Liss, Inc.