A clinically significant NF1 genotype-phenotype correlation: absence of neurofibromas is associated with a c.2970_2972 delAAT of the NF1 gene
Neurofibromatosis type 1 (NF1) is characterised by café-au-lait spots, cutaneous neurofibromas and axillary freckling. No obvious relationships between small mutations (<20 bp) of the NF1 gene and a specific phenotype have yet been demonstrated, suggesting that either unlinked modifying genes and/or the normal NF1 allele are possibly involved in the development of particular clinical features of NF1.
We have ascertained a cohort of 19 unrelated NF1 probands, (12 familial and 7 sporadic),with the same ΔAAT mutation, of whom 17 had no cutaneous neurofibromas. This is unusual, as such lesions are a major feature of NF1 in adults; being present in all 135 NF1 patients in one study (Huson et al 1988).Three of the patients were from large multi-generation families referred for mutation analysis because of their unusual phenotype. Molecular analysis identified the same 3bp in-frame deletion in exon 17 (c.2970_2972 delAAT) in all of these patients.We then approached colleagues in each of the centres to review their own mutation panels and identified the remainder.This mutation is predicted to result in the loss of one of two adjacent methionine encoded by codons 991-992 (ΔMet991),with a silent ACA>ACG change of codon 990(Thr990Thr).As a soluble protein for the region encompassing this mutation is not yet available, this precludes any studies of the effect of mutation on 3-D structure. These methionine residues are highly conserved and thus likely to have an important functional role in neurofibromin. That the mutation segregates with 21 NF1-affected individuals in three families is further evidence of its pathogenicity.Beside the lack of cutaneous neurofibromas,the clinical phenotype in these patients is generally milder. NF1 patients with large gene deletion have previously been reported to have more severe phenotype,this is the first report demonstrating a correlation between a small mutation and a specific clinical feature of NF1. As cutaneous neurofibromas are one of the most disfiguring features of NF1,elucidation of why these deleted patients are not prone to them will be important.