An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes

Neurofibromatosis (NF) type 1 (NF1) is notable for its variable expression. To determine whether variation in expression has an inherited component, we examined 175 individuals in 48 NF families, including six MZ twin pairs. Three quantitative traits were scored--number of café-au-lait patches, number of cutaneous neurofibromas, and head circumference; and five binary traits were scored--the presence or absence of plexiform neurofibromas, optic gliomas, scoliosis, epilepsy, and referral for remedial education. For café-au-lait patches and neurofibromas, correlation was highest between MZ twins, less high between first-degree relatives, and lower still between more distant relatives. The high correlation between MZ twins suggests a strong genetic component in variation of expression, but the low correlation between distant relatives suggests that the type of mutation at the NF1 locus itself plays only a minor role. All of the five binary traits, with the exception of plexiform neurofibromas, also showed significant familial clustering. The familial effects for these traits were consistent with polygenic effects, but there were insufficient data to rule out other models, including a significant effect of different NF1 mutations. There was no evidence of any association between the different traits in affected individuals. We conclude that the phenotypic expression of NF1 is to a large extent determined by the genotype at other "modifying" loci and that these modifying genes are trait specific.