Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1

Abstract

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder which displays considerable inter- and intra-familial variability in phenotypic expression. To evaluate the genetic component of variable expressivity in NF1, we examined the phenotypic correlations between affected relatives in 750 NF1 patients from 275 multiplex families collected through the NF-France Network. Twelve NF1-related clinical features, including five quantitative traits (number of café-au-lait spots of small size and of large size, and number of cutaneous, subcutaneous and plexiform neurofibromas) and seven binary ones, were scored. All clinical features studied, with the exception of neoplasms, showed significant familial aggregation after adjusting for age and sex. For most of them, patterns of familial correlations indicated a strong genetic component with no apparent influence of the constitutional NF1 mutation. Heritability estimates of the five quantitative traits ranged from 0.26 to 0.62. Moreover, we investigated for the first time the role of the normal NF1 allele in the variable expression of NF1 through a family-based association study. Nine tag SNPs in NF1 were genotyped in 1132 individuals from 313 NF1 families. No significant deviations of transmission of any of the NF1 variants to affected offspring was found for any of the 12 clinical features examined, based on single marker or haplotype analysis. Taken together, our results provided evidence that genetic modifiers, unlinked to the NF1 locus, contribute to the variable expressivity of the disease.

Figure 1.

Location and pairwise LD of the nine NF1 SNPs selected for family-based association study. The chromosomal location and gene structure were taken from NCBI's RefSeq resource with annotations from the UCSC genome browser database (March 2006 Build; NCBI Build 36.1). The locations of the nine tag SNPs in NF1 are indicated by arrows. The LD structure for the nine NF1 SNPs was determined using our own genotype data in the family sample. High pairwise LD (r²) between markers is illustrated with dark shading. The r² values (×100) for the marker pairs are listed in the corresponding boxes.