We present monozygotic twins discordant for the autosomal dominant disorder 
neurofibromatosis type 1 (NF1). The affected twin was diagnosed with NF1 at age 
12, based upon accepted clinical criteria for the disorder. Both twins were 
re-examined at ages 35 and 57, at which times the unaffected twin continued to 
show no clinical manifestations of NF1. Short tandem repeat marker (STR) 
genotyping at 10 loci on chromosome 17 and 10 additional loci dispersed across 
the genome revealed identical genotypes for the twins, confirming their 
monozygosity. The affected twin has three children, two of whom also have NF1, 
while the unaffected twin has two children, both unaffected. Using 
lymphoblastoid, fibroblast, and buccal cell samples collected from both twins 
and from other family members in three generations, we discovered a pathogenic 
nonsense mutation in exon 40 of the NF1 gene. This mutation was found in all 
cell samples from the affected twin and her affected daughter, and in 
lymphoblastoid and buccal cells but not fibroblasts from the unaffected twin. We 
also found a novel non-synonymous change in exon 16 of the NF1 gene that was 
transmitted from the unaffected mother to both twins and co-segregated with the 
pathogenic mutation in the ensuing generation. All cells from the twins were 
heterozygous for this apparent exon 16 polymorphism and for single nucleotide 
polymorphisms (SNPs) within 2.5 kb flanking the site of the exon 40 nonsense 
mutation. This suggests that the NF1 gene of the unaffected twin differed in the 
respective lymphoblastoid cells and fibroblasts only at the mutation site 
itself, making post-zygotic mutation leading to mosaicism the most likely 
mechanism of phenotypic discordance. Although the unaffected twin is a mosaic, 
the distribution of the mutant allele among different cells and tissues appears 
to be insufficient to cause overt clinical manifestations of NF1.