The gene causing autosomal dominant neurofibromatosis, NF1, has been mapped to 17q11.2 and encodes the presumed tumor suppressor, neurofibromin. The gene is large (about 350 Kbp with at least 59 exons) and produces a 2,818 amino acid protein from its 13 Kb transcript. Mutations in the NF1 gene are extremely heterogeneous, if not family-specific, and the clinical presentation can show marked inter- and intra-familial phenotypic variation. Sporadic NF1 cases typically represent new mutations.
A large proportion of NF1 mutations appear to be nonsense mutations leading to neurofibromin loss-of-function. A relatively new assay, the protein truncation test (PTT), provides a powerful method with which to screen NF1 families for possible nonsense mutations. However, even the most optimistic data for NF1 PTT suggests only a 60-70% mutation detection rate. PTT remains particularly valuable for evaluation of suspected sporadic NF1 cases but is not the best strategy for familial cases. Linkage analysis will provide in informative families a > 99% predictive accuracy.
Several highly informative polymorphic markers have been found intragenic to NF1 and are depicted in the figure below. Virtually all families are found to be informative for at least one of these markers.