Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic disorders. NF1 is progressive but the occurrence of complications and the rate of progression vary among patients, within affected members of a family, and even within an individual patient at different times. The resulting uncertainty about the course of the disease confounds clinical management and limits the value of genetic counselling for NF1. Understanding the reasons for such marked phenotypic variabilty in NF1 is an essential prerequisite to understanding the pathogenesis of the disease.

The purpose of this project is to characterise the sources of phenotypic variability in NF1. These studies will be performed on the two largest collections of detailed clinical information on NF1 patients ever assembled: The National Neurofibromatosis Foundation International Database (NNFFID) and the NF Institute Database. All analyses will be performed on NNFFID data initially and then repeated on data from the independent NF Institute Database. Comparison of the results of these parallel analyses will provide an important test of the reproducibility of our findings.

These studies will employ a variety of statistical and genetic epidemiological methods. The contribution of genetic and non-genetic factors to the variability of selected clinical manifestations will be analysed by considering these features as multifactorial traits that may occur within a population of NF1 patients. This approach permits analysis of the phenotypic variability in this mendelian disorder with methods that have been used successfully in studies of multifactorial diseases.

On the basis of these studies, we shall identify a set of clinical phenotypes for which allelic differences at the NF1 locus appear to be important. These Afamilial phenotypes@ will be examined as candidates for genotype-phenotype correlations. Using a strategic screening process developed to identify up to 95% of pathogenic alterations at the NF1 locus, we shall perform mutation analysis on NF1 patients with several different Afamilial phenotypes@ to look for those that appear to have a particular subclass of mutations. Formal case-control studies with targeted mutation detection will then be performed in additional patients from up to four such subgroups to confirm or refute the existence of allele-phenotype correlations.

Our specific objectives are to:

1. identify associations between pairs of clinical features in unrelated NF1 patients;

2. identify associations between the occurrence of clinical features related individuals;

3. derive age-specific risks for particular complications in NF1 patients with and without associated disease manifestations;

4. determine the contribution of genetic factors, non-genetic factors, and chance to the variability in occurrence of serious complications of NF1; and

5. identify allele-phenotype correlations for clinical features for which allelic heterogeneity has been shown to be an important source of clinical variability.

Our findings should provide information that is useful for managing and counselling people with NF1. In addition, better understanding of the basis of clinical variability in NF1 should substantially improve our insight into its pathogenesis.