Challenging issues in clinical genetics of neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disease with complete penetrance and extremely variable expression, affecting approximately 1 in 3,000-4,000 people worldwide. One of the most striking aspects of NF1 genetics is its complexity, both in terms of gene organization and expression. The NF1 gene is large and, when mutated, gives rise to diverse manifestations. The complexity and diversity of the mutations create difficulties for the achievement of satisfactory genotype-phenotype correlations. The clinical phenotypes associated with NF1 are numerous and include both tumor and non-tumor symptoms. The onset and severity of nearly all clinical features of NF1 are age-dependent and extremely variable, even within NF1 families; indeed, the unpredictable expressivity of NF1 is one of the most challenging aspects of NF1 management. Possibly, mutations in the NF1 gene alone may not be responsible for all of the features of this disease. It is now increasingly apparent that genetic modifiers, distinct from the disease locus itself, have a considerable role to play in phenotypic variations of single-gene disorders. Their effect on disease expression may vary from strong effects under a "monogenic-like" model to much milder effects under a "multifactorial-like" model. The identification of these genetic modifiers may be of great interest from the viewpoints of both treatment and genetic counseling.