Neurofibromatosis 1 (NF1) Disease Etiology

Disease Overview

• Neurofibromatosis 1 (NF1) is a panethnic autosomal dominant condition.
• Symptoms of NF1 are most frequently expressed in the skin, eye, skeleton, and nervous system.

Incidence and Genetics

• The incidence of NF1 is 1 in 3500 persons, making it one of the most common autosomal dominant genetic conditions.
• Approximately half of patients have de novo mutations.
• The mutation rate for the NF1 gene is approximately 1 mutation per 10,000 live births.
• Around 80% of de novo mutations are paternal in origin.

Gene Structure and Function

• The NF1 gene is large, with 350 kb and 60 exons.
• The gene encodes neurofibromin, a protein widely expressed in almost all tissues, but most abundantly in the brain, spinal cord, and peripheral nervous system.
• Neurofibromin regulates several intracellular processes, including the activation of Ras GTPase, controlling cellular proliferation and acting as a tumor suppressor.

Mutations and Clinical Manifestations

• Over 500 mutations in the NF1 gene have been identified, with most being unique to an individual family.
• The clinical manifestations result from a loss of function of the gene product.
• 80% of mutations cause protein truncation.
• A disease-causing mutation can be identified for more than 95% of individuals diagnosed with NF1.

Clinical Variability

• NF1 is characterized by extreme clinical variability, both between and within families.
• This variability is likely caused by a combination of genetic, nongenetic, and stochastic factors.
• No clear genotype-phenotype correlations have been recognized, although large deletions are more common in NF1 patients with neurodevelopmental difficulties.