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.

Learn about the genetic condition Neurofibromatosis 1, its incidence, symptoms, and mutation rates. NF1 affects the skin, eye, skeleton, and nervous system.