How is Neurofibromatosis (NF) type 1 (NF1) and type 2 (NF2) inherited?

Inheritance of Neurofibromatosis Type 1 and Type 2

Both Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are autosomal dominant disorders, meaning each child of an affected individual has a 50% chance of inheriting the condition.

Neurofibromatosis Type 1 (NF1)

NF1 is caused by pathogenic variants in the NF1 gene located on chromosome 17, which encodes neurofibromin, a key negative regulator in the RAS-MAPK pathway 1, 2.

Key inheritance characteristics:

• Autosomal dominant inheritance pattern
• Approximately 50% of cases occur de novo (new mutations)
• Complete penetrance with variable expressivity 1
• Birth prevalence of 1/2,000 to 1/3,000 persons 1

Important genetic counseling considerations:

• 50% risk of transmitting the pathogenic variant to offspring 2
• Prenatal diagnosis and preimplantation genetic diagnosis are available options 2
• Somatic mosaicism is well-documented in NF1, which may result in variable or minimal clinical features 1
• Recent research suggests that offspring of male NF1 patients may have an increased risk of experiencing de novo NF1 pathogenic variants beyond the expected 50% inheritance risk 3

Neurofibromatosis Type 2 (NF2)

NF2 is caused by mutations in the NF2 gene located on chromosome 22, which functions as a tumor suppressor gene 4, 5.

Key inheritance characteristics:

• Autosomal dominant inheritance pattern
• 50-60% of cases represent de novo mutations 4
• Up to 33% of de novo cases are mosaic for the disease-causing mutation 4
• Much rarer than NF1, with different clinical manifestations despite sharing the "neurofibromatosis" name 6

Clinical Implications of Inheritance Patterns

The inheritance patterns have important implications for:

1. Genetic testing:

   • NF1 testing is now included as a clinical criterion for NF1 diagnosis 3
   • Presymptomatic genetic testing is possible in the majority of NF2 families 5

2. Family planning:

   • Genetic counseling should address the 50% recurrence risk in offspring
   • Referral to high-risk obstetricians may be warranted for pregnant women with NF1 2

3. Surveillance:

   • Family members at risk should be offered appropriate screening
   • Different surveillance protocols are needed for NF1 versus NF2 due to their distinct clinical manifestations 2, 7

Pitfalls and Caveats

• Despite sharing a name, NF1 and NF2 are clinically and genetically distinct diseases and should be considered separate entities 6
• Mosaicism can complicate diagnosis and genetic counseling in both conditions
• The severity of disease cannot be predicted based on specific variants for the majority of NF1 cases 1
• When a patient is suspected to have NF1 but does not meet clinical criteria and has negative NF1 testing, other conditions with overlapping features should be considered 1

Understanding the inheritance patterns of NF1 and NF2 is crucial for accurate genetic counseling, appropriate family screening, and optimal clinical management of affected individuals.