NF is a group of genetic disorders that primarily affects the nervous system, causing tumors to grow on nerve tissue throughout the body. The development of NF is directly linked to a change, or mutation, in a person’s genetic code. This article focuses on the underlying genetic mechanisms, explaining how a person acquires and transmits the genetic change that leads to neurofibromatosis.
The Primary Inheritance Pattern
Neurofibromatosis typically follows a pattern known as Autosomal Dominant inheritance. This means a person only needs to inherit one copy of the altered gene from one parent to develop the condition. The term “autosomal” indicates the gene is located on a non-sex chromosome, affecting males and females equally.
If a parent has neurofibromatosis, they carry one altered copy and one typical copy of the gene. Because the altered gene is dominant, they have a 50% chance of passing that altered gene copy to their child with each pregnancy. A child who inherits the altered gene will develop some features of the disorder, although the severity can vary widely, even within the same family.
The Role of Spontaneous Mutations
The condition does not always follow a clear family history, which can be confusing for newly diagnosed individuals. In approximately half of all cases, the neurofibromatosis mutation is not inherited from an affected parent. Instead, the genetic change occurs spontaneously, which is referred to as a de novo mutation.
This spontaneous change happens randomly in the sperm or egg cell before conception, or very early in embryonic development. The parents themselves do not have the condition, nor do they carry the altered gene in all their cells. Once this de novo mutation occurs, the affected individual carries the dominant gene. Like anyone else with NF, they will face a 50% chance of passing the altered gene to their offspring.
Different Types, Different Genes
While the inheritance pattern is the same across the major forms of the disorder, the specific gene involved determines the type of neurofibromatosis and the resulting clinical outcomes. The most common form is Neurofibromatosis Type 1 (NF1), which is caused by a mutation in the NF1 gene located on chromosome 17. This gene produces a protein called neurofibromin, which acts as a tumor suppressor. Primary symptoms of NF1 include skin changes such as café-au-lait spots and neurofibromas, which are tumors on the nerves near the skin.
Neurofibromatosis Type 2 (NF2) and Schwannomatosis are distinct conditions caused by mutations in different genes. NF2 is linked to the NF2 gene on chromosome 22, which is responsible for producing the tumor-suppressing protein merlin. The hallmark of NF2 is the development of bilateral vestibular schwannomas, which are tumors on the nerves connecting the inner ear to the brain, frequently leading to hearing loss and balance issues. Schwannomatosis, the third type, is less common and is associated with mutations in genes like INI1 (or SMARCB1) and LZTR1, primarily causing chronic pain from multiple schwannomas on peripheral and spinal nerves.
Genetic Counseling and Family Planning
Understanding the genetic basis of neurofibromatosis allows for informed decision-making concerning family planning. Genetic counselors assess the specific risk based on family history and the type of NF involved. They help interpret genetic testing results, which can confirm the presence of the gene mutation, even when the diagnosis is clinically unclear.
For individuals planning to have children, genetic counseling provides information on various reproductive options. These include prenatal diagnosis, where testing is performed during pregnancy to determine if the fetus inherited the gene change. Another option is preimplantation genetic diagnosis (PGD), which involves testing embryos created through in vitro fertilization before implantation, allowing parents to select an embryo without the altered gene.