Genetic testing analyzes an individual’s DNA to identify changes, or variants, within genes. These changes can indicate a predisposition to certain health conditions. For neurofibromatosis, a group of genetic disorders affecting the nervous system, genetic testing helps confirm a diagnosis, assess risks for family members, and inform family planning decisions.
Understanding Neurofibromatosis
Neurofibromatosis (NF) encompasses a group of genetic disorders that cause tumors to form on nerve tissue. The three primary forms are Neurofibromatosis Type 1 (NF1), Neurofibromatosis Type 2 (NF2), and Schwannomatosis. These conditions arise from specific genetic alterations that disrupt normal cell growth, leading to the development of both benign and, less commonly, cancerous tumors.
NF1 is the most common type, affecting approximately 1 in 3,000 individuals, and is characterized by features such as multiple café-au-lait macules (light brown skin spots), neurofibromas (benign tumors on or under the skin), and sometimes learning disabilities. It is caused by mutations in the NF1 gene. NF2 is rarer, affecting about 1 in 25,000 people, and is primarily associated with the growth of bilateral vestibular schwannomas, tumors on the nerves leading from the ears to the brain, which can cause hearing loss and balance issues. This condition results from mutations in the NF2 gene.
Schwannomatosis is the least common form, affecting around 1 in 40,000 individuals, and typically presents with multiple painful schwannomas on spinal and peripheral nerves. Mutations in the SMARCB1 and LZTR1 genes are linked to Schwannomatosis. While these conditions can arise from spontaneous new mutations, they are often inherited in an autosomal dominant pattern, meaning only one copy of the altered gene is needed for the condition to develop.
How Genetic Testing for Neurofibromatosis is Performed
Genetic testing for neurofibromatosis is performed in various scenarios, such as confirming a clinical diagnosis, especially in younger children where symptoms may not be fully developed, or in uncertain cases. It is also used for prenatal screening, preimplantation genetic diagnosis (PGD) before embryo implantation, or to assess risk for asymptomatic family members when a pathogenic variant has been identified in a relative.
Samples for genetic testing are typically collected through a blood draw or saliva sample, as these provide easily accessible sources of DNA. In some cases, particularly for mosaic forms of NF where the genetic change is not present in all cells, a tissue biopsy from a neurofibroma or café-au-lait spot may be used to increase the likelihood of detecting the specific mutation. Archived tumor tissue, even from surgeries performed years ago, can also be utilized for testing.
Laboratories analyze specific genes associated with each type of neurofibromatosis. For NF1, the NF1 gene is examined. For NF2, the NF2 gene is the focus, while for Schwannomatosis, the SMARCB1 and LZTR1 genes are analyzed, sometimes alongside NF2 due to shared tumor characteristics. Techniques like next-generation sequencing (NGS) are commonly employed to detect a wide range of genetic changes, including small mutations, and can sometimes identify mosaicism. More specialized RNA-based testing may be used if NGS results are negative or inconclusive.
What Genetic Test Results Mean
Genetic test results for neurofibromatosis can generally fall into three categories: positive, negative, or a variant of uncertain significance (VUS). A positive result means a significant, disease-causing genetic change, known as a pathogenic variant, has been identified in a gene associated with NF. This outcome is consistent with a genetic diagnosis of the condition and provides a clear molecular confirmation. Identifying such a variant can help guide health management and inform family members about their potential risks.
A negative result indicates that no pathogenic variant was found in the genes tested. While this usually suggests the individual does not have the specific genetic form of neurofibromatosis, it does not always completely rule out a diagnosis, especially if clinical signs are present.
A “variant of uncertain significance” (VUS) means a genetic change was identified, but its effect on health is currently unknown. This means it is unclear whether the variant increases the risk of NF symptoms. VUS findings are common, as everyone has minor genetic changes, and most are not disease-causing. The interpretation of a VUS can evolve as more scientific data becomes available, with some VUS being reclassified as pathogenic or benign over time.
Genetic counseling helps individuals and families interpret these results and understand the implications for their health management and family planning. Genetic counselors explain the meaning of the results, discuss potential future health risks, and explore options such as prenatal diagnosis or preimplantation genetic diagnosis for future pregnancies. The results can also inform prognosis and potential treatment strategies, allowing for more personalized care based on the specific genetic alteration identified.