• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The NF1 gene is associated with autosomal dominant neurofibromatosis type 1 (NF1) (MedGen UID: 18013), neurofibromatosis-Noonan syndrome (NFNS) (MedGen UID: 419089), and Watson syndrome (MedGen UID: 107817).

NF1 encodes Neurofibromin 1, a tumor suppressor that is a negative regulator of the RAS signaling pathway.

OMIM: 162200

Clinical condition
The NF1 gene is associated with autosomal dominant neurofibromatosis type 1 (NF1; MedGen UID: 18013), neurofibromatosis-Noonan syndrome (NFNS; MedGen UID: 419089), and Watson syndrome (MedGen UID: 107817). Additionally, evidence of varying degrees suggests a possible association between the NF1 gene and several cancer types (PMID: 23257896, 23165953, 25130111, 20833335).

NF1 is a neurocutaneous condition with extremely variable clinical features that increase in frequency with age and include multiple cafe-au-lait spots, axillary and inguinal freckling, iris Lisch nodules, choroidal freckling, optic gliomas, and cutaneous neurofibromas (PMID: 19117870, 26486853, 23931823). Plexiform neurofibromas develop in approximately half of individuals with NF1; however, many occur internally and therefore escape clinical detection unless they become symptomatic (PMID: 18559970, 22558206, 23035791). Nevus anemicus and juvenile xanthogranuloma are more common in individuals with NF1 than in the general population (PMID: 27019377, 24258576).

Approximately 50% of individuals diagnosed with NF1 have been noted to exhibit learning disabilities (PMID: 22934576). More significant intellectual disability has been observed in 6-7% of individuals with NF1, while autistic spectrum disorder has been noted in approximately 30% of children with NF1 (PMID: 24190681, 23163951, 22934576). Individuals with NF1 often have a larger head circumference than members of the general population and tend to be below average in height (PMID: 23466600, 22752476).

Some individuals with NF1 develop polyneuropathy from multiple nerve root tumors, which can also result in a higher risk for malignant peripheral nerve sheath tumors (PMID: 15289270, 15520408). Individuals with NF1 are at a higher risk for seizures and osteopenia/osteoporosis than those in the general population (PMID: 21621428, 24032542, 2793925, 23713011, 19066167). Long bone dysplasia, typically congenital anterolateral bowing of the lower leg, pseudarthrosis, scoliosis, sphenoid wing dysplasia, and vertebral dysplasia have all been associated with NF1 (PMID: 19764036, 15811002, 23414129, 25293439, 20592374).

Vasculopathy and cardiac issues associated with NF1 can include pulmonary valve stenosis, hypertrophic cardiomyopathy, pulmonary hypertension, renal artery stenosis, coarctation of the aorta, stroke, stenotic or ectatic cerebral arteries, moyamoya disease, and intracranial aneurysms (PMID: 12180143, 14991390, 10955932, 15838492, 26645253, 17372129, 23373626).

There are risks of various malignancies, including peripheral nerve sheath tumors, optic gliomas, brain tumors, pheochromocytomas, and gastrointestinal stromal tumors (GIST; PMID: 23257896). Recent evidence suggests that there is also an increased risk of adult-onset breast cancer in women (PMID: 23165953).

NFNS is clinically variable and associated with features found in NF1 along with features of Noonan syndrome, such as short stature, ptosis, midface hypoplasia, pulmonic stenosis, learning disabilities, pectus anomalies, webbed neck, and muscle weakness (PMID: 2411134, 3135755, 8985499, 8740913, 16380919).

Watson syndrome is characterized by short stature, cafe-au-lait spots, Lisch nodules, axillary freckling, intellectual disability, pulmonary valvular stenosis, and relative macrocephaly (PMID: 6025371, 1770531). Neurofibromas have been observed in up to 33% of patients with Watson syndrome (PMID: 1770531).

Gene information
NF1 encodes the protein neurofibromin 1, a tumor suppressor that is a negative regulator of the RAS signaling pathway (PMID: 16813595). The neurofibromin 1 protein is located in the cytoplasm and is primarily expressed in neurons, Schwann cells, oligodendrocytes, and leukocytes (PMID: 16813595). Neurofibromin 1 is involved in a variety of intracellular processes and acts as a tumor suppressor gene by activating the RAS GTPase and controlling cellular proliferation (PMID: 16813595, 25877329, 26860753). Additional functions of neurofibromin 1 include regulation of adenylyl cyclase activity, intracellular cyclic-AMP generation, and involvement in somatic cell division (PMID: 25486365, 26490262, 20668197, 264090262). Somatic mosaicism for a pathogenic variant in NF1 has been observed and may be generalized or localized to one segment of the body (e.g., localized NF1; PMID: 21280148, 26338194).

NF1, NFNS, and Watson syndrome are all inherited as autosomal dominant conditions. This means that an individual with a pathogenic variant in NF1 has a 50% chance of passing the variant to their offspring. However, due to the extreme variability of these conditions, it is not possible to predict the specific phenotype that will be exhibited by the offspring (PMID: 23931823, 26486853). Approximately half of NF1 cases are inherited, and the remainder is the result of de novo pathogenic variants (PMID: 20082463). Germline mosaicism for NF1 has been demonstrated (PMID: 25872886, 15224714).

Due to the multisystemic nature of these conditions, recommended management for individuals with NF1, NFNS, and Watson syndrome is ideally performed in an NF specialty clinic (PMID: 17105749). If that is not possible, the care team should consist of a geneticist/genetic counselor, a neurologist, an ophthalmologist, a dermatologist, a cardiologist, and potentially an orthopedist and an oncologist (PMID: 18310216, 23931823, 26485853, 17105749).

Initial evaluations upon diagnosis should include the following:

  • Obtain a thorough medical history with a specific focus on features associated with NF1 (PMID: 17636453)
  • Provide a thorough physical exam to evaluate for the presence of neurocutaneous, cardiovascular, and musculoskeletal features, tumors, and any other relevant findings (PMID: 18310216)
  • Obtain a detailed evaluation by an ophthalmologist (PMID: 18310216)
  • Obtain a developmental assessment (PMID: 23931823)
  • Obtain molecular testing of the proband’s parents to determine whether the proband has inherited the NF1 variant or if it has occurred de novo (PMID: 17636453)
    Surveillance needs to include the following:
  • Annual evaluation at an NF specialty center or by a physician experienced in treating patients with NF1 (PMID: 18310216)
  • Regular developmental evaluations throughout childhood and implementation of additional support services, such as individualized education plans, occupational therapy, and behavioral therapy, when indicated (PMID: 17105749)
  • Annual ophthalmologic exam throughout childhood and less frequent evaluations in adulthood (PMID: 18310216)
  • Regular blood pressure monitoring (PMID: 18310216)
  • MRI or other imaging studies as indicated, based on clinical symptoms (PMID: 23931823)
  • Ongoing consultation with subspecialists to address cardiovascular, orthopedic, oncology, and neurological symptoms if they arise (PMID: 18310216)
  • NF1 patients who become pregnant should be referred to a perinatologist to monitor for hypertension and the development of neurofibromas that could complicate delivery (PMID: 17636453)
  • Annual mammogram with consideration of tomosynthesis starting at age 30 to monitor for breast cancer and consideration of breast MRI at ages 30 to 50 years (option of risk-reducingmastectomy should be based on family history; NCCN. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2018)
  • Referral to an NF specialist for evaluation and management related to nerve sheath tumors, GIST, and other tumors (NCCN. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2018)

Additional reference
Referenced with permission from the NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2018 © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed April 2018. To view the most recent and complete version of the guideline, go online to NCCN.org. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Review date: April 2018

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
NF1 NM_000267.3