Invitae Neurofibromatosis Type 1 Test


Test description

This test analyzes the NF1 gene, which is associated with neurofibromatosis type 1 (NF1). NF1 is one of the RASopathies, which are a class of pediatric disorders associated with genes that are members of the mitogen-activated protein kinase (Ras/MAPK) pathway. This pathway is involved in a signal transduction cascade that is necessary for the proper formation of several types of tissue during embryonic and postnatal development.

NF1 is characterized by café-au-lait macules, cutaneous neurofibromas, axillary and inguinal freckling, Lisch nodules, optic glioma, and learning disabilities. There are risks of various malignancies, including peripheral nerve sheath tumors, optic gliomas, brain tumors, and gastrointestinal stromal tumors (GIST). Recent evidence suggests there is also an increased risk of adult-onset breast cancer in women.

Genetic testing of this gene may establish or confirm a diagnosis and help guide treatment and management decisions. Many of the typical signs and symptoms of NF1 evolve with age, but genetic testing of the NF1 gene can confirm a diagnosis in early childhood. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.

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Primary panel (1 gene)


Add-on Legius syndrome gene (1 gene)

The RASopathies exhibit several overlapping phenotypic features due to their common underlying Ras/MAPK pathway dysregulation. NF1 overlaps clinically with Legius syndrome. Both syndromes are characterized by the presence of multiple café-au-lait spots and axillary and inguinal freckling, but NF1 has the additional features of neurofibromas, Lisch nodules, and optic gliomas. SPRED1 is the gene associated with Legius syndrome. Depending on the clinical presentation of the patient, clinicians may wish to include SPRED1 in this test for a broader analysis.


Alternative tests to consider

The RASopathies are multisystemic disorders whose clinical expressions are highly variable, even among family members. Many of the clinical features that can differentiate RASopathy conditions manifest later in childhood or change with age, making accurate clinical diagnosis difficult. The phenotypes of many RASopathy conditions are expanding: Individuals are being discovered with a molecular genetic finding in a RASopathy gene but clinical findings that are not typically described in the specific condition associated with that gene. Additionally, some genes are associated with more than one RASopathy syndrome.

Testing for Legius syndrome is also included in the broader Invitae RASopathies Comprehensive Panel. Depending on the individual’s clinical and family history, this broader panel may be appropriate. This broader panel can be ordered at no additional charge.

Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a progressive condition characterized by skin discolorations, including large, café-au-lait-colored freckles (macules) and freckling in the armpit (axillary freckling) and groin (inguinal freckling). Affected individuals also typically develop several types of benign tumors, including nerve sheath tumors (cutaneous and plexiform neurofibromas) and benign tumors of the iris (Lisch nodules).

In some cases of NF1, cancerous tumors may develop, arising from the nerve sheath (malignant peripheral nerve sheath tumors), the central nervous system (gliomas), or the stomach (gastrointestinal stromal tumor), among other places. Recent literature suggests that there may be an increased risk of adult-onset breast cancer in women with NF1.

Other common symptoms associated with NF1 include mild cognitive impairment, scoliosis, and macrocephaly. Essentially everyone with NF1 will express symptoms and meet diagnostic criteria by adulthood, although the clinical presentation can vary significantly, even among individuals in the same family. NF1 has similar features to another disorder called Legius syndrome, but Legius syndrome is not associated with neurofibromas or other NF1-related cancerous tumors.

More than 95% of individuals with NF1 have an identifiable pathogenic variant in the NF1 gene.

NF1 is inherited in an autosomal dominant pattern. Approximately 50% of affected individuals inherit NF1 from a parent. The remainder of the cases are the result of a spontaneous de novo mutation.

The prevalence of NF1 is estimated at 1 in 3,000 individuals.

A clinical diagnosis of NF1 can be established in an individual who meets the diagnostic criteria developed by the National Institutes of Health:

  • six or more café-au-lait macules that are more than 5 mm in greatest diameter in prepubertal individuals or more than 15 mm in greatest diameter in postpubertal individuals
  • two or more neurofibromas of any type or one plexiform neurofibroma
  • freckling in the axillary or inguinal regions
  • optic glioma
  • two or more Lisch nodules
  • a distinctive osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis
  • a first-degree relative with NF1, as defined by the above criteria

Many of the typical signs and symptoms of NF1 evolve with age, but genetic analysis of the NF1 gene can confirm a diagnosis in a child who does not yet meet the clinical diagnostic criteria but in whom this condition is suspected. An accurate diagnosis of NF1 enables immediate implementation of NF1-specific medical management guidelines.

  1. Friedman, JM. Neurofibromatosis 1. 1998 Oct 02. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301288
  2. Hersh, JH, American, Academy, of, Pediatrics, Committee, on, Genetics. Health supervision for children with neurofibromatosis. Pediatrics. 2008; 121(3):633-42. doi: 10.1542/peds.2007-3364. PMID: 18310216
  3. Korf, BR. Malignancy in neurofibromatosis type 1. Oncologist. 2000; 5(6):477-85. doi: 10.1634/theoncologist.5-6-477. PMID: 11110599
  4. Madanikia, SA, et al. Increased risk of breast cancer in women with NF1. Am. J. Med. Genet. A. 2012; 158A(12):3056-60. doi: 10.1002/ajmg.a.35550. PMID: 23165953
  5. National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md., USA, July 13-15, 1987. Neurofibromatosis. 1988; 1(3):172-8. PMID: 3152465
  6. Seminog, OO, Goldacre, MJ. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br. J. Cancer. 2013; 108(1):193-8. doi: 10.1038/bjc.2012.535. PMID: 23257896
  7. Sharif, S, et al. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J. Med. Genet. 2007; 44(8):481-4. doi: 10.1136/jmg.2007.049346. PMID: 17369502
  8. Walker, L, et al. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br. J. Cancer. 2006; 95(2):233-8. doi: 10.1038/sj.bjc.6603227. PMID: 16786042
  9. Wang, X, et al. Breast cancer and other neoplasms in women with neurofibromatosis type 1: a retrospective review of cases in the Detroit metropolitan area. Am. J. Med. Genet. A. 2012; 158A(12):3061-4. doi: 10.1002/ajmg.a.35560. PMID: 22965642

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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
NF1 NM_000267.3
SPRED1 NM_152594.2