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Neurofibromatosis Type 1 and Related Disorders via the NF1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
NF1 81408 81408,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4361NF181408 81408,81479 $990 Order Options and Pricing

Pricing Comments

Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Brett Deml, PhD

Clinical Features and Genetics

Clinical Features

Neurofibromatosis type 1 (NF1) is characterized by cutaneous neurofibromas, café-au-lait spots, iris hamartoma (Lisch nodules) and freckling of axillary and inguinal regions. These features usually become apparent during puberty. Additional features include plexiform neurofibromas, central nervous system gliomas, including optic glioma, macrocephaly, scoliosis, pseudoarthritis, overgrowth and learning difficulties (Riccardi 1993). There is extensive clinical variability between individuals in age of onset, tumor burden, and disease progression. NF1 is panethnic and affects 1 in 3,000 people (Rasmussen and Friedman 2000).

Neurofibromatosis-Noonan Syndrome patients (NFNS) present with clinical features characteristic of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). The NF1 features include café-au-lait spots, freckling, neurofibromas, hamartoma of the iris, optic gliomas, and other MRI findings, such as unidentified bright objects (UBO). The NS features include facial anomalies such as hypertelorism, low-set ears, short stature, congenital heart defects, primary pulmonary valve stenosis, webbed neck and thoracic abnormalities. In NFNS patients, features common to both NF1 and NS include macrocephaly, scoliosis, mental retardation or learning difficulties (Allanson et al.1985; De Luca et al. 2005).

Spinal Neurofibromatosis (SNF) is characterized by multiple bilateral spinal neurofibromas and other tumors of the central nervous system, with few or no other clinical features of NF1. Symptoms usually begin in adulthood (Kluwe et al. 2003; Quintáns et al. 2011).

Features of Watson Syndrome (WS) overlap with those of NF1 and Noonan syndrome. WS is characterized by café-au-lait spots, pulmonary valvular stenosis, low intelligence and short stature (Watson et al. 1967). WS is also referred to as Pulmonic Stenosis with Café au Lait Spots.


NF1 is caused by loss-of-function mutations in the NF1 gene. It is inherited as an autosomal dominant trait in about half of cases, and is caused by de novo mutations in the other half. Over 2,000 NF1 germline variants have been reported and include all types. Large deletions account for ~ 5% of patients with NF1 and are usually associated with a severe phenotype (Friedman, 2014). Gross insertions and complex rearrangements are rare. Nearly all de novo mutations occur in the paternal chromosomes (Jadayel et al.1990), with the exception of large deletions, which occur in maternal chromosomes (Lázaro et al. 1996; Upadhyaya et al. 1998). Parental germline mosaicism has been reported (Lázaro et al. 1994).

The vast majority of NFNS cases are sporadic, although several families transmitting the trait in an autosomal dominant manner have been reported (Quattrin et al.1987; Abuelo et al. 1988; Colley et al. 1996). Heterozygous mutations in the NF1 gene were reported in patients with NFNS, including sporadic and familial cases (Baralle et al. 2003; De Luca et al. 2005; Stevenson et al. 2006; Huffmeier et al. 2006). These data led the authors to suggest that NFNS represents an allelic variation of NF1. At least 10 different pathogenic variants in the NF1 gene were detected in patients with NFNS. About half of these are missense, the other half are small deletions or insertions that are predicted to result either in frameshift or in-frame deletions. The majority of the NFNS-causing variants are clustered in exons 27 to 35. Four of the NFNS-causing pathogenic variants were found in patients with classic NF1; these pathogenic variants, however, were outside of exons 27-35.

WS is also caused by autosomal dominant variants in the NF1 gene (Tassabehji et al. 1993). To date, one large deletion and one small in-frame duplication have been reported (Tassabehji et al. 1993; HGMD).

NF1 encodes the neurofibromin protein, a negative regulator of the RAS/MAPK pathway.

Clinical Sensitivity - Sequencing with CNV PG-Select

This test will detect pathogenic variants in NF1 in 80-93% of patients that meet the NIH clinical diagnostic criteria for neurofibromatosis type 1 (Maruoka et al. 2014; van Minkelen et al. 2014; Pasmant et al. 2015; Zhang et al. 2015; Calì et al. 2017).

Deletions and duplications of NF1 represent ~5% of cases (Friedman 2014).

Testing Strategy

This test provides full coverage of all coding exons of the NF1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Deletion and duplication testing for NF1 is performed using NGS, but CNVs detected in this gene are usually confirmed via multiplex ligation-dependent probe amplification (MLPA). Please see limitations for CNV detection via NGS.

Indications for Test

Patients with NF1, NFNS, SNF, and WS are candidates.


Official Gene Symbol OMIM ID
NF1 613113
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Interstitial Lung Disease Panel
Neurofibromatosis (NF) Type 1 and Legius Syndrome Panel


  • Abuelo DN, Meryash DL. 1988. Neurofibromatosis with fully expressed Noonan syndrome. Am. J. Med. Genet. 29: 937–941. PubMed ID: 3135755
  • Allanson JE, Hall JG, Allen MI Van. 1985. Noonan phenotype associated with neurofibromatosis. Am. J. Med. Genet. 21: 457–462. PubMed ID: 2411134
  • Baralle D, Mattocks C, Kalidas K, Elmslie F, Whittaker J, Lees M, Ragge N, Patton MA, Winter RM, ffrench-Constant C. 2003. Different mutations in the NF1 gene are associated with Neurofibromatosis-Noonan syndrome (NFNS). Am. J. Med. Genet. A 119A: 1–8. PubMed ID: 12707950
  • Calě et al. 2017. PubMed ID: 27838393
  • Colley A, Donnai D, Evans DG. 1996. Neurofibromatosis/Noonan phenotype: a variable feature of type 1 neurofibromatosis. Clin. Genet. 49: 59–64. PubMed ID: 8740913
  • De Luca A, Bottillo I, Sarkozy A, Carta C, Neri C, Bellacchio E, Schirinzi A, Conti E, Zampino G, Battaglia A, Majore S, Rinaldi MM, Carella M, Marino B, Pizzuti A, Digilio MC, Tartaglia M, Dallapiccola B. 2005. NF1 Gene Mutations Represent the Major Molecular Event Underlying Neurofibromatosis-Noonan Syndrome. Am J Hum Genet 77: 1092-1101. PubMed ID: 16380919
  • Friedman JM. 2014. Neurofibromatosis 1. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301288
  • HGMD (Human Gene Mutation Database)
  • Hüffmeier U, Zenker M, Hoyer J, Fahsold R, Rauch A. 2006. A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene. Am. J. Med. Genet. A 140: 2749–2756. PubMed ID: 17103458
  • Jadayel D, Fain P, Upadhyaya M, Ponder MA, Huson SM, Carey J, Fryer A, Mathew CG, Barker DF, Ponder BA. 1990. Paternal origin of new mutations in von Recklinghausen neurofibromatosis. Nature 343: 558–559. PubMed ID: 2105472
  • Kluwe L, Tatagiba M, Fünsterer C, Mautner V-F. 2003. NF1 mutations and clinical spectrum in patients with spinal neurofibromas. J. Med. Genet. 40: 368–371. PubMed ID: 12746402
  • Lázaro C, Gaona A, Ainsworth P, Tenconi R, Vidaud D, Kruyer H, Ars E, Volpini V, Estivill X. 1996. Sex differences in mutational rate and mutational mechanism in the NF1 gene in neurofibromatosis type 1 patients. Hum. Genet. 98: 696–699. PubMed ID: 8931703
  • Lázaro C, Ravella A, Gaona A, Volpini V, Estivill X. 1994. Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father. N. Engl. J. Med. 331: 1403–1407. PubMed ID: 7969279
  • Maruoka et al. 2014. PubMed ID: 25325900
  • Pasmant et al. 2015. PubMed ID: 25074460
  • Quattrin T, McPherson E, Putnam T. 1987. Vertical transmission of the neurofibromatosis/Noonan syndrome. Am. J. Med. Genet. 26: 645–649. PubMed ID: 3105315
  • Quintáns B, Pardo J, Campos B, Barros F, Volpini V, Carracedo á, Sobrido MJ. 2011. Neurofibromatosis without Neurofibromas: Confirmation of a Genotype-Phenotype Correlation and Implications for Genetic Testing. Case Reports in Neurology 3: 86–90. PubMed ID: 21532985
  • Rasmussen SA, Friedman JM. 2000. NF1 gene and neurofibromatosis 1. American Journal of Epidemiology 151: 33–40. PubMed ID: 10625171
  • Riccardi VM. 1993. Genotype, malleotype, phenotype, and randomness: lessons from neurofibromatosis-1 (NF-1). American journal of human genetics 53: 301. PubMed ID: 8328448
  • Stevenson DA, Viskochil DH, Rope AF, Carey JC. 2006. Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype. Clin. Genet. 69: 246–253. PubMed ID: 16542390
  • Tassabehji M, Strachan T, Sharland M, Colley A, Donnai D, Harris R, Thakker N. 1993. Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome. American journal of human genetics 53: 90-95. PubMed ID: 8317503
  • Upadhyaya M, Ruggieri M, Maynard J, Osborn M, Hartog C, Mudd S, Penttinen M, Cordeiro I, Ponder M, Ponder BA, Krawczak M, Cooper DN. 1998. Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. Hum. Genet. 102: 591–597. PubMed ID: 9654211
  • van Minkelen et al. 2014. PubMed ID: 23656349
  • Watson GH. 1967. Pulmonary stenosis, café-au-lait spots, and dull intelligence. Archives of disease in childhood 42: 303-307. PubMed ID: 6025371
  • Zhang et al. 2015. PubMed ID: 26056819


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

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