Neurofibromatosis Type 1 and Related Disorders via MLPA of NF1
Summary and Pricing 
Test Method
Multiplex Ligation-Dependent Probe Amplification Assay
| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 2057 | NF1 | 81479 | 81479 | $540 | Order Options and Pricing |
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
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.
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.
Genetics
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 - MLPA
Deletions and duplications of the NF1 gene represent approximately 5% of cases (Friedman 2014).
Testing Strategy
Multiplex Ligation-dependent Probe Amplification (MLPA) is a semi-quantitative technique that is used to determine the relative copy number of up to 60 DNA sequences in a single multiplex PCR-based reaction. It is based on amplification of up to 60 probes, each of which detects a specific complementary DNA sequence of approximately 60 bp in length (often exons in genes of interest). Briefly, each MLPA probe is made up of two half-probes that hybridize immediately adjacent to each other at the target DNA. These adjacent probes are then ligated into one single probe before being amplified in a PCR reaction. Multiplexing is achieved by different probes varying in sizes ranging from 150-500 bp, that are all amplified using a common PCR primer pair. One of the PCR primers is fluorescently labelled enabling separation and detection of the amplification products in a capillary electrophoresis instrument. The peak heights of the amplification products of the target DNA sequence is then compared to the peak heights in various reference DNA samples. A deletion or a duplication is inferred from the relative decrease or increase in peak height respectively.
Indications for Test
Patients with NF1, NFNS, SNF, and WS are candidates.
Patients with NF1, NFNS, SNF, and WS are candidates.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| NF1 | 613113 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| Neurofibromatosis, Familial Spinal | AD | 162210 |
| Neurofibromatosis, Type 1 | AD | 162200 |
| Neurofibromatosis-Noonan Syndrome | AD | 601321 |
| Watson Syndrome | AD | 193520 |
Related Tests
| Name |
|---|
| Neurofibromatosis (NF) Type 1 and Legius Syndrome Panel |
| Neurofibromatosis Type 1 and Related Disorders via the NF1 Gene |
Citations
- 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
- 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
- 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
- Watson GH. 1967. Pulmonary stenosis, café-au-lait spots, and dull intelligence. Archives of disease in childhood 42: 303-307. PubMed ID: 6025371
Ordering/Specimens
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