RAF1-Related Disorders via the RAF1 Gene
Summary and Pricing 
Test Method
Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 8151 | RAF1 | 81406 | 81406,81479 | $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.
Clinical Features and Genetics
Clinical Features
Noonan syndrome (NS, OMIM 163950) is a relatively common developmental disorder. NS is characterized by dysmorphic facial features, growth and congenital heart defects, and musculoskeletal abnormalities. Cardiac abnormalities are found in up to 80% of patients and include pulmonary valve stenosis, atrial septal defect, atrioventricular canal defect, and hypertrophic cardiomyopathy. Musculoskeletal abnormalities include short stature, chest deformity with sunken or raised sternum, and short webbed neck. Several additional abnormalities have been described and include renal, genital, hematological, neurologic, cognitive, behavioral, gastrointestinal, dental, and lymphatic findings. Intelligence is usually normal; however, learning disabilities may be present. NS is characterized by an extensive clinical heterogeneity, even among members of the same family. Diagnosis is often made in infancy or early childhood. Symptoms often change and lessen with advancing age. Infants with NS are at risk of developing juvenile myelomonocytic leukemia (JMML OMIM 607785). The prevalence of NS is estimated at 1 in 1000-2500 births worldwide (Allanson et al. Am J Med Genet 21:507-514, 1985; Romano et al. Pediatrics 126:746-759, 2010).
LEOPARD syndrome (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, sensorineural deafness, OMIM 151100) is a rare congenital developmental disorder characterized by skin pigmentation anomalies including multiple lentigines and café au lait spots, hypertrophic cardiomyopathy, pulmonary valve stenosis, and deafness. Other less common features include short stature, mild mental retardation, and abnormal genitalia (Legius et al. J Med Genet 39:571-574, 2002; Sarkozy et al. J Med Genet 41:e68, 2004).
Genetics
NS is caused by gain of function variants in various genes within the RAS/MAPK pathway, including RAF1. These variants appear to activate the gene product (SHP2 protein). To date, seven RAS/MAPK genes (PTPN11, SOS1, RAF1, KRAS, SHOC2, BRAF, and NRAS) have been involved in patients with NS. Sixteen different causative RAF1 variants, all missense, were reported. Although, most variants were found in three RAF1 exons (7, 14 and 17; Pandit et al. Nat Genet 39:1007-1012, 2007; Razzaque et al. Nat Genet 39:1013-1017, 2007), variants were found in other exons (Kobayashi et al. Hum Mutat 31:284-294, 2010). Genotype-phenotype correlations are slowly being made. In particular, studies have shown that hypertrophic cardiomyopathy is found in ~ 95% of NS patients with RAF1 variants.
LEOPARD syndrome is caused by defects in three genes within the RAS/MAPK pathway: PTPN11, RAF1, and BRAF (Digilio et al. Am J Hum Genet 71:389-394, 2002; Pandit et al. 2007; Sarkozy et al. Hum Mutat 30:695-702, 2009). Unlike NS, LEOPARD syndrome variants act through a dominant negative effect, which appears to disrupt the function of the wild-type gene product (SHP2 protein; Jopling et al. PLOS Genetics 3:e225, 2007). Parents of patients are often asymptomatic, and de novo variants are common. However, familial cases have been reported. In these families, affected relatives are diagnosed only after the birth of a visibly affected child, and the disease is transmitted in an autosomal dominant manner with variable penetrance and expressivity. Genotype-phenotype correlations have been proposed (see for example Limongelli et al. Am J Med Genet A 146:620-628, 2008).
Somatic RAF1 variants have also been implicated in human cancers (Pandit et al. 2007).
Clinical Sensitivity - Sequencing with CNV PG-Select
RAF1 variants were found in 3% of White NS patients (Pandit et al. 2007) and 17% of Japanese NS patients (Razzaque et al. 2007). Approximately 5% of LEOPARD syndrome patients carry RAF1 variants (Gelb and Tartaglia, 2010).
Testing Strategy
This test provides full coverage of all coding exons of the RAF1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
Indications for Test
All NS and LEOPARD syndrome patients that are negative for PTPN11 variants are candidates for this test. For NS patients with HCM, it may be better to perform the RAF1 test ahead of the SOS1 and KRAS gene sequencing tests.
All NS and LEOPARD syndrome patients that are negative for PTPN11 variants are candidates for this test. For NS patients with HCM, it may be better to perform the RAF1 test ahead of the SOS1 and KRAS gene sequencing tests.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| RAF1 | 164760 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| LEOPARD Syndrome 2 | AD | 611554 |
| Noonan Syndrome 5 | AD | 611553 |
Related Test
| Name |
|---|
| Comprehensive Cardiology Panel |
Citations
- Allanson JE, Hall JG, Hughes HE, Preus M, Witt RD. 1985. Noonan syndrome: the changing phenotype. Am. J. Med. Genet. 21: 507-514. PubMed ID: 4025385
- Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B. 2002. Grouping of Multiple-Lentigines/LEOPARD and Noonan Syndromes on the PTPN11 Gene. The American Journal of Human Genetics 71: 389–394. PubMed ID: 12058348
- Jopling C, Geemen D van, Hertog J den. 2007. Shp2 knockdown and Noonan/LEOPARD mutant Shp2–induced gastrulation defects. PLoS genetics 3: e225. PubMed ID: 18159945
- Kobayashi et al. Hum Mutat 31:284-294, 2010 PubMed ID: 20052757
- Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns J-P. 2002. PTPN11 mutations in LEOPARD syndrome. J. Med. Genet. 39: 571–574. PubMed ID: 12161596
- Limongelli, G., et.al. (2008). "Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome." Am J Med Genet A 146A(5): 620-8. PubMed ID: 18241070
- Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, López Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD. 2007. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature Genetics 39: 1007–1012. PubMed ID: 17603483
- Razzaque, M. A., et.al. (2007). "Germline gain-of-function mutations in RAF1 cause Noonan syndrome." Nat Genet 39(8): 1013-7. PubMed ID: 17603482
- Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. 2010. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 126: 746-759. PubMed ID: 20876176
- Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, Scioletti AP, Esposito G, Cordeddu V, Lepri F, Petrangeli V, Dentici ML, Mancini GM, Selicorni A, Rossi C, Mazzanti L, Marino B, Ferrero GB, Silengo MC, Memo L, Stanzial F, Faravelli F, Stuppia L, Puxeddu E, Gelb BD, Dallapiccola B, Tartaglia M. 2009. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: Molecular diversity and associated phenotypic spectrum. Human Mutation 30: 695–702. PubMed ID: 19206169
- Sarkozy A, Conti E, Digilio MC, Marino B, Morini E, Pacileo G, Wilson M, Calabrň R, Pizzuti A, Dallapiccola B. 2004. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. Journal of Medical Genetics 41: e68–e68. PubMed ID: 15121796
Ordering/Specimens
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Requisition Form
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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.
Specimen Types
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