CBL-Related Disorders via the CBL 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 | |
|---|---|---|---|---|---|
| 4569 | CBL | 81479 | 81479,81479 | $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) is characterized by dysmorphic facial features, growth retardation, 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 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. The prevalence of NS is estimated at 1 in 1000 to 1 in 2,500 births worldwide (Allanson et al. 1985; Romano et al. 2010; Smpokou et al. 2012). Pathogenic variants in the CBL gene have been reported both in patients who fulfilled the clinical criteria for the diagnosis of Noonan syndrome and patients with clinical features suggestive of Noonan syndrome, but did not fulfill the clinical criteria for a definitive diagnosis (Martinelli et al. 2010; Lepri et al. 2014). Clinical features identified in these patients include developmental delay; short stature; facial dysmorphism, hypertelorism, ptosis and strabismus; low-set and posteriorly rotated ears, widely spaced nipples; chest abnormalities; dark skin and café-au-lait spots; and cardiologic findings in the form of enlarged left atrium, dysrhythmias and dysplastic leaflets. MRI findings include delayed myelinization without structural abnormalities; abnormal corpus callosum and hypoplasia of the cerebellar vermis. Hypotonia, severe feeding problems, pleural effusions, hydrops and chylothorax were reported in newborn and infant patients (Bulow et al. 2015, Martinelli et al. 2015).
Genetics
Noonan Syndrome is caused by defects in various genes within the RAS/MAPK pathway. At least 70% of patients with a diagnosis of Noonan syndrome have heterozygous germline pathogenic variants in thirteen genes (Romano et al. 2010; Tartaglia et al. 2010; Aoki et al. 2013). Ten of these genes (PTPN11, SOS1, RAF1, KRAS, HRAS, SHOC2, BRAF, NRAS, MAP2K1, MAP2K1) encode components of the main Ras/MAPK signaling pathway; while three (CBL, KAT6B, and RIT1) encode proteins that are involved in its regulation (Rauen 2013; Martinelli et al. 2010; Niemeyer et al. 2010; Kraft et al. 2011, Aoki et al. 2013). Although most causative Noonan syndrome variants occur de novo, familial cases have been reported. In these families, Noonan syndrome is inherited in an autosomal dominant manner with complete penetrance and variable expressivity (Romano et al. 2010). Defects in the CBL gene appear to be a rare cause of Noonan syndrome. Pathogenic variants are found in about 1% of patients with clinical features within the Rasopathy phenotypic spectrum, and without defects in the remaining genes that have been associated with this group of disorders. Eleven variants have been reported to date. The majority are missense; although splicing, nonsense and small deletions are reported (Martinelli et al. 2015, Human Gene Mutation Database). Germline pathogenic variants in CBL have also been reported in children with juvenile myelomonocytic leukemia (JMML) with or without congenital anomalies that overlap with those of Noonan syndrome (Nieemeyer et al. 2010; Martinelli et al. 2015). The CBL gene encodes an E3 ubiquitin ligase that negatively regulates intracellular signaling through degradation of activated tyrosine kinase receptors. It also positively regulates signal transduction through its role as an adaptor protein (Kales et al. 2010).
Clinical Sensitivity - Sequencing with CNV PG-Select
Defects in the CBL gene were found in about 1% of patients with clinical features within the Rasopathy phenotypic spectrum, and without defects in the remaining genes that have been associated with this group of disorders (Martinelli et al. 2015). Heterozygous germline pathogenic variants in CBL were found in 9% patients with a clincal diagnosis of JMML (Strullu et al. 2013).
Testing Strategy
This test provides full coverage of all coding exons of the CBL gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
Indications for Test
Patients with clinical features suggestive of Noonan syndrome and no pathogenic variants in the PTPN11, SOS1, RAF1, KRAS, HRAS, SHOC2, BRAF, NRAS, MAP2K1, MAP2K1, KAT6B, or RIT1 genes (Martinelli et al. 2015). Children with juvenile myelomonocytic leukemia and congenital anomalies that overlap with those of Noonan syndrome (Nieemeyer et al. 2010).
Patients with clinical features suggestive of Noonan syndrome and no pathogenic variants in the PTPN11, SOS1, RAF1, KRAS, HRAS, SHOC2, BRAF, NRAS, MAP2K1, MAP2K1, KAT6B, or RIT1 genes (Martinelli et al. 2015). Children with juvenile myelomonocytic leukemia and congenital anomalies that overlap with those of Noonan syndrome (Nieemeyer et al. 2010).
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| CBL | 165360 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Disease
| Name | Inheritance | OMIM ID |
|---|---|---|
| Noonan Syndrome-Like Disorder With Or Without Juvenile Myelomonocytic Leukemia | AD | 613563 |
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
- Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, Inoue S, Watanabe Y, Ogura T, Matsubara Y. 2013. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am. J. Hum. Genet. 93:173-180.
PubMed ID: 23791108 - Bülow L, Lissewski C, Bressel R, Rauch A, Stark Z, Zenker M, Bartsch O. 2015. Hydrops, fetal pleural effusions and chylothorax in three patients with CBL mutations. Am. J. Med. Genet. A 167A: 394–399. PubMed ID: 25358541
- Human Gene Mutation Database (Bio-base).
- Kales SC, Ryan PE, Nau MM, Lipkowitz S. 2010. Cbl and human myeloid neoplasms: the Cbl oncogene comes of age. Cancer Res. 70: 4789–4794. PubMed ID: 20501843
- Kraft M, Cirstea IC, Voss AK, Thomas T, Goehring I, Sheikh BN, Gordon L, Scott H, Smyth GK, Ahmadian MR, Trautmann U, Zenker M, Tartaglia M, Ekici A, Reis A, Dörr HG, Rauch A, Thiel CT. 2011. Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome–like phenotype and hyperactivated MAPK signaling in humans and mice. Journal of Clinical Investigation 121: 3479–3491. PubMed ID: 21804188
- Lepri FR, Scavelli R, Digilio MC, Gnazzo M, Grotta S, Dentici ML, Pisaneschi E, Sirleto P, Capolino R, Baban A, Russo S, Franchin T, Angioni A, Dallapiccola B. 2014. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med. Genet. 15: 14. PubMed ID: 24451042
- Martinelli S, Luca A De, Stellacci E, Rossi C, Checquolo S, Lepri F, Caputo V, Silvano M, Buscherini F, Consoli F, Ferrara G, Digilio MC, Cavaliere ML, van Hagen JM, Zampino G, van der Burgt I, Ferrero GB, Mazzanti L, Screpanti I, Yntema HG, Nillesen WM, Savarirayan R, Zenker M, Dallapiccola B, Gelb BD, Tartaglia M. 2010. Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype. Am J Hum Genet 87: 250–257. PubMed ID: 20619386
- Martinelli S, Stellacci E, Pannone L, D’Agostino D, Consoli F, Lissewski C, Silvano M, Cencelli G, Lepri F, Maitz S, Pauli S, Rauch A, Zampino G, Selicorni A, Melançon S, Digilio MC, Gelb BD, De Luca A, Dallapiccola B, Zenker M, Tartaglia M. 2015. Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations. Human Mutation n/a–n/a. PubMed ID: 25952305
- Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Sakamoto KM, Gorr TA, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Schneider M, Starý J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S, Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML. 2010. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nature Genetics 42: 794–800. PubMed ID: 20694012
- Rauen KA. 2013. The RASopathies. Annu Rev Genomics Hum Genet 14: 355–369. PubMed ID: 23875798
- 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
- Smpokou P, Tworog-Dube E, Kucherlapati RS, Roberts AE. 2012. Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome. American Journal of Medical Genetics Part A 158A: 3106–3111. PubMed ID: 23165751
- Strullu M, Caye A, Cassinat B, Fenneteau O, Touzot F, Blauwblomme T, Rodriguez R, Latour S, Petit A, Barlogis V, Galambrun C, Leblanc T, Baruchel A, Chomienne C, Cavé H. 2013. In hematopoietic cells with a germline mutation of CBL, loss of heterozygosity is not a signature of juvenile myelo-monocytic leukemia. Leukemia 27: 2404–2407. PubMed ID: 23823657
- Tartaglia M, Zampino G, Gelb BD. 2010. Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis. Mol Syndromol 1: 2–26. PubMed ID: 20648242
Ordering/Specimens
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.
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- PGnome sequencing panels can be ordered via the myPrevent portal only at this time.
Requisition Form
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- Billing information along with specimen and shipping instructions are within the 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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