Noonan Syndrome via the MAP3K8 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
12023 MAP3K8 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
12023MAP3K881479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

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

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

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

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Noonan Syndrome (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 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). The prevalence of NS is estimated at 1 in 1,000 to 1 in 2,500 births worldwide (Allanson. 1987. PubMed ID: 3543368; Romano et al. 2010. PubMed ID: 20876176; Smpokou et al. 2012. PubMed ID: 23165751; Cao et al. 2017. PubMed ID: 28643916).

Clinical features of Noonan syndrome overlap with those of Cardio-Facio-Cutaneous syndrome (Gripp et al. 2007. PubMed ID: 17551924; Rauen. 2016. PubMed ID: 20301365), and Costello syndrome (Gripp and Lin. 2012. PubMed ID: 20301680).

Genetics

Noonan and Noonan-like syndromes are caused by pathogenic variants in PTPN11, SOS1, RAF1, KRAS, SHOC2, BRAF, NRAS, CBL, KAT6B, RIT1, SOS2, LZTR1, MAP3K8, SPRY1, NF1, RRAS, RASA2, and A2ML1 (Human Gene Mutation Database).

To date, one pathogenic missense variant in the MAP3K8 gene has been identified via whole exome sequencing in a three-year-old male patient who presented with short stature, typical facies and mild aortic stenosis, consistent with Noonan syndrome (Chen et al. 2014. PubMed ID: 25049390). Evidence for pathogenicity includes: de novo origin of a variant in an individual with clinical features consistent with Noonan syndrome; and functional studies in cell lines suggesting that MAP3K8 is an agonist of the MAPK pathway (Hagemann et al. 1999. PubMed ID: 10050876, Johannessen et al. 2010. PubMed ID: 21107320). These studies have primarily used cancer and non-human cell-lines and, as such, may have limited application to Noonan syndrome.

MAP3K8 is an oncogene that encodes mitogen activated protein kinase kinase kinase 8, a member of the serine/threonine protein kinase family that activates MAPK and JNK pathways through MEK-dependent mechanisms (Aoki et al. 1993. PubMed ID: 8226782, Hagemann et al. 1999, PubMed ID: 10050876, Clark et al. 2004. PubMed ID: 15287022, Johannessen et al. PubMed ID: 21107320). The MAP3K8 gene, also known as COT and TPL2, has been implicated in inflammation and tumorigenesis (Vougioukalaki et al. 2011. PubMed ID: 21377269).

Clinical Sensitivity - Sequencing with CNV PG-Select

Pathogenic variants in the MAP3K8 gene appear to be a rare cause of Noonan Syndrome. A whole exome sequencing study of 27 individuals with Noonan Syndrome lacking a causative variant in a known disease-associated gene identified a single individual carrying a de novo missense variant in MAP3K8 (Chen et al. 2014. PubMed ID: 25049390).

Testing Strategy

This test provides full coverage of all coding exons of the MAP3K8 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Candidates for this test are patients with clinical features within the Noonan spectrum disorders.

Gene

Official Gene Symbol OMIM ID
MAP3K8 191195
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID

Citations

  • Allanson. 1987. PubMed ID: 3543368
  • Aoki et al. 1993. PubMed ID: 8226782
  • Cao et al. 2017. PubMed ID: 28643916
  • Chen et al. 2014. PubMed ID: 25049390
  • Clark et al. 2004. PubMed ID: 15287022
  • Gripp and Lin. 2012. PubMed ID: 20301680
  • Gripp et al. 2007. PubMed ID: 17551924
  • Hagemann et al. 1999. PubMed ID: 10050876
  • Human Gene Mutation Database (Biobase).
  • Johannessen et al. 2010. PubMed ID: 21107320
  • Rauen. 2016. PubMed ID: 20301365
  • Romano et al. 2010. PubMed ID: 20876176
  • Smpokou et al. 2012. PubMed ID: 23165751
  • Vougioukalaki et al. 2011. PubMed ID: 21377269

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.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

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


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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