Noonan Syndrome via the LZTR1 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
4597 LZTR1 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4597LZTR181479 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.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

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

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Noonan Syndrome (NS) is a relatively common developmental disorder that 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 prenatal lymphatic abnormalities such as nuchal translucency, cystic hygroma, bilateral chylothorax, pleural effusion and polyhydramnios. 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). The prevalence of NS is estimated at 1 in 1000 to 1 in 2,500 births worldwide (Allanson et al. 1985; Nisbet et al. 1999; van der Burgt 2007; Romano et al. 2010).

Genetics

NS is caused by gain of function pathogenic variants in various genes within the RAS/MAPK pathway. Several RAS/MAPK genes (PTPN11, SOS1, SOS2, RAF1, KRAS, SHOC2, BRAF, NRAS, MAP2K1, RIT1, and CBL) have been involved in NS. Recently, five different pathogenic missense variants in the LZTR1 gene were reported in 5 patients affected with NS without detectable pathogenic variants in the remaining Noonan-related genes. Three of the variants occurred de novo, and two co-segregated with NS in two families with a history of the disease (Yamamoto et al. 2015).

Somatic LZTR1 pathogenic variants have been reported in patients with glioblastoma multiforme, a malignant central nervous tumor (Frattini et al. 2013).

In addition to Noonan syndrome, heterozygous germline pathogenic variants have been associated with schwannomatosis-2 (Piotrowski et al. 2014; Smith et al. 2015; Paganini et al. 2015). Schwannomatosis (SWNTS) is the third main type of neurofibromatosis (Plotkin et al. 2013).

The LZTR1 gene encodes for leucine zipper-like transcriptional regulator 1 protein, a member of the BTB-kelch superfamily that has not been previously associated with the RAS/MAPK pathway (Aoki et al. 2016). The mechanism by which LZTR1 pathogenic variants lead to NS is unknown at this time.

Clinical Sensitivity - Sequencing with CNV PG-Select

Pathogenic variants in LZTR1 were detected in ~ 2.5 % of patients with Noonan syndrome (Yamamoto et al. 2015).

Testing Strategy

This test provides full coverage of all coding exons of the LZTR1 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 a clinical diagnosis of NS without pathogenic variants in the remaining Noonan-related genes.

Symptoms of NS patients overlap with those for CardioFacioCutaneous Syndrome (CFCS) and Costello Syndrome (CS) patients. NS patients who test negative for mutations in (PTPN11, SOS1, RIT1, RAF1, KRAS, SHOC2, BRAF, NRAS and CBL may be candidates for CFCS (MAP2K1 and MAP2K2 genes) or CS (HRAS gene) testing. Conversely, CFCS or CS Syndrome patients who test negative for BRAF, MAP2K1, MAP2K2 and KRAS genes or HRAS, respectively, may be candidates for NS testing. A comprehensive NGS sequencing panel that includes genes that have been implicated in NS, CFCS and CS is available.

Gene

Official Gene Symbol OMIM ID
LZTR1 600574
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Noonan Syndrome 10 AD 616564
Schwannomatosis 2 AD 615670

Related Tests

Name
Cancer Panel
Schwannomatosis Panel

Citations

  • Allanson J.E. et al. 1985. American Journal of Medical Genetics. 21: 507-14. PubMed ID: 4025385
  • Aoki Y. et al. 2016. Journal of Human Genetics. 61: 33-9. PubMed ID: 26446362
  • Frattini V. et al. 2013. Nature Genetics. 45: 1141-9. PubMed ID: 23917401
  • Nisbet D.L. et al. 1999. Prenatal Diagnosis. 19: 642-7. PubMed ID: 10419612.
  • Paganini I. et al. 2015. European Journal of Human Genetics. 23: 963-8. PubMed ID: 25335493
  • Piotrowski A. et al. 2014. Nature Genetics. 46: 182-7. PubMed ID: 24362817
  • Plotkin S.R. et al. 2013. American Journal of Medical Genetics. Part A. 161A: 405-16. PubMed ID: 23401320
  • Romano A.A. et al. 2010. Pediatrics. 126: 746-59. PubMed ID: 20876176
  • Smith M.J. et al. 2015. Neurology. 84: 141-7. PubMed ID: 25480913
  • van der Burgt I. 2007. Noonan syndrome. Orphanet J. Rare Dis. 2:4. PubMed ID: 17222357
  • Yamamoto G.L. et al. 2015. Journal of Medical Genetics. 52: 413-21. PubMed ID: 25795793

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

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2) Select Additional Test Options

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

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