Test Catalog

Test Id : NSRGP

Noonan Syndrome and Related Disorders Multi-Gene Panel, Blood

Useful For
Suggests clinical disorders or settings where the test may be helpful

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of Noonan syndrome (NS) or related disorders

 

Establishing a diagnosis of a NS or related disorders, in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved

 

Identifying variants within genes known to be associated with increased risk for disease features allowing for predictive testing of at-risk family members

Genetics Test Information
Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test uses next-generation sequencing to test for variants in the BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, SHOC2, and SOS1 genes.

 

This test may aid in the diagnosis of Noonan syndrome, LEOPARD syndrome, cardiofaciocutaneous syndrome, Costello syndrome, or a related disorder. This test cannot distinguish between germline variants associated with Noonan syndrome and related disorders versus somatic (oncogenic, nongermline) variants, which may be associated with hematologic neoplasms. Therefore, this test does not provide diagnostic, prognostic, or therapeutic information for somatic variants. Variants detected by this test are interpreted as germline unless otherwise noted in the interpretation.

 

Identification of a pathogenic variant may assist with prognosis, clinical management, familial screening, and genetic counseling.

 

Prior Authorization is available for this assay.

Highlights

This test includes next-generation sequencing and supplemental Sanger sequencing to evaluate the genes tested on this panel.

Special Instructions
Library of PDFs including pertinent information and forms related to the test

Method Name
A short description of the method used to perform the test

Custom Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Supplemental Sanger Sequencing

NY State Available
Indicates the status of NY State approval and if the test is orderable for NY State clients.

Yes

Reporting Name
Lists a shorter or abbreviated version of the Published Name for a test

Noonan Syndrome and Related Panel,B

Aliases
Lists additional common names for a test, as an aid in searching

Cardiofaciocutaneous (CFC)

Costello Syndrome (CS)

LEOPARD Syndrome (LS)

Multiple Lentigines

Noonan Syndrome (NS)

BRAF

CBL

HRAS

KRAS

MAP2K1

MAP2K2

NRAS

PTPN11

RAF1

SHOC2

SOS1

Next Gen Sequencing Test

Specimen Type
Describes the specimen type validated for testing

Whole Blood EDTA

Ordering Guidance

This test has been validated for testing prenatal specimens. Contact a laboratory genetic counselor at 800-533-1710 for specimen collection requirements or questions related to prenatal testing for Noonan syndrome and related disorders. Targeted testing for familial variants (also called site-specific or known mutation testing) is available for the genes on this panel. See FMTT / Familial Mutation, Targeted Testing, Varies.

Necessary Information

1. Noonan Spectrum Gene Testing Patient Information Sheet (T689) is strongly recommended, but not required, to be filled out and sent with the specimen. This information aids in providing a more thorough interpretation of test results. Ordering providers are strongly encouraged to complete the form and send it with the specimen.

2. Include physician name and phone number with specimen.

3. Prior Authorization is available for this assay. Submit the required form with the specimen.

Specimen Required
Defines the optimal specimen required to perform the test and the preferred volume to complete testing

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions: Send specimen in original tube. Do not aliquot.

Special Instructions
Library of PDFs including pertinent information and forms related to the test

Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Noonan Spectrum Gene Testing Patient Information Sheet (T689)

3. Noonan Syndrome and Related Disorders Multi-Gene Panel Prior Authorization Ordering Instructions

4. If not ordering electronically, complete, print, and send a Cardiovascular Test Request (T724) with the specimen.

Specimen Minimum Volume
Defines the amount of sample necessary to provide a clinically relevant result as determined by the Testing Laboratory

1 mL

Reject Due To
Identifies specimen types and conditions that may cause the specimen to be rejected

No specimen should be rejected.

Specimen Stability Information
Provides a description of the temperatures required to transport a specimen to the performing laboratory, alternate acceptable temperatures are also included

Specimen Type Temperature Time Special Container
Whole Blood EDTA Ambient (preferred)
Refrigerated

Useful For
Suggests clinical disorders or settings where the test may be helpful

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of Noonan syndrome (NS) or related disorders

 

Establishing a diagnosis of a NS or related disorders, in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved

 

Identifying variants within genes known to be associated with increased risk for disease features allowing for predictive testing of at-risk family members

Genetics Test Information
Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test uses next-generation sequencing to test for variants in the BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, SHOC2, and SOS1 genes.

 

This test may aid in the diagnosis of Noonan syndrome, LEOPARD syndrome, cardiofaciocutaneous syndrome, Costello syndrome, or a related disorder. This test cannot distinguish between germline variants associated with Noonan syndrome and related disorders versus somatic (oncogenic, nongermline) variants, which may be associated with hematologic neoplasms. Therefore, this test does not provide diagnostic, prognostic, or therapeutic information for somatic variants. Variants detected by this test are interpreted as germline unless otherwise noted in the interpretation.

 

Identification of a pathogenic variant may assist with prognosis, clinical management, familial screening, and genetic counseling.

 

Prior Authorization is available for this assay.

Clinical Information
Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Noonan syndrome (NS) is an autosomal dominant disorder of variable expressivity characterized by short stature, congenital heart defects, characteristic facial dysmorphology, unusual chest shape, developmental delay of varying degree, cryptorchidism, and coagulation defects, among other features.

 

Heart defects include pulmonary valve stenosis (20%-50%), hypertrophic cardiomyopathy (20%-30%), atrial septal defects (6%-10%), ventricular septal defects (approximately 5%), and patent ductus arteriosus (approximately 3%). Facial features, which tend to change with age, may include hypertelorism, downward-slanting eyes, epicanthal folds, and low-set and posteriorly rotated ears. Mild mental retardation is seen in up to one-third of adults.

 

The incidence of NS is estimated to be between 1 in 1000 and 1 in 2500, although subtle expression in adulthood may cause this number to be an underestimate. NS is genetically heterogeneous, with 4 genes currently associated with the majority of cases: PTPN11, RAF1, SOS1, and KRAS. Heterozygous variants in NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, and CBL have also been associated with a smaller percentage of NS and related phenotypes. All of these genes are involved in a common signal transduction pathway known as the Ras-mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is important for cell growth, differentiation, senescence, and death. Molecular genetic testing of all of the known genes identifies a variant in approximately 75% of affected individuals. NS can be sporadic and due to new variants; however, an affected parent can be recognized in 30% to 75% of families.

 

Some studies have shown that there is a genotype-phenotype correlation associated with NS. An analysis of a large cohort of individuals with NS has suggested that PTPN11 variants are more likely to be found when pulmonary stenosis is present, while hypertrophic cardiomyopathy is commonly associated with RAF1 variants, but rarely associated with PTPN11.

 

A number of related disorders exist that have phenotypic overlap with NS and are caused by variants in the same group of genes. PTPN11 and RAF1 variants have been associated with LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and deafness) syndrome, an autosomal dominant disorder sharing several clinical features with NS. Variants in BRAF, MAP2K1, MAP2K2, and KRAS have been identified in individuals with cardiofaciocutaneous (CFC) syndrome, a condition involving congenital heart defects, cutaneous abnormalities, Noonan-like facial features, and severe psychomotor developmental delay. Costello syndrome, which is characterized by coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, failure to thrive, cardiac anomalies, and developmental disability has been primarily associated with variants in HRAS. Variation in SHOC2 has been associated with a distinctive phenotype involving features of NS and loose anagen hair.

 

Genes included in the Noonan Syndrome and Related Disorders Multi-Gene Panel

Gene

Protein

Inheritance

Disease association

BRAF

V-RAF murine sarcoma viral oncogene homolog b1

AD

Noonan/CFC/Costello syndrome

CBL

CAS-BR-M murine ecotropic retroviral transforming sequence homolog

AD

Noonan syndrome-like disorder

HRAS

V-HA-RAS Harvey rat sarcoma viral oncogene homolog

AD

Costello syndrome

KRAS

V-KI-RAS Kirsten rat sarcoma viral oncogene homolog

AD

Noonan/CFC/Costello syndrome

MAP2K1

Mitogen-activated protein kinase kinase 1

AD

Noonan/CFC

MAP2K2

Mitogen-activated protein kinase kinase 2

AD

Noonan/CFC

NRAS

Neuroblastoma ras viral oncogene homolog

AD

Noonan syndrome

PTPN11

Protein-tyrosine phosphatase, nonreceptor-type, 11

AD

Noonan/CFC/LEOPARD syndrome

RAF1

V-raf-1 murine leukemia viral oncogene homolog 1

AD

Noonan/LEOPARD syndrome

SHOC2

Suppressor of clear, c. Elegans, homolog of

AD

Noonan-syndrome like with loose anagen hair

SOS1

Son of sevenless, drosophila, homolog 1

AD

Noonan-syndrome like with loose anagen hair

 

Abbreviations: Autosomal dominant (AD)

Reference Values
Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Interpretation
Provides information to assist in interpretation of the test results

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

 

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Cautions
Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Clinical Correlations:

Some individuals who have involvement of 1 or more of the genes on the panel may have a variant that is not identified by the methods performed (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of Noonan syndrome (NS) or a related disorder.

 

Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

If testing was performed because of a family history of NS or a related disorder, it is often useful to first test an affected family member. Identification of a pathogenic variant in an affected individual would allow for more informative testing of at-risk individuals.

 

If clinical or family history suggests that a detected variant may be somatic and not germline, additional genetic testing of alternate tissue types or appropriate counseling and medical management may be indicated. In addition, a negative result does not preclude the presence of a somatic variant at low (<10%) variant allele frequency.

 

Technical Limitations:

Next-generation sequencing may not detect all types of genetic variants. Additionally, rare alterations (ie, polymorphisms) may be present that could lead to false-negative or false-positive results. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion/duplication analysis.

 

If the patient has had an allogeneic blood or marrow transplant or a recent (ie, less than 6 weeks from time of sample collection) heterologous blood transfusion these results may be inaccurate due to the presence of donor DNA.

 

Reclassification of Variants Policy:

At this time, it is not standard practice for the laboratory to systematically review likely pathogenic variants or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

 

Contact the laboratory if additional information is required regarding the transcript or human genome assembly used for the analysis of this patient's results.

Clinical Reference
Recommendations for in-depth reading of a clinical nature

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424

2.Tartaglia M, Gelb BD, Zenker M: Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab. 2011 Feb;25(1):161-179

3. Rauen KA: Cardiofaciocutaneous syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2007. Updated March 3, 2016. Accessed August 2, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK1186/

4. Allanson JE, Roberts AE: Noonan syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington. Seattle; 2001. Updated August 8, 2019. Accessed August 2, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK1124/

5. Gripp KW, Rauen KA: Costello syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2006. Updated August 29, 2019. Accessed August 2, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK1507/

6. Gelb BD, Tartaglia M: Noonan syndrome with multiple lentigines. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2007. Updated May 14, 2015. Accessed August 2, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK1383/

Special Instructions
Library of PDFs including pertinent information and forms related to the test

Method Description
Describes how the test is performed and provides a method-specific reference

Next-generation sequencing (NGS) is performed using an Illumina instrument with paired-end reads. The DNA is prepared for NGS using a custom Agilent SureSelect Target Enrichment System. Data is analyzed with a bioinformatics software pipeline. Supplemental and/or confirmatory Sanger sequencing is performed when necessary.(Unpublished Mayo method)

 

Genes analyzed: BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, SHOC2, and SOS1.

PDF Report
Indicates whether the report includes an additional document with charts, images or other enriched information

No

Day(s) Performed
Outlines the days the test is performed. This field reflects the day that the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time before the test is performed. Some tests are listed as continuously performed, which means that assays are performed multiple times during the day.

Monday

Report Available
The interval of time (receipt of sample at Mayo Clinic Laboratories to results available) taking into account standard setup days and weekends. The first day is the time that it typically takes for a result to be available. The last day is the time it might take, accounting for any necessary repeated testing.

2 to 4 weeks after prior authorization approved

Specimen Retention Time
Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded

Extracted DNA: 2 months

Performing Laboratory Location
Indicates the location of the laboratory that performs the test

Rochester

Fees
Several factors determine the fee charged to perform a test. Contact your U.S. or International Regional Manager for information about establishing a fee schedule or to learn more about resources to optimize test selection.

  • Authorized users can sign in to Test Prices for detailed fee information.
  • Clients without access to Test Prices can contact Customer Service 24 hours a day, seven days a week.
  • Prospective clients should contact their Regional Manager. For assistance, contact Customer Service.

Test Classification
Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR) product.

This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information
Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Clinic Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.

CPT codes are provided by the performing laboratory.

81479-CBL

81404-HRAS

81311-NRAS

81405 x 2-KRAS, SHOC2

81406 x 6-BRAF, MAP2K1, MAP2K2, PTPN11, RAF1, SOS1

Prior Authorization
Prior Authorization may be required by your insurance carrier.

Insurance preauthorization is available for this testing; forms are available.

 

Patient financial assistance may be available to those who qualify. Patients who receive a bill from Mayo Clinic Laboratories will receive information on eligibility and how to apply.

LOINC® Information

Test Id Test Order Name Order LOINC Value
Provides guidance in determining the Logical Observation Identifiers Names and Codes (LOINC) values for the order and results codes of this test. LOINC values are provided by the performing laboratory.
NSRGP Noonan Syndrome and Related Panel,B In Process
Result Id Test Result Name Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
36821 Gene(s) Evaluated 48018-6
36822 Result Summary 50397-9
36823 Result Details 82939-0
36824 Interpretation 59462-2
36953 Additional Information 48767-8
36954 Method 85069-3
36955 Disclaimer 62364-5
36825 Reviewed by 18771-6

Test Setup Resources

Setup Files
Test setup information contains test file definition details to support order and result interfacing between Mayo Clinic Laboratories and your Laboratory Information System.

Excel | Create a PDF

Sample Reports
Normal and Abnormal sample reports are provided as references for report appearance.

Normal Reports | Abnormal Reports

SI Sample Reports
International System (SI) of Unit reports are provided for a limited number of tests. These reports are intended for international account use and are only available through MayoLINK accounts that have been defined to receive them.

SI Normal Reports | SI Abnormal Reports