Test Catalog

Test Id : PMNSR

Postmortem Noonan and Related Panel, Varies

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

Providing a comprehensive postmortem genetic evaluation in the setting of sudden cardiac death and suspicion for Noonan syndrome or related disorders

 

Identification of a pathogenic variant in the decedent, which may assist with risk assessment and 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 includes next-generation sequencing and supplemental Sanger sequencing to evaluate the BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, SHOC2, and SOS1 genes.

Highlights

This test is intended for use on postmortem samples (eg, formalin-fixed, paraffin-embedded [FFPE] tissue block; dried blood spot) when whole blood is not available.

 

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 postmortem diagnosis of Noonan syndrome, LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and deafness) syndrome, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, or a related disorder.

 

Identification of a pathogenic variant may assist with familial risk assessment, screening, and genetic counseling.

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

Postmortem Noonan and Related Panel

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

BRAF

Cardiofaciocutaneous (CFC)

CBL

Costello Syndrome (CS)

HRAS

KRAS

LEOPARD Syndrome (LS)

MAP2K1

MAP2K2

Multiple Lentigines

Next Gen Sequencing Test

Noonan Syndrome (NS)

NRAS

PTPN11

RAF1

SHOC2

SOS1

FFPE

Postmortem

Sudden cardiac arrest

Sudden cardiac death

Sudden unexplained death

Sudden death

Specimen Type
Describes the specimen type validated for testing

Varies

Ordering Guidance

This test is intended for use when EDTA whole blood is not available and formalin-fixed, paraffin-embedded (FFPE) tissue or dried blood spots are the only available samples. If EDTA whole blood is available, order NSRGP / Noonan Syndrome and Related Disorders Multi-Gene Panel, Blood.

 

Targeted testing for familial variants (also called site-specific or known mutations 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 required, see Special Instructions. Testing may proceed without the patient information however it aids in providing a more thorough interpretation. Ordering providers are strongly encouraged to complete the form and send it with the specimen.

2. Pathology report must accompany specimen in order for testing to be performed. Include physician name and phone number with the specimen.

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

Preferred:

Specimen Type: Tissue

Container/Tube: Tissue block

Collection Instructions: Submit a formalin-fixed, paraffin-embedded tissue block.

Additional Information: Testing will be attempted on blocks of any age but may be canceled if adequate DNA concentration cannot be obtained.

Specimen Stability Information: Ambient

 

Acceptable:

Specimen Type: Blood spot

Container/Tube: Whatman FTA Classic Card or Whatman Protein Saver 903 Card

Specimen Volume: 3-5 blood spots

Collection Instructions:

1. Completely fill at least 3 circles on the filter paper card

2. Let blood dry on the filter paper at ambient temperature in a horizontal position for 3 hours.

3. Do not expose specimen to heat or direct sunlight.

4. Do not stack wet specimens.

5. Keep specimen dry.

Specimen Stability Information: Ambient (preferred)/Refrigerated

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 in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. 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

Tissue: See Specimen Required

Blood Spots: 3

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
Varies Ambient (preferred)
Frozen
Refrigerated

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

Providing a comprehensive postmortem genetic evaluation in the setting of sudden cardiac death and suspicion for Noonan syndrome or related disorders

 

Identification of a pathogenic variant in the decedent, which may assist with risk assessment and 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 includes next-generation sequencing and supplemental Sanger sequencing to evaluate the BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, SHOC2, and SOS1 genes.

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 whose characteristic features can include short stature, congenital heart defects, characteristic facial dysmorphology, unusual chest shape, developmental delay of varying degree, cryptorchidism, and coagulation defects, among other features. In approximately 20% to 30% of cases, Noonan syndrome and related disorders are associated with hypertrophic cardiomyopathy, which may lead to sudden cardiac death. Postmortem diagnosis of Noonan syndrome or a related disorder may assist in confirmation of the cause of death, as well as risk assessment in living family members. Other heart defects associated with Noonan syndrome and related disorders include pulmonary valve stenosis (20%-50%), 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 intellectual disability is seen in up to one-third of adults. 

 

The incidence of NS is estimated to be between 1 in 1,000 and 1 in 2,500, 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 pathogenic variant in approximately 75% of affected individuals. NS can be sporadic and due to new (de novo) 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 Noonan syndrome and loose anagen hair.

 

Genes included in the Postmortem Noonan and Related 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-like syndrome 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- like syndrome 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.

An interpretive report will be provided.

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. 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

Sample Quality:

This test is intended for use when EDTA whole blood is not available and formalin-fixed, paraffin-embedded (FFPE) tissue or blood spots are the only available samples. DNA extracted from FFPE tissue can be degraded, which results in a higher failure rate (approximately 5%) for next-generation sequencing when compared to DNA extracted from whole blood. Due to the quality of DNA extracted from FFPE, the acceptable coverage threshold is lower than that of the equivalent blood assays. Coverage of at least 40X is expected for all regions assessed but may be adjusted on a case-by-case basis at the discretion of the laboratory director. Sanger sequencing may be used in regions that do not achieve this rate of coverage at the discretion of laboratory director. Genomic regions that are not sufficiently covered for analysis and interpretation will be indicated on the laboratory report. Sanger sequencing on DNA extracted from FFPE may also result in quality limitations when compared to testing on DNA extracted from blood.

 

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 used (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of Noonan syndrome 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 Noonan syndrome 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.

 

Technical Limitations:

Next-generation sequencing may not detect all types of genetic variants. Additionally, rare variants 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.

 

For blood spot sample type: If the patient has had an allogeneic blood or marrow transplant or a recent (ie, <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. Online Mendelian Inheritance in Man. Accessed 10/5/2017. Available at www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM

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

3. Rauen KA: Cardiofaciocutaneous Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. University of Washington, Seattle. 1993-2018. 2007 Jan 18 (Updated 2016 Mar 3). Accessed 2/2018. Available at www.ncbi.nlm.nih.gov/books/NBK1186/

4. Allanson JE, Roberts AE: Noonan Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. University of Washington. Seattle. 1993-2018. 2001 Nov 15 (Updated 2016 Feb 25). Accessed 2/2018. Available at www.ncbi.nlm.nih.gov/books/NBK1124/

5. Gripp KW, Lin AE: Costello Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. University of Washington, Seattle. 1993-2018. 2006 Aug 29 (Updated 2012 Jan 12). Accessed 2/2018. Available at www.ncbi.nlm.nih.gov/books/NBK1507/

6. Gelb BD, Tartaglia M: Noonan Syndrome with Multiple Lentigines. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. University of Washington, Seattle. 1993-2018. 2007 Nov 30 (Updated 2015 May 14) Accessed 2/2018. 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)

 

The following genes are evaluated in this multigene panel: 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.

6 to 8 weeks

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; Client provided paraffin blocks (FFPE) and dried blood spots (DBS) will be returned to client after testing is complete.

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

81404

81311

81405 X2

81406 X6

LOINC® Information
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.

Test Id Test Order Name Order LOINC Value
PMNSR Postmortem Noonan and Related Panel 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.
BA1423 Gene(s) Evaluated 48018-6
BA1424 Result Summary 50397-9
BA1425 Result Details 82939-0
BA1426 Interpretation 69047-9
BA1427 Additional Information 48767-8
BA1428 Method 85069-3
BA1429 Disclaimer 62364-5
BA1430 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 | 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