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Test ID: NSRGP Noonan Syndrome and Related Disorders Multi-Gene Panel, Blood

Useful For

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

Reporting Name

Noonan Syndrome and Related Panel,B

Specimen Type

Whole Blood EDTA


Advisory Information


Alternative tests designed to detect somatic variants associated with hematologic neoplasms are available; see NGSHM / OncoHeme Next-Generation Sequencing (NGS), Hematologic Neoplasms.

 

Targeted testing for familial variants (also called site-specific or known mutation testing) is available for the genes on this panel. See:

-KVAR1 / Known Variant Analysis-1 Variant, Varies

-KVAR2 / Known Variant Analysis-2 Variants, Varies

-KVAR3 / Known Variant Analysis-3+ Variants, Varies

 

Call 800-533-1710 to confirm the appropriate test for targeted testing.



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. Include physician name and phone number with specimen.



Specimen Required


Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions: Send specimen in original tube.

Additional Information: Prior Authorization is available for this assay; see Special Instructions. Submit the required form with the specimen.


Specimen Minimum Volume

1 mL

Specimen Stability Information

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

Clinical Information

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 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 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

An interpretive report will be provided. 

Interpretation

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.

Clinical Reference

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

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

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

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

5. Gelb BD, Tartaglia M: Noonan Syndrome with Multiple Lentigines. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle. 1993-2018. 2007 Nov 30 (Updated 2015 May 14) Accessed February 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1383/

Day(s) and Time(s) Performed

Wednesday; Varies

Analytic Time

2 weeks after prior authorization approved

CPT Code Information

81479-CBL

81404-HRAS

81311-NRAS

81405 x 2-KRAS, SHOC2

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

LOINC Code Information

Test ID Test Order Name Order LOINC Value
NSRGP Noonan Syndrome and Related Panel,B In Process

 

Result ID Test Result Name Result LOINC Value
36821 Gene(s) Evaluated 36908-2
36822 Result Summary 50397-9
36823 Result Details 82939-0
36824 Interpretation 59462-2
36953 Additional Information 48767-8
36954 Method 49549-9
36955 Disclaimer 62364-5
36825 Reviewed by 18771-6

Test Classification

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 U.S. Food and Drug Administration.

Method Name

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

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

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

Mayo Clinic Laboratories | Cardiology Catalog Additional Information:

mml-cardio-ngs