PMNSR - Clinical: Postmortem Noonan and Related Panel

Test Catalog

Test Name

Test ID: PMNSR    
Postmortem Noonan and Related Panel

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.

 

Targeted testing for familial variants (also called site-specific or known mutation testing) is available for all genes on this panel; see KVAR1 / Known Variant Analysis-1 Variant, KVAR2 / Known Variant Analysis-2 Variants, or KVAR3 / Known Variant Analysis-3+ Variants. Contact Mayo Medical Laboratories to confirm the appropriate test code for targeted testing if testing for a gene not included on this panel is needed.

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 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 mutations 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) mutations; 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 mutations are more likely to be found when pulmonary stenosis is present, while hypertrophic cardiomyopathy is commonly associated with RAF1 mutations, but rarely associated with PTPN11.

 

A number of related disorders exist that have phenotypic overlap with NS and are caused by mutations in the same group of genes. PTPN11 and RAF1 mutations 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. Mutations 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 mutations 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 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.

 

In addition, FFPE samples older than 10 years have increased failure rates when compared to more recent blocks and are not recommended for testing.

 

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 mutations, deep intronic mutations). 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. Updated 2016 March 3.In GeneReviews Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle. 1993-2017. Accessed 8/30/2017. Available at www.ncbi.nlm.nih.gov/books/NBK1186/

4. Allanson JE, Roberts AE: Noonan Syndrome. Updated 2016 Feb 25. In GeneReviews Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington. Seattle. 1993-2017. Accessed 8/30/2017. Available at  www.ncbi.nlm.nih.gov/books/NBK1124/

5. Gripp KW, Lin AE: Costello Syndrome. Updated 2012 Jan 12. In GeneReviews Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle. 1993-2017. Accessed 8/30/2017. Available at www.ncbi.nlm.nih.gov/books/NBK1507/

6. Gelb BD, Tartaglia M: Noonan Syndrome with Multiple Lentigines. Updated 2015 May 14. In GeneReviews Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle. 1993-2017. Accessed 8/30/2017. Available at www.ncbi.nlm.nih.gov/books/NBK1383/

Special Instructions and Forms Library of PDFs including pertinent information and consent forms, specimen collection and preparation information, test algorithms, and other information pertinent to test