Test Id : PMMFR

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. If EDTA whole blood is available, order MFRGP / Marfan Syndrome and Related Disorders Multi-Gene Panel, Varies.

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.

1. Marfan and Related Disorders Patient Information (T636) 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.

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

• Informed Consent for Genetic Testing
• Marfan and Related Disorders Patient Information
• Informed Consent for Genetic Testing for Deceased Individuals
• Informed Consent for Genetic Testing (Spanish)

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)

-Informed Consent for Genetic Testing for Deceased Individuals (T782)

2. Marfan and Related Disorders Patient Information (T636) in Special Instructions.

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

Tissue: See Specimen Required

Blood Spots: 3

Providing a comprehensive postmortem genetic evaluation in the setting of a sudden death attributed to thoracic aortic dissection or with a personal or family history suggestive of Marfan syndrome, Loeys-Dietz syndrome, thoracic aortic aneurysm and dissections, or a related disorder

Identification of a pathogenic variant in the decedent, which may assist with risk assessment and predictive testing of at-risk family members

This test includes next-generation sequencing and supplemental Sanger sequencing to evaluate for variants in the ACTA2, CBS, COL3A1, FBN1, FBN2, MYH11, MYLK, SKI, SLC2A10, SMAD3, TGFB2, TGFBR1, and TGFBR2 genes.

Sudden cardiac death (SCD) is estimated to occur at an incidence of between 50 to 100 per 100,000 individuals in North America and Europe each year, claiming between 250,000 and 450,000 lives in the United States annually. In younger individuals (ages 15-35), the incidence of SCD is between 1 to 2 per 100,000 young individuals. Sudden cardiac death, particularly in young individuals, may suggest an inherited form of heart disease. In some cases of sudden death, autopsy may identify a structural abnormality such as aortic aneurysm or dissection. Postmortem diagnosis of a hereditary form of aortic aneurysm/dissection may assist in confirmation of the cause of death, as well as risk assessment in living family members.

Marfan syndrome (MFS) is an autosomal dominant genetic disorder affecting the connective tissue and occurs in approximately 1 to 2 per 10,000 individuals. It is characterized by the presence of skeletal, ocular, and cardiovascular manifestations and is caused by variants in the FBN1 gene. Skeletal findings may include tall stature, chest wall deformity, scoliosis, and joint hypermobility. Lens dislocation (ectopia lentis) is the cardinal ocular feature, and aortic root dilatation/dissection and mitral valve prolapse are the main cardiovascular features. Diagnosis is based on the revised Ghent nosology and genetic testing of FBN1. Management aims to monitor and slow the rate of aortic root dilatation, and initiate appropriate medical and/or surgical intervention as needed. Other phenotypes associated with the FBN1 gene include autosomal dominant ectopia lentis (displacement of the lens of the eye), familial thoracic aortic aneurysm and dissections (TAAD), isolated skeletal features of MFS, MASS phenotype (mitral valve prolapse, aortic diameter increased, stretch marks, skeletal features of MFS), Shprintzen-Goldberg syndrome (Marfanoid-craniosynostosis; premature ossification and closure of sutures of the skull), and autosomal dominant Weill-Marchesani syndrome (short stature, short fingers, ectopia lentis).

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disease with significant overlap with Marfan syndrome, but may include involvement of other organ systems and is primarily caused by variants in TGFBR1 and TGFBR2. Features of LDS that are not typical of MFS include craniofacial and neurodevelopmental abnormalities and arterial tortuosity with increased risk for aneurysm and dissection throughout the arterial tree. Variants in the SMAD3 gene have been reported in families with a LDS-like phenotype with arterial aneurysms and tortuosity and early onset osteoarthritis.

Thoracic aortic aneurysm and dissections (TAAD) is a genetic condition primarily involving dilatation and dissection of the thoracic aorta, but may also include aneurysm and dissection of other arteries. TAAD has a highly variable age of onset and presentation, and may involve additional features such as congenital heart defects and other features of connective tissue disease or smooth muscle abnormalities depending on the causative gene. The gene most commonly involved in familial TAAD is ACTA2, followed by TGFBR1 and TGFBR2, and MYH11. Variants in the MYLK gene have been reported in a small subset of families with familial TAAD. TGFB2 variants have also been reported in families with TAAD and systemic features that overlap with LDS and MFS.

The COL3A1 gene causes Ehlers Danlos syndrome type IV (vascular type), an autosomal dominant connective tissue disease with characteristic facial features, thin, translucent skin, easy bruising, and arterial, intestinal, and uterine fragility. Arterial rupture may be preceded by aneurysm or dissection, or may occur spontaneously.

Autosomal dominant variants of the FBN2 gene are known to cause congenital contractural arachnodactyly (CCA), which has several overlapping features with Marfan syndrome, including dolichostenomelia, scoliosis, pectus deformity, arachnodactyly, and a risk for thoracic aortic aneurysm.

Variants of the CBS gene cause homocystinuria an autosomal recessive disorder of amino acid metabolism with clinical overlap with Marfan syndrome; including lens dislocation and skeletal abnormalities, as well as increased risk for abnormal blood clotting.

Variants in the SKI gene cause Shprintzen-Goldberg syndrome (SGS), an autosomal dominant condition with overlap with LDS and MFS. Distinguishing features of SGS include hypotonia and intellectual disability. Aortic root dilatation is less frequent in SGS than in LDS or MFS but, when present, it can be severe.

Homozygous and compound heterozygous loss of function variants in the SLC2A10 gene have been described in arterial tortuosity syndrome, a condition characterized by generalized tortuosity and elongation of all major arteries in addition to other connective tissue disease features.

Many of these described disorders have distinct genetic causes but may present phenotypically similarly, leading to difficulty in accurate diagnosis. However, gene-based management strategies have been described for some of these disorders. Therefore, comprehensive genetic analysis may be useful for accurate diagnosis and gene-based management.

Genes included in Postmortem Marfan and Related Panel:

Abbreviations: Autosomal dominant (AD), autosomal recessive (AR)

An interpretive report will be provided.

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics 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.

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 mutations, deep intronic mutations). The absence of a variant, therefore, does not eliminate the possibility of Marfan 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 Marfan 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 and/or human genome assembly used for the analysis of this patient's results.

1. Fishman GI, Chugh SS, DiMarco JP, et al: Sudden cardiac death prediction and prevention: report from the National Heart, Lung and Blood Institute and Heart Rhythm Society Workshop. Circulation. 2010;122(22):2335-2348

2. Semsarian C, Ingles J: Molecular autopsy in victims of inherited arrhythmias. J Arrhythm. 2016;32(5):359-365

3. Stattin EL, Westin IM, Cederquist K, et al.:Genetic screening in sudden cardiac death in the young can save future lives. Int J Legal Med. 2016;130(1):59-66

4. Loeys BL, Dietz HC, Braverman AC, et al: The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47:476-485

5. Loeys BL, Schwarze U, Holm T, et al: Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006 Aug 24;355(8):788-798

6. Loeys BL, Chen J, Neptune ER, et al: A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005 Mar;37(3):275-281

7. Milewicz DM, Regalado E: Thoracic Aortic Aneurysms and Aortic Dissections. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. Updated 2012 Jan 12. University of Washington, Seattle. 1993-2017. Accessed 8/29/2017. Available at www.ncbi.nlm.nih.gov/books/NBK1120/

8. Campens L, Vanakker OM, Trachet B, et al: Characterization of cardiovascular involvement in pseudoxanthoma elasticum families. Arterioscler Thromb Vasc Biol. 2013;33:2646-2652

9. Guo DC, Pannu H, Tran-Fadulu V, et al: Mutations in smooth muscle a-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2007 Dec;39(12):1488-1493

10. Pepin M, Schwarze U, Superti-Furga A, Byers PH: Clinical and genetic features of Ehlers-Danlos syndrome type IV, The vascular type. N Engl J Med. 2000 Mar 9;342(10):673-680

11. Pannu H, Tran-Fadulu V, Papke CL, et al: MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II. Hum Mol Genet. 2007;16(20):2453-2462

12. Wang L, Guo DC, Cao J, et al: Mutations in myosin light chain kinase cause familial aortic dissections. Am J Hum Genet. 2010;87(5):701-707

13. Doyle AJ, Doyle JJ, Bessling SL, et al: Mutations in the TGF-beta repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet. 2012;44(11):1249-1254

14. Coucke PJ, Willaert A, Wessels MW, et al: Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet. 2006;38(4):452-457

15. van de Laar IM, van der Linde D, Oei EH, et al: Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet. 2012;49:47-57

16. Boileau C, Guo DC, Hanna N, et al: TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet. 2012;44(8):916-921

• Informed Consent for Genetic Testing
• Marfan and Related Disorders Patient Information
• Informed Consent for Genetic Testing for Deceased Individuals
• Informed Consent for Genetic Testing (Spanish)

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 are 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: ACTA2, CBS, COL3A1, FBN1, FBN2, MYH11, MYLK, SKI, SLC2A10, SMAD3, TGFB2, TGFBR1, and TGFBR2.

Monday

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• 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.

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.

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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