Test Catalog

Test Name

Test ID: PMMFR    
Postmortem Marfan 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 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

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 for variants in the ACTA2, CBS, COL3A1, FBN1, FBN2, MYH11, MYLK, SKI, SLC2A10, SMAD3, TGFB2, TGFBR1, and TGFBR2 genes.

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

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:

Gene

Protein

Inheritance

Known Association

ACTA2

Actin, alpha-2, smooth muscle, aorta

AD

TAAD

CBS

Cystathionine beta-synthase

AR

Homocystinuria

COL3A1

Collagen, type III, alpha-1

AD

Ehlers-Danlos syndrome type IV (vascular type)

FBN1

Fibrillin 1

AD

Marfan syndrome/TAAD/ectopia lentis/ MASS phenotype/Shprintzen-Goldberg syndrome/Weill-Marchesani syndrome

FBN2

Fibrillin 2

AD

Congenital contractural arachnodactyly

MYH11

Myosin, heavy chain 11, smooth muscle

AD

TAAD

MYLK

Myosin light chain kinase

AD

TAAD

SKI

V-SKI avian sarcoma viral oncogene homolog

AD

Shprintzen-Goldberg syndrome

SLC2A10

Solute carrier family 2 (facilitated glucose transporter), member 10

AR

Arterial Tortuosity syndrome/TAAD (autosomal recessive)

SMAD3

Mothers against decapentaplegic, drosophila, homolog of, 3

AD

Loeys-Dietz syndrome/TAAD

TGFB2

Transforming growth factor, beta-2

AD

TAAD

TGFBR1

Transforming growth factor-beta receptor, type I

AD

Loeys-Dietz syndrome/TAAD

TGFBR2

Transforming growth factor-beta receptor, type II

AD

Loeys-Dietz syndrome/TAAD

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

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 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 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.

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

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 GeneReviews. Updated 2012 Jan 12. Edited by RA Pagon, MP Adam, HH Ardinger, et al: 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

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