Test Catalog

Test ID: MFRGP    
Marfan Syndrome and Related Disorders Multi-Gene Panel, Varies

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

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of Marfan syndrome, Loeys-Dietz syndrome, thoracic aortic aneurysm and dissections, or a related disorder

 

Second-tier testing for patients in whom previous targeted gene variant analyses for specific Marfan and related genes were negative

 

Establishing a diagnosis of a Marfan or a related disorder in some cases, allowing for appropriate management and surveillance for aneurysms and other disease features based on the gene involved

 

Identifying variants within genes known to be associated with increased risk for aneurysms and other disease features allowing for 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 (NGS) and supplemental Sanger sequencing to evaluate for variants in the ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, MFAP5, MYH11, MYLK, NOTCH1, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, and TGFBR2 genes. Additionally, NGS is used to test for the presence of large deletions and duplications in a subset of genes.

 

Prior Authorization is available for this assay; see Special Instructions.

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

Marfan syndrome (MFS) is an autosomal dominant genetic disorder affecting the connective tissue that 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 mitral valve prolapse and aortic root dilatation/dissection 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), 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 of the SMAD3 gene have been reported in families with a LDS-like phenotype with arterial aneurysms and tortuosity and early onset osteoarthritis. Variants of the TGFB3 gene have also been reported in families with an LDS-like phenotype, although these individuals tended to not have arterial tortuosity.

 

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. For other genes also implicated in TAAD, refer to the table below.

 

The COL3A1 gene causes Ehlers Danlos syndrome, vascular type (type IV), 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. The COL5A1 and COL5A2 genes cause Ehlers Danlos syndrome, classic type (type I and type II), an autosomal dominant connective tissue disorder characterized by skin hyperextensibility, widened atrophic scars, joint hypermobility, smooth, velvety skin, and easy bruising. The FLNA gene causes FLNA-related periventricular nodular heterotopia (PVNH), an X-linked neuronal migration disorder where the majority of affected individuals are female. This condition is characterized by seizures, hyperflexible joints, and cardiac findings, which include thoracic aortic aneurysm and dissection. Some individuals show clinical overlap with EDS.

 

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.

 

Variants in the NOTCH1 gene cause aortic valve disease, with individuals displaying a range of aortic valve abnormalities and severe valve calcification.

 

Genes included in Marfan Syndrome and Related Disorders Multi-Gene 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, vascular type (EDS type IV)

COL5A1

Collagen, type V alpha-1

AD

Ehlers-Danlos Syndrome, Classic Type (EDS type I, EDS type II)

COL5A2

Collagen, type V alpha-2

AD

Ehlers-Danlos Syndrome, Classic Type (EDS type I, EDS type II)

FBN1

Fibrillin 1

AD

Marfan syndrome/TAAD/Ectopia Lentis/ MASS phenotype/Shprintzen-Goldberg syndrome/Weill-Marchesani syndrome

FBN2

Fibrillin 2

AD

Congenital Contractural Arachnodactyly

FLNA

Filamin A

X-linked

Ehlers-Danlos syndrome and periventricular nodular heterotopia/X-linked cardiac valvular dysplasia/ otopalatodigital spectrum disorders/TAAD

MFAP5

Microfibril-associated protein 5

AD

TAAD

MYH11

Myosin, heavy chain 11, smooth muscle

AD

TAAD

MYLK

Myosin light chain kinase

AD

TAAD

NOTCH1

Notch, drosophila, homolog of, 1

AD

Aortic valve disease/Adams-Oliver Syndrome

PRKG1

Protein kinase, cGMP-dependent, type 1

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

SMAD4

Mothers against decapentaplegic, drosophila, homolog of, 4

AD

TAAD/JPS/JPS-HHT

TGFB2

Transforming growth factor, beta-2

AD

TAAD

TGFB3

Transforming growth factor, beta-3

AD

Loeys-Dietz syndrome (Rienhoff syndrome)/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); thoracic aortic aneurysm and dissection (TAAD); juvenile polyposis syndrome (JPS); juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia (JPS-HHT)

 

Indications for testing include but are not limited to:

-Patients who meet clinical diagnostic criteria (Revised Ghent nosology) for Marfan syndrome

-Patients in whom no specific Marfan or related disorder is evident but for whom there is a clear familial component

-Patients whose family history is consistent with TAAD

-Patients with a personal or family history of thoracic aortic aneurysm and/or dissection or a personal or family history of multiple arterial aneurysms

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

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 performed (eg, promoter variants, deep intronic variants). 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 polymorphisms may be present that could lead to false negative or positive results. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion/duplication analysis. 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. Loeys BL, Dietz HC, Braverman AC, et al: The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-485

2. 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

3. 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

4. Milewicz DM, Regalado E: Heritable Thoracic Aortic Disease Overview. In GeneReviewsUpdated 2016 Dec 29. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington,. Seattle WA. 1993-2017. Available at www.ncbi.nlm.nih.gov/books/NBK1120/

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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. Chen MH, Walsh CA: FLNA-Related Periventricular Nodular Heterotopia. In GeneReviews. Updated 2015 Sept 17. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle WA. 1993-2017. Available atwww.ncbi.nlm.nih.gov/books/NBK1213/

15. Malfait F, Wenstrup R, Paepe AD: Ehlers-Danlos Syndrome, Classic Type. In GeneReviews. Updated 2011 August 18. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle WA. 1993-2017. Available at www.ncbi.nlm.nih.gov/books/NBK1244/

16. Online Mendelian Inheritance in Man. Available at www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM

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