Marfan syndrome (MFS) is a systemic connective tissue disease (CTD) with a high degree of clinical variability and phenotypes overlapping with other syndromes and disorders. The diagnosis of most suspected CTDs can be based on clinical findings and family history. Some of these disorders are associated with a predisposition to the development of progressive thoracic aortic aneurysms and dissection. Accurate diagnosis of one of these syndromes can lead to changes in clinical management, including surveillance of the aorta, and surgical repair of the aorta, when necessary, as well as surveillance for multisystem involvement in syndromic forms of thoracic aortic aneurysms and dissection. Known pathogenic variants are associated with MFS and the other connective tissue disorders that share clinical features with MFS.

The use of genetic testing to establish a diagnosis in an individual with a suspected connective tissue disorder is most useful in individuals who do not meet sufficient clinical diagnostic criteria at the time of initial examination, in individuals who have an atypical phenotype and other connective tissue disorders cannot be ruled out, and in individuals who belong to a family in which a pathogenic variant is known (presymptomatic diagnosis).

POLICY

Genetic testing for Marfan syndrome, Ehlers-Danlos syndrome type IV, other syndromes associated with thoracic aortic aneurysms and dissections, and related disorders is considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
Genetic testing panels for Marfan syndrome, Ehlers-Danlos syndrome type IV, other syndromes associated with thoracic aortic aneurysms and dissections, and other related connective tissue disorders that are not limited to focused genetic testing are considered investigational.

MEDICAL APPROPRIATENESS

Genetic testing for Marfan syndrome, Ehlers-Danlos syndrome type IV, other syndromes associated with thoracic aortic aneurysms and dissections, and related disorders is considered medically appropriate if ANY ONE of the following are met:
- Genetic testing of a symptomatic individual to determine diagnosis if ALL of the following are met:
  - Panels comprised entirely of focused genetic testing limited to the following genes: FBN1 and MYH11; ACTA2, TGFBR1 and TGFBR2; and COL3A1
  - Individual has signs and symptoms of a connective tissue disorder
  - A definitive diagnosis cannot be made using established clinical diagnostic criteria (e.g., Ghent criteria, characteristic systemic clinical findings)
- Targeted familial variant genetic testing for assessing future risk of disease if ALL of the following are met:
  - Individual is asymptomatic
  - Known pathogenic variant in the family

IMPORTANT REMINDERS

Any specific products referenced in this policy are just examples and are intended for illustrative purposes only. It is not intended to be a recommendation of one product over another and is not intended to represent a complete listing of all products available. These examples are contained in the parenthetical e.g. statement.
We develop Medical Policies to provide guidance to Members and Providers. This Medical Policy relates only to the services or supplies described in it. The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy. For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed. If there is a conflict between the Medical Policy and a health plan or government program (e.g., TennCare), the express terms of the health plan or government program will govern.

SOURCES

American Academy of Pediatrics (2023, April). Health supervision for children and adolescents with marfan syndrome. Retrieved November 21, 2024 from http://www.aap.org.

American College of Cardiology and American Heart Association (2022, December). 2022 ACC/AHA guideline for the diagnosis and management of aortic disease: a report of the American Heart Association/American College of Cardiology joint committee on clinical practice guidelines. Retrieved November 19, 2024 from http://www.acc.org.

American College of Cardiology Foundation, American Heart Association, et al (2010, April). 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease. Retrieved November 20, 2024 from http://www.acc.org.

American College of Medical Genetics (2012, January). Evaluation of the adolescent or adult with some features of marfan syndrome. Retrieved November 21, 2024 from http://www.acmg.net.

American Heart Association (2020, August). Genetic testing for inherited cardiovascular diseases. Retrieved November 25, 2024 from http://www.heart.org.

American Heart Association (2021, October). Cardiovascular management of aortopathy in children: a scientific statement from the American Heart Association. Retrieved November 22, 2024 from http://www.heart.org.

American Heart Association (2024, September). Genetic testing for heritable cardiovascular diseases in pediatric patients. Retrieved November 22, 2024 from http://www.heart.org.

Beridze, N., & Frishman, W. H. (2012). Vascular Ehlers-Danlos syndrome: pathophysiology, diagnosis, and prevention and treatment of its complications. Cardiology in Review, 20 (1), 4-7. Abstract retrieved November 26, 2024 from PubMed database.

BlueCross BlueShield Association. Evidence Positioning System. (3:2024). Genetic testing for marfan syndrome, thoracic aortic aneurysms and dissections, and related disorders (2.04.129). Retrieved October 17, 2024 from https://www.bcbsaoca.com/eps/. (26 articles and/or guidelines reviewed)

Campens, L., Callewaert, B., Muiño Mosquera, L., Renard, M., Symoens, S., et al. (2015). Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. Orphanet Journal of Rare Diseases, 10, 9, doi: 10.1186/s13023-014-0221-6. (Level 2 evidence)

Loeys, B. L., Dietz, H. C., Braverman, A. C., Callewaert, B. L., De Backer, J., et al. (2010). The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics, 47 (7), 476-485. (Level 2 evidence)

Wooderchak-Donahue, W., VanSant-Webb, C., Tvrdik, T., Plant, P., Lewis, T., et al. (2015). Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. American Journal of Medical Genetics, Part A, 167A (8), 1747-1757. Abstract retrieved November 27, 2024 from PubMed database.

Zeigler, S. M., Sloan, B., & Jones, J. A. (2021). Pathophysiology and pathogenesis of Marfan syndrome. Advances in Experimental Medicine and Biology, 1348, 185-206. (Level 1 evidence)

ORIGINAL EFFECTIVE DATE: 4/2/2025

MOST RECENT REVIEW DATE: 4/2/2025

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Policies included in the Medical Policy Manual are not intended to certify coverage availability. They are medical determinations about a particular technology, service, drug, etc. While a policy or technology may be medically necessary, it could be excluded in a member's benefit plan. Please check with the appropriate claims department to determine if the service in question is a covered service under a particular benefit plan. Use of the Medical Policy Manual is not intended to replace independent medical judgment for treatment of individuals. The content on this Web site is not intended to be a substitute for professional medical advice in any way. Always seek the advice of your physician or other qualified health care provider if you have questions regarding a medical condition or treatment.

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