LCD L39933: MolDX: Genetic Testing for Heritable Thoracic Aortic Disease

This policy defines coverage for Lab-Developed Tests (LDTs), Federal Drug Administration (FDA)-cleared, and FDA-approved clinical laboratory tests for heritable thoracic aortic disease including Next Generation Sequencing (NGS) tests. This policy’s scope is specific for hereditary germline testing.

Criteria for Coverage

Genetic testing for Heritable Thoracic Aortic Disease (HTAD) is covered when ALL the following are met:

• The patient presents with an aortic root/ascending aortic dilation, aneurysm or dissection (as defined by national consensus guidelines) AND at least one of the following are true:

• Presentation before age 60 years, OR

• Presence of syndromic features of Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome, OR

• Family history of thoracic aortic disease or peripheral/intracranial aneurysm in a first- or second-degree relative, OR

• Family history of unexplained sudden death at a relatively young age in a first- or second-degree relative.

• Demonstration that the patient has been offered counseling regarding the test and potential results.

• The test performed includes at least the minimum genetic content (genes or genetic variants) with definitive or well-established guidelines-based evidence (as determined by ClinGen and the American College of Cardiology (ACC) and American Heart Association (AHA) Guideline for the Diagnosis and Management of Aortic Disease) required for clinical decision making for its intended use that can be reasonably detected by the test. A single variant may be tested if it is the only variant considered to be reasonable and necessary for a patient given that it is a known familial variant.

• The test does not include additional genetic content that is not properly validated, or of unclear clinical validity or utility such that it could reasonably or possibly be mis-utilized by the patient or treating physician and result in impaired patient outcomes.

• Testing does not conflict with other applicable policy, specifically provisions of repeat germline testing defined in L38274.

• The test has satisfactorily completed a Technical Assessment (TA) by Molecular Diagnostic Services Program (MolDX ® ).

Thoracic aortic aneurysms (TAA) occur with an incidence of approximately 5 to 10 per 100,000 individuals per year. 1-4 The incidence is similar in men and women, but the average age at diagnosis is a decade higher in women (70s) than in men (60s). 5 The etiology and location of a given TAA dictates its natural history and the approach to management. Medical literature and guidelines define the aorta into five main anatomic segments: the root or sinus segment, which extends from the aortic valve annulus to the sinotubular junction; the ascending thoracic aorta, which extends from the sinotubular junction to the innominate artery; the aortic arch, which extends from the innominate to the left subclavian artery; the descending thoracic aorta, which extends from the left subclavian artery to the diaphragm; and the abdominal aorta, which extends from the diaphragm to the level of the aortic bifurcation. 4,6 A true aneurysm is a segmental full-thickness dilation of the blood vessel that affects the three layers of the arterial wall (intima, media, adventitia). 4 Acute aortic dissection (AAD) of the ascending aorta is defined according to the DeBakey (Type I, Type II) or Stanford classification scheme (Type A). 4 Approximately 60% of TAAs are found at the aortic root or ascending aorta, 40% occur in the descending aorta, 10% are localized to the aortic arch, and 10% to the thoracoabdominal aorta. 7 Notably, a TAA can involve more than one aortic segment. 3,7 Most TAAs are asymptomatic and discovered incidentally when imaging studies, such as chest x-rays, CT scans, or echocardiograms are performed for seemingly unrelated indications. 3 When symptomatic, TAAs can present with upper back or chest pain, as well as compression-related symptoms affecting the surrounding structures, leading to nerve dysfunction or arterial compression with ischemia or thromboembolism. 3 Aneurysms of the aortic root or ascending aorta may result in secondary aortic regurgitation with an accompanying diastolic murmur. 3 Nevertheless, the vast majority of TAAs are asymptomatic before an acute event and a high mortality rate is associated with aortic rupture or dissection, with an early mortality of 1% to 2% per hour after onset of symptoms following acute aortic dissection of the ascending aorta. 4,8 TAAs account for approximately one third of hospitalizations related to aortic aneurysms, with the remaining two thirds occurring due to aneurysms of the abdominal aorta. 4

The etiology and natural history of a TAA are the most important considerations in determination of diameter thresholds for the purpose of clinical management. 4 Correlation of aortic diameter with body size and sex is also key in threshold determination. 5 A community study by Paruchuri et al demonstrated an increased risk of type A aortic dissection between 4.0 cm and 4.4 cm when compared to a control diameter of ≤ 3.4 cm. 9 This in turn formed the basis for the definition of a dilated ascending aorta as ≥ 4.0 cm by the American College of Cardiology (ACC) and American Heart Association (AHA) Guideline for the Diagnosis and Management of Aortic Disease 4 (ACC/AHA Guidelines) and is congruent with the 2014 European Society of Cardiology guideline on the diagnosis and treatment of aortic diseases, in which aortic dilation was similarly defined as a diameter of the ascending aorta > 4.0 cm. 4,10 Subsequently, the abrupt increase in risk at a diameter of ≥ 4.5 cm justifies definition of an aneurysm. 9 These thresholds apply to individuals whose height, body surface area (BSA) or both are within 1-2 standard deviations of the population mean and may need to be adjusted downward or upward depending on the individual. 4 Risk assessment can also be conducted using aortic z-scores and other diameter indexing methods. 4

TAAs can be caused by congenital conditions, heritable disorders, multifactorial degenerative conditions, previous aortic dissection, infections, and inflammatory diseases. 2,4,11 Heritable causes are more likely to be identified for aortic root aneurysms and aneurysms of the ascending thoracic aorta, which are more likely to present at a younger age (60 years) when compared with aneurysms of the descending aorta (72 years). 4,12 Ascending TAAs also typically lack risk factors for atherosclerosis, such as diabetes, hypertension, and smoking and demonstrate low prevalence of aortic calcifications or atheromas, which are more prevalent in descending TAAs, wherein these “degenerative” injuries are considered preconditions. 4,12 Aortic root and ascending thoracic aortic aneurysms are also often associated with bicuspid aortic valve (BAV). Finally, many aortic root and ascending thoracic aortic aneurysms are sporadic and idiopathic in nature. 4

A variety of genetic or heritable conditions are thought to account for approximately 20% of TAAs; collectively, these are referred to as heritable thoracic aortic disease (HTAD). This encompasses syndromic HTAD, which is associated with multiorgan features, and nonsyndromic HTAD, wherein abnormalities are limited to the aorta with or without its branches. 4,13 HTAD is most often is associated with aneurysms of the aortic root, ascending aorta, or both, but may present with distal aortic disease and aortic dissection and pathogenic variants in multiple genes can lead to TAA, cerebral aneurysms, and abdominal aortic aneurysms (AAA). For example, mutations in TGFBR2 predispose to TAA as well as intracranial aneurysms and aneurysms and dissections of other arteries. 4 ACTA2 mutations lead to TAA and occlusive vascular disease, including early onset stroke and coronary artery disease. 4