Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• Curation Status (Adult): Released 1.0.1
• GENE/GENE PANEL: FBN1, TGFBR1, TGFBR2, SMAD3, ACTA2, MYLK, MYH11
• Condition: Familial thoracic aortic aneurysms and dissections (FTAAD)
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• FBN1 ⇔ 154700: Assertion Pending
• TGFBR1 ⇔ 609192: Assertion Pending
• TGFBR2 ⇔ 610168: Assertion Pending
• SMAD3 ⇔ 613795: Assertion Pending
• ACTA2 ⇔ 611788: Assertion Pending
• MYLK ⇔ 613780: Assertion Pending
• MYH11 ⇔ 132900: Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Clinically significant aortic aneurysm / Aortic surveillance	3	2D	3C	3	11DC
Aortic dilation progression / Beta blockers	3	2D	3C	3	11DC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Prevalence estimates for familial thoracic aortic aneurysms and dissections (FTAAD) were unavailable. [1, 2, 3, 4, 5]

Clinical Features

The diagnosis of FTAAD is clinical, based on the presence of dilation and/or dissection of the thoracic aorta and the absence of non-cardiovascular features of Marfan syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome as well as the presence of a family history of TAAD. Abdominal aortic aneurysms and cerebral and peripheral artery aneurysms have been observed in patients. [1]

Natural History

In the absence of surgical repair of the ascending aorta, affected individuals typically have progressive enlargement of the ascending aorta leading to an acute aortic dissection or, in rare cases, aortic rupture. The age of onset and presentation of the aortic disease are highly variable, as are the other vascular diseases and features. The mean age of onset of familial TAAD is earlier than for non-familial TAAD. Aortic dissections have occurred in children with FTAAD as young as 12 years. Predisposition to FTAAD is not known to be increased in any ethnic or racial group. Pregnant women are at increased risk for complications such as rapid aortic root enlargement and aortic dissection or rupture during pregnancy, delivery, or the post-partum period. [1]

2. How effective are interventions for preventing harm?

Patient Management

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with mutations in MYH11, SMAD3, and ACTA2 and at >4.2 cm for patients with mutations in TGFBR1 or TGFBR2 mutations. Earlier repair can be considered in patients with a family history of aortic dissection, growth of the aorta at 1 cm/year, or aortic regurgitation. Timely repair of aortic aneurysms prolongs survival and approaches that of age-matched controls in patients with Marfan syndrome; however, evidence on effectiveness was not provided for patients with FTAAD. (Tier 2) [2, 3, 4]

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. (Tier 2) [4]

Individuals with TGFBR1 or -2 a mutation should be taught the signs and symptoms of aortic dissection and should consider wearing a medical alert bracelet. (Tier 2) [4]

Hypertension should be aggressively treated and controlled. (Tier 4) [1]

Surveillance

Patients should undergo complete aortic imaging at initial diagnosis and 6 months later to determine the rate of aortic enlargement followed by imaging annually or every 6 months for those with a >4.5 com diameter, a significant rate of growth, or aortic regurgitation. (Tier 2) [2, 3, 4]

Cerebrovascular imaging to assess for cerebrovascular disease and cardiac evaluation to assess for coronary artery disease should be considered in individuals with an ACTA2 mutation. (Tier 4) [1]

Pregnant women with a known aortic root or ascending thoracic dilatation should be monitored during pregnancy and postpartum by a cardiologist and a high-risk obstetrician, and undergo monthly or bimonthly echocardiographic assessment of the ascending aorta. It is recommended that pregnant women found to have dilatation of the aortic arch, descending thoracic aorta, or the abdominal aorta undergo MRI or transesophageal echocardiogram. (Tier 4) [1]

Circumstances to Avoid

Patients should not participate in sports that involve the potential for bodily collision. (Tier 2) [5]

Patients should avoid isometric exercise that could lead to significant blows to the chest as these could accelerate aortic root dilatation or cause dissection/rupture. (Tier 4) [1]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Information regarding the prevalence of genetic mutations associated with FTAAD was unavailable.

Penetrance

FTAAD displays incomplete penetrance, primarily in women. (Tier 3) [3]

Relative Risk

Information regarding relative risk was unavailable.

Expressivity

The age of onset and presentation of the aortic disease, vascular diseases, and other clinical features are highly variable, even within families (Tier 4) [1]

4. What is the Nature of the Intervention?

Nature of Intervention

The identified interventions involve invasive prophylactic surgery, which is likely associated with some risk of mortality and morbidity

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Thoracic aortic aneurysms tend to be asymptomatic and may not be diagnosed until a catastrophic acute aortic dissection occurs. (Tier 4) [1]

Reference List

1. DM Milewicz, E Regalado. Heritable Thoracic Aortic Disease Overview. 2003 Feb 13 [Updated 2016 Dec 29]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1120

2. Svensson LG, Adams DH, Bonow RO, Kouchoukos NT, Miller DC, O'Gara PT, Shahian DM, Schaff HV, Akins CW, Bavaria JE, Blackstone EH, David TE, Desai ND, Dewey TM, D'Agostino RS, Gleason TG, Harrington KB, Kodali S, Kapadia S, Leon MB, Lima B, Lytle BW, Mack MJ, Reardon M, Reece TB, Reiss GR, Roselli EE, Smith CR, Thourani VH, Tuzcu EM, Webb J, Williams MR. Aortic valve and ascending aorta guidelines for management and quality measures. Ann Thorac Surg. (2013) 95(6 Suppl):S1-66.

3. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, Lytle BW, Milewicz DM, Reich DL, Sen S, Shinn JA, Svensson LG, Williams DM. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology,American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons,and Society for Vascular Medicine. J Am Coll Cardiol. (2010) 55(14):e27-e129.

4. Pyeritz RE. Evaluation of the adolescent or adult with some features of Marfan syndrome. Genet Med. (2012) 14(1):171-7.

5. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol. (2005) 45(8):1340-5.