Familial thoracic aortic aneurysms and dissections (FTAAD)

Actionability Adult Summary Report

Gene:
Mode(s) of Inheritance:Autosomal Dominant
Literature Search:
Curation Status: Released (1.0.2)
Release History

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

Actionability Assertions

Gene Condition (MONDO ID) OMIM ID Final Assertion
No assertions found.

Actionability Assertion 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.

Actionability Scores

Outcome / Intervention Pair Severity Likelihood Effectiveness Nature of Intervention Total Score
Clinically significant aortic aneurysm / Aortic surveillance 3 2D 3C 3 11DC
Aortic dilation progression / Beta blockers 3 2D 3C 3 11DC
View scoring key
Domain of Actionability Scoring Metric State of the Knowledgebase
Severity: What is the nature of the threat to health to an individual? 3 = Sudden death as a reasonably possible outcome
2 = Reasonable possibility of death or major morbidity
1 = Modest morbidity
0 = Minimal or no morbidity 		N/A
Likelihood: What is the chance that the outcome will occur? 3 = >40% chance
2 = 5%-39% chance
1 = 1%-4% chance
0 = <1% chance 		A = Substantial evidence or evidence from a high tier (tier 1)
B = Moderate evidence or evidence from a moderate tier (tier 2)
C = Minimal evidence or evidence from a lower tier (tier 3 or 4)
D = Poor evidence or evidence not provided in the report
N = Evidence based on expert contributions (tier 5)
Effectiveness: What is the effectiveness of a specific intervention in preventing or diminishing the risk of harm? 3 = Highly effective
2 = Moderately effective
1 = Minimally effective
0 = Controversial or unknown effectiveness
IN = Ineffective/No interventiona 		A = Substantial evidence or evidence from a high tier (tier 1)
B = Moderate evidence or evidence from a moderate tier (tier 2)
C = Minimal evidence or evidence from a lower tier (tier 3 or 4)
D = Poor evidence or evidence not provided in the report
N = Evidence based on expert contributions (tier 5)
Nature of intervention: How risky, medically burdensome, or intensive is the intervention? 3 = Low risk, or medically acceptable and low intensity
2 = Moderate risk, moderately acceptable or intensive
1 = Greater risk, less acceptable and substantial intensity
0 = High risk, poorly acceptable or intensive 		N/A
a Do not score the remaining categories

Prevalence of the Genetic Condition

Prevalence estimates for familial thoracic aortic aneurysms and dissections (FTAAD) were unavailable.
View Citations

DM Milewicz, et al. (2003) NCBI: NBK1120, Svensson LG, et al. (2013) PMID: 23688839, Hiratzka LF, et al. (2010) PMID: 20359588, Pyeritz RE, et al. (2012) PMID: 22237449, Maron BJ, et al. (2005) PMID: 15837284

Clinical Features (Signs / symptoms)

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.
View Citations

DM Milewicz, et al. (2003) NCBI: NBK1120

Natural History (Important subgroups & survival / recovery)

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.
View Citations

DM Milewicz, et al. (2003) NCBI: NBK1120

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

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

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown
FTAAD displays incomplete penetrance, primarily in women.
Tier 3 View Citations

Hiratzka LF, et al. (2010) PMID: 20359588

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown
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 View Citations

DM Milewicz, et al. (2003) NCBI: NBK1120

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

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 View Citations

Svensson LG, et al. (2013) PMID: 23688839, Hiratzka LF, et al. (2010) PMID: 20359588, Pyeritz RE, et al. (2012) PMID: 22237449

Beta adrenergic-blocking agents are recommended to reduce aortic dilation.
Tier 2 View Citations

Pyeritz RE, et al. (2012) PMID: 22237449

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 View Citations

Pyeritz RE, et al. (2012) PMID: 22237449

Hypertension should be aggressively treated and controlled.
Tier 4 View Citations

DM Milewicz, et al. (2003) NCBI: NBK1120

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 View Citations

Svensson LG, et al. (2013) PMID: 23688839, Hiratzka LF, et al. (2010) PMID: 20359588, Pyeritz RE, et al. (2012) PMID: 22237449

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 View Citations

DM Milewicz, et al. (2003) NCBI: NBK1120

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 View Citations

DM Milewicz, et al. (2003) NCBI: NBK1120

Circumstances to Avoid

Patients should not participate in sports that involve the potential for bodily collision.
Tier 2 View Citations

Maron BJ, et al. (2005) PMID: 15837284

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 View Citations

DM Milewicz, et al. (2003) NCBI: NBK1120

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Nature of Intervention

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

Chance to Escape Clinical Detection

Thoracic aortic aneurysms tend to be asymptomatic and may not be diagnosed until a catastrophic acute aortic dissection occurs.
Context: Adult
Tier 4 View Citations

DM Milewicz, et al. (2003) NCBI: NBK1120

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Gene Condition Associations
OMIM Identifier Primary MONDO Identifier Additional MONDO Identifiers

References List

DM Milewicz, E Regalado. Heritable Thoracic Aortic Disease Overview. (2003) [Updated Dec 29 2016]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1120/

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) 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. Journal of the American College of Cardiology. 55(14):e27-e129.

Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. (2005) Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. Journal of the American College of Cardiology. 45(8):1340-5.

Pyeritz RE. (2012) Evaluation of the adolescent or adult with some features of Marfan syndrome. Genetics in medicine : official journal of the American College of Medical Genetics. 14(1):171-7.

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. (2013) Aortic valve and ascending aorta guidelines for management and quality measures. The Annals of thoracic surgery. 95(6 Suppl):S1-66.

Early Rule-Out Summary

This topic did not pass the early rule out stage due to insufficient evidence for actionability. Thus, this topic did not move forward for a full evidence curation and summary report. This topic may be reconsidered if additional evidence becomes available.

Findings of Early Rule-Out Assessment

  1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
  2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?

    3. a. Patient Management

    b. Surveillance or Screening

    c. Circumstances to Avoid

  3. Is it actionable in an undiagnosed adult with the condition?
  4. Is this condition an important health problem?
  5. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?