Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released - Under Revision 1.1.4 Status (Pediatric): Passed (Consensus scoring is Complete) P

Condition: Familial thoracic aortic aneurysms and dissections (FTAAD)
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Condition Pairs(s)
Final Assertion
ACTA20019625 (familial thoracic aortic aneurysm and aortic dissection)
Strong Actionability
FBN10019625 (familial thoracic aortic aneurysm and aortic dissection)
Strong Actionability
LOX0019625 (familial thoracic aortic aneurysm and aortic dissection)
Strong Actionability
MYH110019625 (familial thoracic aortic aneurysm and aortic dissection)
Strong Actionability
PRKG10019625 (familial thoracic aortic aneurysm and aortic dissection)
Strong Actionability
SMAD30019625 (familial thoracic aortic aneurysm and aortic dissection)
Strong Actionability
TGFB20019625 (familial thoracic aortic aneurysm and aortic dissection)
Strong Actionability
TGFBR10019625 (familial thoracic aortic aneurysm and aortic dissection)
Strong Actionability
TGFBR20019625 (familial thoracic aortic aneurysm and aortic dissection)
Strong Actionability
Actionability Rationale
All experts agreed with the assertion computed according to the rubric. Unlike Marfan syndrome, this was not asserted as definitive since the evidence for the effectiveness of the intervention was based on Marfan syndrome rather than isolated thoracic aortic aneurysm.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Clinically significant aortic aneurysm / Aortic surveillance
Aortic dilation progression / Pharmacotherapy

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Condition
The estimated population prevalence of familial thoracic aortic aneurysms and dissections (FTAAD) ranges between 1:5,000 and 1:4,000,000 in adults depending on the occurrence of an isolated thoracic aortic aneurysm or as a symptom of a syndromic disorder, excluding non-genetic causes.
Clinical Features
(Signs / symptoms)
FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). While in the past, FTAAD of known genetic cause may have been considered to be either syndromic (part of a set of clinical findings such as in Marfan syndrome, Loeys-Dietz syndrome, or Ehlers-Danlos syndrome) or non-syndromic (occurring as an isolated finding), the distinction between syndromic and non-syndromic FTAAD has become increasingly blurred as it is common for pathogenic variants in a gene to result in a phenotypic spectrum that ranges from syndromic to non-syndromic. This report focuses on non-syndromic FTAAD; syndromic forms of FTAAD have been summarized in other reports. Depending on the size, location, and progression rate of dilatation/dissection, patients may be asymptomatic or may present with dyspnea, cough, jaw, neck, chest or back pain, head, neck or upper limb edema, difficulty swallowing, voice hoarseness, pale skin, faint pulse, and/or numbness/tingling in limbs.
2 3 4
Natural History
(Important subgroups & survival / recovery)
In the absence of surgical repair, affected individuals typically have progressive enlargement of the aorta leading to a life-threatening acute dissection or rupture. The age of onset and presentation of aortic disease are highly variable across genes, as are other vascular diseases and features. Pregnant women are at an increased risk for complications such as rapid aortic root enlargement and aortic dissection or rupture during pregnancy, delivery, and the post-partum period. Onset can range from childhood to adulthood.
2 4
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Management of thoracic aortic aneurysm and/or dissection requires coordinated input from a multidisciplinary team of specialists familiar with FTAAD, including a clinical geneticist, cardiologist, and cardiothoracic and vascular surgeons. (Tier 4)
Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Earlier repair can be considered in patients with a family history of aortic dissection, growth of the aorta approaches 1 cm/year, or aortic regurgitation. In patients with Marfan syndrome (MFS), timely repair of aortic aneurysms prolongs survival and approaches that of age-matched controls; however, evidence on effectiveness was not provided for patients with FTAAD. (Tier 2)
5 6 7 8 9
For female patients considering pregnancy, a prophylactic repair may be considered when the aortic root exceeds 4.0 cm. (Tier 2)
Beta adrenergic-blocking agents are recommended to reduce aortic dilation. (Tier 2)
Though no evidence for effectiveness of these medications is available for FTAAD, a meta-analysis of five cohort studies among children and adolescents with MFS indicated that beta-blocker treatment decreased the rate of aortic dilation compared to no treatment (standardized mean difference: -1.30; 95% CI: -2.11 to -0.49; p=0.002). A randomized trial of 70 patients with MFS aged 12-50 years showed that beta-blocker vs. no treatment slowed the rate of aortic dissection as measured by the slope of the aortic ratio, calculated by dividing the measured aortic diameter by the diameter predicted by the participant’s height, weight, and age (mean slope of the aortic ratio plotted against time: 0.084 vs. 0.023, respectively). However, none of the studies demonstrated an impact on mortality, occurrence of aortic dissection, or the need for elective repair of the aorta and/or aortic valve, though these studies were likely underpowered. (Tier 1)
10 11
Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. (Tier 3)
A meta-analysis of six randomized clinical trials among children and adults with MFS indicated that losartan, an angiotensin II receptor antagonist, significantly decreased the rate of aortic dilation compared to no losartan treatment (standardized mean difference: -0.13; 95% CI: -0.25 to 0.00; p=0.04). However, improvements in mortality, cardiovascular surgery, or aortic dissection or rupture were assessed but not observed. Follow-up time in these studies ranged from 35 months to 3.5 years, which may have limited the ability to assess these outcomes. (Tier 1)
Hypertension should be promptly identified and treated. (Tier 2)
Other cardiovascular risk factors, including hyperlipidemia, should be addressed (Tier 4)
Individuals with a pathogenic variant in TGFBR1/2 should be taught the signs and symptoms of aortic dissection and should consider wearing a medical alert bracelet. (Tier 2)
Pregnancy and the post-partum period confer a higher risk for aortic complications. Among women with aortopathy with aortic dissection and/or rupture during this period, about 50% of events occur in the third trimester and 33% in the peripartum period. Women should be managed closely throughout the pregnancy, ideally in a high-risk obstetric clinic with a multidisciplinary team. Pregnant women should have strict blood pressure control to prevent stage II hypertension. 4.4% of carefully monitored patients with MFS developed aortic dissection and in unmonitored patients, the risk is likely higher. (Tier 2)
3 6
Patients with a confirmed genetic variant known to predispose to aortic aneurysms and aortic dissections 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 cm diameter, a significant rate of growth, or aortic regurgitation. (Tier 2)
5 6 7 9 13
Circumstances to Avoid
Athletes with a pathogenic variant in a gene associated with FTAAD should not participate in low and moderate static/low dynamic competitive sports if they have more than one of the following:
• Aortic root dilation
• Moderate to severe mitral regurgitation
• Family history of aortic dissection
• Cerebrovascular disease
• Branch vessel aneurysm or dissection. (Tier 2)
Athletes with FTAAD should not participate in any competitive sports that involve intense physical exertion or the potential for bodily collision. (Tier 2)
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.
(Include any high risk racial or ethnic subgroups)
FTAAD displays incomplete penetrance, primarily in women. (Tier 3)
A study of 965 patients with FBN1 pathogenic variants indicated that 29% had an aortic event defined as either aortic dissection or prophylactic aortic aneurysm repair (estimated cumulative risk by age 60 was 74%, 95% CI: 67-81%). Specifically, 19% had an aortic dissection (estimated cumulative risk by age 60 was 51%, 95% CI: 42-60%) and 10% underwent prophylactic surgery (estimated cumulative risk by age 60 was 40%, 95% CI: 33-49%). (Tier 3)
A study of 277 individuals with ACTA2 pathogenic variants indicated that 48% had an aortic event defined as either an aortic dissection (42%) or surgical repair of aortic aneurysms (6%). An additional 9% had an aneurysm that did not require repair. The overall cumulative risk of an aortic event by age 86 was estimated as 76% (95% CI: 64-86%). (Tier 3)
A study of 176 individuals with TGFBR1 pathogenic variants and 265 with TGFBR2 pathogenic variants indicated that the first aortic event was aortic dissection in 20% for TGFBR1 and 21% for TGFBR2 and aortic aneurysm repair in 20% for TGFBR1 and 24% for TGFBR2. Survival estimates indicated that 100% of individuals with TGFBR1 variants would have a vascular or aortic event (including surgery or dissection) by age 80 and 100% of individuals with TGFBR2 variants would have a vascular or aortic event by age 90. (Tier 3)
A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%). (Tier 3)
A study of 44 individuals with SMAD3 pathogenic variants indicated that 71% had an aortic root aneurysm, 29% had an aortic dissection, and 34% underwent prophylactic aortic aneurysm repair. (Tier 3)
A study of 23 individuals with TGFB2 pathogenic variants indicated that 74% had an aortic root aneurysm, 3% had an aortic dissection, and 9% underwent aortic aneurysm repair. (Tier 3) (Tier 3)
A study of 12 individuals with MYH11 pathogenic variants indicated that 34% had an aortic dissection and one individual (8%) underwent prophylactic aortic aneurysm repair. (Tier 3)
A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection. (Tier 3)
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information regarding relative risk was unavailable.
No information on variable expressivity was available.
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 settting of recommended care?
Chance to Escape Clinical Detection
Thoracic aortic aneurysms are usually asymptomatic and enlarge over time. Undiagnosed or untreated thoracic aortic aneurysms can lead to life-threatening acute ascending aortic dissections. (Tier 4)
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
Condition Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. Arslan-Kirchner M, Arbustini E, Boileau C, Charron P, Child AH, Collod-Beroud G, De Backer J, De Paepe A, Dierking A, Faivre L, Hoffjan S, Jondeau G, Keyser B, Loeys B, Mayer K, Robinson PN, Schmidtke J. Clinical utility gene card for: Hereditary thoracic aortic aneurysm and dissection including next-generation sequencing-based approaches. Eur J Hum Genet. (2016) 24(1):e1-5.
2. 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:
3. Zentner, D., West, M., Ades, L. Updated on the diagnosis and management of inherited aortopathies, including Marfan Syndrome. (2016) Website:
4. Familial thoracic aortic aneurysm and aortic dissection. Orphanet encyclopedia,
5. 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.
6. 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.
7. Pyeritz RE. Evaluation of the adolescent or adult with some features of Marfan syndrome. Genet Med. (2012) 14(1):171-7.
8. Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Rodriguez Munoz D, Rosenhek R, Sjogren J, Tornos Mas P, Vahanian A, Walther T, Wendler O, Windecker S, Zamorano JL. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. (2017) 38(36):2739-2791.
9. Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J, Siu SC. Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Can J Cardiol. (2014) 30(6):577-89.
10. Gao L, Mao Q, Wen D, Zhang L, Zhou X, Hui R. The effect of beta-blocker therapy on progressive aortic dilatation in children and adolescents with Marfan's syndrome: a meta-analysis. Acta Paediatr. (2011) 100(9):e101-5.
11. Koo HK, Lawrence KA, Musini VM. Beta-blockers for preventing aortic dissection in Marfan syndrome. Cochrane Database Syst Rev. (2017) 11:CD011103.
12. Gao L, Chen L, Fan L, Gao D, Liang Z, Wang R, Lu W. The effect of losartan on progressive aortic dilatation in patients with Marfan's syndrome: a meta-analysis of prospective randomized clinical trials. Int J Cardiol. (2016) 217:190-4.
13. Braverman AC, Harris KM, Kovacs RJ, Maron BJ. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 7: Aortic Diseases, Including Marfan Syndrome: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol. (2015) 66(21):2398-2405.
14. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. AORTIC ANEURYSM, FAMILIAL THORACIC 10; AAT10. MIM: 617168: 2016 Oct 24. World Wide Web URL:
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