The Genetics of Aortic Aneurysms

Editor's Note: Please participate in the associated poll on this topic by clicking here.

Aortic aneurysms and dissection were the primary cause of 17,215 deaths in 2009 according to data from the Center for Disease Control and Prevention. Recent studies have suggested the number of cases of aortic disease is increasing over time, which may be related to improved diagnostic modalities and/or increased awareness of aortic disease.1,2 Left untreated, one-third of patients with an acute ascending aortic dissection will die within the first 24 hours and 50% will die within 48 hours.3,4 The clinical burden coupled with the often silent, insidious and unpredictable nature of aortic disease necessitates better clinical understanding of pathophysiologic mechanisms of disease and modifiable risk factors. The burst of new genome sequencing technologies in the last decade has improved knowledge of the genetic underpinnings and heritable nature of aneurysmal disease.

Aortic aneurysms are broadly classified by their anatomic involvement of the thoracic (TAA) or abdominal aorta (AAA). Abdominal aortic aneurysms are the most commonly identified aortic aneurysm and the majority are thought to be related to atherosclerosis. Thoracic aortic aneurysms are more likely to be associated with a genetic cause and are further subdivided into subgroups involving the ascending aorta (60%), aortic arch (10%), descending aorta (40%) and thoracoabdominal aorta (10%).5 TAAs, which can occur at a young age without significant cardiovascular risk factors are commonly stratified into either clusters of "syndromic" disorders with extravascular organ involvement or seemingly isolated aberrations denoted "non-syndromic" disorders.6 Table 1 briefly outlines these disorders based upon the mechanistic pathway, involved genetic lesion, and characteristic phenotype.

Table 1: Syndromic and Non-Syndromic Thoracic Aortic Aneurysms


Involved Cellular Pathway

Disease Process

Implicated Gene(s)

Implicated Protein(s)

Clinical Characteristics & Phenotype

Syndromic Disorders


Extracellular Matrix Proteins

Marfans Syndrome



  • Joint laxity, scoliosis, pectus
  • Myopia and ectopia lentis
  • Mitral valve prolapse

Type IV (vascular) Ehlers-Danlos Syndrome


Collagen, type III

  • Thin and translucent skin
  • Fragile tissue prone to rupture (arteries, muscles, internal organs)
  • Easy bruising
  • Joint laxity and hypermobility
  • Characteristic facial features (pinched nose, thin lips, prominent ears)


TGF-β Pathway

Loeys-Dietz Syndrome



  • “Facial Dysmorphogenic type:” cleft palate, craniosynostosis, micrognathia
  • “Vascular EDS-like type:” easy bruising, joint laxity, translucent skin, atrophic scars and risk of visceral rupture
  • LDS type III: see Aneurysm-Osteoarthritis Syndrome below
  • LDS type IV: arterial aneurysms, dissections and tortuosity, mild craniofacial feature, and skeletal and cutaneous anomalies.
  • LDS type V: aortic aneurysms and dissections, cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity

Aneurysm-Osteoarthritis Syndrome



  • Velvety skin and striae
  • Umbilical/Inguinal hernias
  • Joint pain 


Autosomal Dominant Polycystic Kidney Disease


Polycystin 1
Polycystin 2

  • Cysts of the kidney, liver, pancreas, seminal vesicles and arachnoid
  • ESRD

Meiotic Error with Monosomy, Mosaicism, or De Novo Germ Cell Mutation

Turner Syndrome


Partial or Complete Absence of X Chromosome

  • Short stature
  • Gonadal dysgenesis
  • Associated with BAV & pseudocoarctation in rare cases

Non-Syndromic Disorders


Neural Crest Migration


Bicuspid Aortic Valve with TAA




Notch 1





Smooth Muscle Contraction Proteins

Familial TAA


α-Smooth Muscle Actin

  • Premature CAD
  • Ischemic stroke
  • Associated with Moyamoya disease

Familial TAA with Patent Ductus Arteriosus


Smooth Muscle Myosin

  • Associated with PDA

Familial TAA


Myosin Light Chain Kinase


Familial TAA


Protein Kinase c-GMP Dependent, type I

  • Coronary artery aneurysms/dissection
  • Arterial tortuosity

TGF-β Pathway

Loeys-Dietz Syndrome variants



See TGF-β pathway in Syndromic section above

The structural integrity of the vascular wall is provided by the extracellular matrix (ECM), elastic lamina and vascular smooth muscle cells. The primary cellular pathways implicated in heritable aneurysm formation include mutations in genes encoding ECM, as well as, smooth muscle structure and signaling proteins. The formation and propagation of aneurysms was initially felt to be related to structural weakness of the aortic wall from altered extracellular matrix (ECM) proteins as occurs in Marfan Syndrome (MFS) and vascular Ehlers-Danlos syndrome (vEDS).7,8 However, recent studies suggest that a common pathway involving transforming growth factor beta (TGF-β) may underlie the development of many aortic aneurysms and dissections. TGF-β is a regulatory cytokine produced by many cells including those of the vessel wall and a growing body of pre-clinical evidence points to alterations in TGF-β signaling may be a primary etiologic driver of many thoracic aortic aneurysms.9,10

Syndromic Thoracic Aortic Aneurysms

Patients with syndromic TAA often have characteristic phenotypic changes on physical exam that may help inform clinicians to assess for aneurysmal disease. The most well described syndromic thoracic aorta aneurysms were detailed more than a decade ago. Collectively, syndromic TAA constitute 10-15% of families with heritable thoracic aneurysmal disease. These syndromic conditions include Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), vascular Ehlers-Danlos syndrome (vEDS) and aneurysm-osteoarthritis syndrome (AOS). Despite the phenotypic overlap of these syndromes, important differences in prognosis underline the importance of accurate diagnosis to optimize management strategies. This is highlighted by the differences in median survival of LDS (37 years), vEDS (48 years) and treated MFS (70 years), respectively.8

Marfan Syndrome

MFS is an autosomal dominant syndromic disorder arising from mutations in the FBN-1 gene resulting in defects in the skeletal, ocular and cardiovascular systems. MFS affects approximately 1 in every 5000 persons and is implicated in 3-5% of all aortic dissections.1,11 Fibrillin-1 is located in the extracellular matrix where it sequesters TGF-β. The normal tissue distribution of fibrillin is reflected in the characteristic phenotype of ectopic lentis, joint hypermobility, arachnodactyly and aortic root dilation.

Aortic dilation in MFS typically occurs at the sinuses of Valsalva and the tubular portion of the ascending aorta to form a "pear-shaped" annuloaortic ectasia. The primary cause of death in patients with MFS is progressive aortic root enlargement with subsequent dissection. The natural history of disease is underscored by the fact that 90% of patients with MFS will develop an aortopathy that requires aortic surgery or will suffer a dissection.12 However, advances in medical management including the use of beta-blockers and advanced surgical techniques have improved survival.

Loeys-Dietz Syndrome

LDS is an autosomal dominant aortopathy characterized by aggressive TAAs. Several variants of LDS exist including types 1, 2, 3, 4 and 5 that vary according to which member of the TGF-β signaling pathway is dysregulated. LDS type 1 is associated with craniofacial defects, while LDS type 2 features include easy bruising, joint laxity, thin translucent skin and propensity for visceral rupture events. LDS types 1 and 2 are caused by mutations in the TGF-β receptor (TGFBR1 and/or TGFBR2). The vascular mortality of LDS is dramatic and TAA in LDS can grow at rates greater than1.0 cm/year, nearly 10 times the average growth of aneurysms in MFS.13 In one series of patients with LDS, the mean age of death was 26 years old with TAA dissection implicated in 67% of deaths, AAA dissections implicated in 22%, and intracranial bleeding events related to 7%.10 Thus, for most patients with LDS, early prophylactic surgery is recommended.

Vascular Ehlers-Danlos Syndrome

vEDS or Ehlers-Danlos syndrome type IV is an autosomal dominant disorder of COL3A1 which encodes type III collagen, an important component of the connective tissue in skin, blood vessel walls and visceral organs. Degradation of collagen leads to loss of tensile strength in the aorta and vascular fragility. The prevalence is estimated to be between 1 in 10,000 to 25,000 in the United States, with most going undiagnosed until they develop a vascular complication.14 One in four people diagnosed with vascular type EDS develop a significant health problem by age 20 and more than 80% develop life-threatening complications by age 40.15 vEDS has a surgical mortality of approximately 40% largely attributed to tissue fragility, poor wound healing and perioperative bleeding complications in this patient population.16

In addition to the syndromes described above, a number of other disorders are implicated in aneurysm formation including: RAAS-mediated aneurysms; adult polycystic kidney disease (ADPKD); Turner syndrome; vasculitides; atherosclerosis and infections of the aortic wall. Table 1 outlines some heritable causes aortopathy.

Non-Syndromic Thoracic Aortic Aneurysms

In recent years, there has been a growing appreciation and recognition of patients with TAA but without evidence of an overt connective tissue disorder or bicuspid aortic valve. These non-syndromic aneurysms can be clustered as Familial Thoracic Aortic Aneurysms (FTAA) or sporadic TAA (STAA) based on the presence of affected family members. While STAA's are not related to defined mutations, studies have reported an approximately 20% co-occurrence of TAA in first-degree family members suggesting that there may be a heritable component of disease not yet appreciated.17 FTAA typically present earlier in life than sporadic aneurysms, have a higher annual growth rate, and are not associated with traditional risk factors for aortic disease.17,18 Mutations in effectors of ECM maintenance or vascular smooth muscle function render the aorta vulnerable to dilation and/or rupture. Loss-of-function mutations in ECM proteins that predispose to aneurysms include MFS and vEDS. A number of defects in abnormal smooth muscle function have recently been identified that may result in non-syndromic FTAA. These are a genetically heterogeneous population of syndromes that display autosomal dominance inheritance patterns and include mutations in the following genes primarily involved in smooth muscle function including ACTA2, MYH11, TGF-β, MYLK and PRKG1. However, mutations in these genes account for only a fraction of the total number of FTAA, and the search for additional implicated genes is underway. This task has been challenging in part due to incomplete penetrance and/or locus heterogeneity of disease.

Mutations in ACTA2, which encodes alpha smooth muscle actin, are the most common genetic cause of thoracic aortic aneurysms, accounting for 10-15% of all FTAA.19 In addition to thoracic aneurysms, ACTA2 mutations have been associated with CNS aneurysms and neurovascular malformations. To date, there have been >30 identified pathogenic ACTA2 mutations.19 These have an insidious course, and the majority of ACTA2 aortic aneurysms are <5 cm at the time of dissection. Early surgical intervention is often considered in patients with ACTA2 mutations with even minimal change in aortic diameter.19

Defects in the smooth muscle myosin heavy chain protein, encoded by MYH11 have been associated with FTAA and ascending TAA in association with patent ductus arteriosus. MYLK encodes myosin light chain kinase and is associated with a familial syndrome characterized by acute aortic dissection often with absent, or very small, preceding aneurysms. PRKG1 encodes type I cGMP-dependent protein kinase which is responsible for smooth muscle cell relaxation and, as a result, is associated with coronary aneurysms and aortic dissections that often present at a young age.

Bicuspid Aortic Valve

Bicuspid aortic valves (BAV) is the most common developmental cardiovascular malformation affecting between 0.5-1.0% of the general population. Approximately 40-50% of patients with BAV are also found to have aortic root and ascending aorta dilation.11 Patients with BAV may also have coarctation of the aorta or intracranial berry aneurysms. The exact mechanism of aneurysm formation is unclear and the etiology is likely polygenic with incomplete penetrance.11 However, some cases have been associated with aberrant NOTCH-1 signaling, or the mutations in the GATA family of transcription factors.20 Increases in proximal aortic shear wall stress forces with a bileaflet rather than trileaflet aortic valve may also contribute to aneurysm formation and propagation.

Management and Future Directions

The ongoing efforts to clarify the genetic basis for the development of aneurysmal aortic disease is a complex and challenging endeavor. Identification and management of patients with aortic disease remains a challenge as only 5% of TAAs are symptomatic and the remainder are often diagnosed either incidentally on imaging or following potentially deadly complications.12 Diagnosis requires high clinical suspicion, and syndromic conditions associated with aortic aneurysms have clinical characteristics that may clue providers to probe for the presence of aneurysmal disease. However, for those with non-syndromic aortic disease, a detailed family history is paramount to identifying individuals who warrant further evaluation. Despite our growing understanding of aortic diseases the current criteria for prophylactic surgery is largely based upon morphologic criteria alone including aortic size, aortic size by body surface area, and annual growth velocity. This is particularly evident in non-syndromic aortic diseases in which there are no consensus guidelines on timing of prophylactic surgical repair at the moment. Future research and the impending era of personalized medicine may lead to precise and targeted interventions based upon unique clinical characteristics of that mutation. In addition, risk factor and lifestyle modifications are essential components of an aortopathy management plan. Comprehensive care of patients with aortic disease involves a multi-disciplinary team that includes cardiovascular genetic counselors and surgical and medical experts in aortic disease.

Figure 1: Ascending TAA in BAV

Figure 1
CT Angiogram with 3D reconstruction of a patient with history of bicuspid aortic valve and a fusiform aneurysm involving the ascending aorta and proximal arch, measuring 4.8 cm in diameter.


  1. Elefteriades JA. Thoracic aortic aneurysm: reading the enemy's playbook. Curr Probl Cardiol 2008;33:203-77.
  2. Ramanath VS, Oh JK, Sundt TM, Eagle KA. Acute aortic syndromes and thoracic aortic aneurysm. Mayo Clin Proc 2009;84:465-81.
  3. Tsai TT, Trimarchi S, Nienaber CA. Acute aortic dissection: perspectives from the International Registry of Acute Aortic Dissection (IRAD). Eur J Vasc Endovasc Surg 2009;37:149-59.
  4. Isselbacher EM. Epidemiology of Thoracic Aortic Aneurysms, Aortic Dissection, Intramural Hematoma, and Penetrating Atherosclerotic Ulcers. In: Eagle KA, Baliga RR, Isselbacher EM, Nienaber CA (eds). Aortic Dissection and Related Syndromes. Developments in Cardiovascular Medicine, vol. 260. 2007. Springer, Boston, MA.
  5. Isselbacher EM. Thoracic and abdominal aortic aneurysms. Circulation 2005;111:816-28.
  6. Luychx I, Loeys BL. The genetic architecture of non-syndromic thoracic aortic aneurysm. Heart 2015;101:1678-84.
  7. Lindsay ME, Dietz HC. Lessons on the pathogenesis of aneurysm from heritable conditions. Nature 2011;473:308-16.
  8. Goyal A, Keramati AR, Czarny MJ, Resar JR, Mani A. The genetics of aortopathies in clinical cardiology. Clin Med Insights Cardiol 2017;11:1179546817709787.
  9. Isselbacher EM, Lino Cardenas CL, Lindsay ME. Hereditary Influence in Thoracic Aortic Aneurysm and Dissection. Circulation 2016;133:2516-28.
  10. Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006;355:788-98.
  11. Paterick TE, Humphries JA, Ammar KA, et al. Aortopathies: etiologies, genetics, differential diagnosis, prognosis and management. Am J Med 2013;126:670-8.
  12. Elefteriades JA, Farkas EA. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J Am Coll Cardiol 2010;55:841-57.
  13. Kuzmik GA, Sang AX, Elefteriades JA. Natural history of thoracic aortic aneurysms. J Vasc Surg 2012;56:565-71.
  14. Germain DP. Ehlers-Danlos syndrome type IV. Orphanet J Rare Dis 2007;2:32.
  15. Pepin MG, Murray ML, Byers PH. Vascular Ehlers-Danlos Syndrome. In: Adam MP (ed). GeneReviews 1993. University of Seattle, Seattle, WA.
  16. Goldfinger JZ, Halperin JL, Marin ML, Stewart AS, Eagle KA, Fuster V. Thoracic aortic aneurysm and dissection. J Am Coll Cardiol 2014;64:1725-39.
  17. Coady MA, Davies RR, Roberts M, et al. Familial patterns of thoracic aortic aneurysms. Arch Surg 1999;134:361-7.
  18. Pomianowski P, Elefteriades JA. The genetics and genomics of thoracic aortic disease. Ann Cardiothorac Surg 2013;2:271-9.
  19. Guo DC, Papke CL, Tran-Fadulu V, et al. Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet 2009;84:617-27.
  20. Yang B, Zhou W, Jiao J, et al. Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve. Nat Commun 2017;8:15481.

Clinical Topics: Cardiac Surgery, Cardiovascular Care Team, Congenital Heart Disease and Pediatric Cardiology, Stable Ischemic Heart Disease, Valvular Heart Disease, Vascular Medicine, Aortic Surgery, Cardiac Surgery and CHD and Pediatrics, Cardiac Surgery and SIHD, Cardiac Surgery and VHD, Congenital Heart Disease, CHD and Pediatrics and Prevention, Chronic Angina

Keywords: Actins, Aneurysm, Dissecting, Aorta, Aorta, Abdominal, Aortic Aneurysm, Aortic Aneurysm, Thoracic, Aortic Aneurysm, Abdominal, Aortic Coarctation, Aortic Valve, Aortic Valve, Atherosclerosis, Heart Valve Diseases, Body Surface Area, Cardiovascular Diseases, Cause of Death, Centers for Disease Control and Prevention, U.S., Collagen Type III, Connective Tissue, Coronary Aneurysm, Cyclic GMP-Dependent Protein Kinases, Diabetes Mellitus, Type 2, Dilatation, Ductus Arteriosus, Patent, Ehlers-Danlos Syndrome, Extracellular Matrix, Extracellular Matrix Proteins, Heart Valve Diseases, Intracranial Aneurysm, Joint Instability, Life Style, Loeys-Dietz Syndrome, Marfan Syndrome, Muscle, Smooth, Vascular, Mutation, Myocytes, Smooth Muscle, Myosin-Light-Chain Kinase, Osteoarthritis, Penetrance, Polycystic Kidney, Autosomal Dominant, Prognosis, Prevalence, Prevalence, Smooth Muscle Myosins, Tensile Strength, Tissue Distribution, Transcription Factors, Transforming Growth Factor beta, Turner Syndrome, Vasculitis, Wound Healing

< Back to Listings