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Genetic Causes of Thoracic Aortic Aneurysm: A Review Cover

Genetic Causes of Thoracic Aortic Aneurysm: A Review

Methodist DeBakey Cardiovascular Journal
Volume 22 (2026): Issue 4
By:  and    
Open Access
|Sep 2026
Figures & tables

Figures & Tables

Figure 1

Pathogenic variants in the extracellular matrix, TGFβ signaling pathway, and smooth muscle contractile apparatus. Schematic of genetic variants associated with thoracic aortopathy. Genetic variants associated with thoracic aortopathy include those involved in the extracellular matrix, TGFβ signaling pathway, and smooth muscle contractile apparatus, all of which are essential to maintain connective tissue homeostasis and vascular wall integrity. During smooth muscle signaling, fibrillin proteins coordinate the co-localization of inactive TGFβ with ligands. Activation of the TGFβ receptor leads to the phosphorylation and activation of SMAD and other transcription factors, which leads to downstream signaling and activation of the smooth muscle contractile apparatus. In the extracellular matrix, variants affect elastin (ELN), fibrillin-1 (FBN), lysyl oxidase (LOX), and type 3 collagen (COL3A1). In the TGFβ signaling pathway, variants affect TGFβ isoforms, the TGFβ receptor, SMAD transcription factors (SMAD2, SMAD3, and SMAD4), and additional factors (ERK, JNK, and p38). In the smooth muscle contractile apparatus, variants affect the actin thin filaments (ACTA2), myosin heavy chain (MYH11), myosin light chains (MYL6), and additional regulatory proteins such as myosin light chain kinase (MYLK) and cGMP-dependent protein kinase (PRKG1). Created in BioRender. Wittenberg R. (2026) https://BioRender.com/mgpwapl.

Table 1

Syndromic heritable thoracic aortic disease.

SYNDROMEGENEAFFECTED PROTEINPREVALENCEPRIMARY INHERITANCE PATTERNOTHER PHENOTYPIC FINDINGSTHRESHOLD FOR PROPHYLACTIC AORTIC SURGERY3,*
Marfan Syndrome13,14,47,61FBN1Fibrillin-11:5,000Autosomal dominantLong bone overgrowth and joint laxity, dolichostenomelia, pectus excavatum/carinatum, scoliosis, myopia, ectopia lentis, retinal detachment, glaucoma, early cataracts, mitral or tricuspid valve prolapse, pulmonary artery enlargement4.5–5.0 cm
Loeys-Dietz Syndrome16,17,19TGFB2
TGFB3
TGFBR1
TGFBR2
SMAD2
SMAD3		TGFβ signaling proteins1:50,000Autosomal dominantPectus excavatum/carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine instability, hypertelorism, strabismus, bifid uvula/cleft palate, craniosynostosis, velvety/translucent skin, easy bruising, dystrophic scars, uterine rupture, extra-aortic aneurysms4.0–5.0 cm
Vascular Ehlers-Danlos Syndrome (Ehlers-Danlos Syndrome Type IV)20,21,62COL3A1Collagen type III alpha 1 chain1:50,000Autosomal dominantSpontaneous pneumothorax, congenital hip dislocation, hypermobility, keratoconus, tendon and muscle rupture, talipes equinovarus, bowel and uterine rupture, sunken eyes, narrow nose, gingival recession, lobeless ears, acrogeria, easy bruising, translucent skin, varicose veins, extra-aortic aneurysms4.0–5.0 cm
Multisystem Smooth Muscle Dysfunction Syndrome24ACTA2 (Arginine 179 Variant)Smooth muscle alpha actin1:1,000,000Autosomal dominant (majority de novo)Congenital mydriasis, patent ductus arteriosus or aorto-pulmonary window, pulmonary artery hypertension, moyamoya-like cerebrovascular disease, intestinal hypoperistalsis and malrotation, hypotonic bladder4.2–4.5 cm
Shprintzen-Goldberg Syndrome25,26,63SKITGFβ signaling proteinVery rareAutosomal dominant (majority de novo)Developmental delay (motor and cognitive), craniosynostosis, dolichostenomelia, arachnodactyly, camptodactyly, pectus excavatum/carinatum, scoliosis, joint hypermobility or contractures, pes planus, foot malposition, cervical spine malformations, abdominal wall defects, myopia, mitral valve prolapse, atrial septal defectsIndividualized recommendations
Arterial Tortuosity Syndrome27,28SLC2A10Glucose transporter in TGFβ signalingVery rareAutosomal RecessivePulmonary artery stenosis, soft or hyperextensible skin, joint hypermobility, inguinal or diaphragmatic hernias, pectus excavatum/carinatum, arachnodactyly, scoliosis, joint contractures, camptodactyly, cerebrovascular and abdominal infarctionIndividualized recommendations
Ehlers-Danlos Syndrome with Periventricular Nodular Heterotopia29,30FLNAFilamin AVery rareX-LinkedSeizures, subependymal gray matter peri-ventricular nodules, hyperextensible skin, joint hypermobility, tissue fragility, patent ductus arteriosus, bicuspid aortic valve, congenital lung diseaseIndividualized recommendations
Meester-Loeys Syndrome31,32,64BGNBiglycanVery rareX-LinkedHypertelorism, bifid uvula, cervical spine instability, pectus excavatum/carinatum, joint hypermobility or contractures, striae, extra-aortic aneurysmsIndividualized recommendations
LOX-Related Thoracic Aortic Aneurysm33,34LOXLysyl oxidaseVery rareAutosomal dominantHigh-arched palate, pectus excavatum/carinatum, dolichostenomelia, scoliosis, joint hypermobility, skin striae, dural ectasia, bicuspid aortic valveIndividualized recommendations

[i] *All surgical recommendations are individualized based on genotype- and phenotype-specific features, family history, and shared decision making.

Table 2

Genes associated with heritable thoracic aortic disease.8

GENEPROTEINOMIM NUMBERHUMAN SYNDROMECLINICAL PATHWAY
Category A: Definite or Strong Gene-Disease Association
ACTA2Alpha smooth muscle actin102620Multisystemic smooth muscle dysfunction syndrome (R179)Cytoskeletal/smooth muscle contraction
COL3A1Collagen 3 alpha-1120180Ehlers-Danlos syndrome, type IVCollagen
FBN1Fibrillin-1134797Marfan syndromeTGFβ signaling
MYH11Smooth muscle myosin160745Cytoskeletal/Smooth Muscle Contraction
MYLKMyosin light chain kinase600922Cytoskeletal/smooth muscle contraction
SMAD3SMAD family member 3603109Loeys-Dietz syndrome, type 3/aneurysms-osteoarthritis syndromeTGFβ signaling
TGFB2Transforming growth factor beta 2190220Loeys-Dietz syndrome, type 4TGFβ signaling
TGFBR1Transforming growth factor beta receptor 1190181Loeys-Dietz syndrome, type 1TGFβ signaling
TGFBR2Transforming growth factor beta receptor 2190182Loeys-Dietz syndrome, type 2TGFβ signaling
Category B: Moderate or Limited Gene-Disease Association (Primarily Associated with Other Features; Do Not Carry Significant Risk of Progression to Aortic Dissection)
ELNElastin130160Cutis laxaExtracellular matrix
FBN2Fibrillin-2612570Congenital contracturesExtracellular matrix
FLNAFilamin A300017Periventricular nodular heterotopiaCytoskeletal/smooth muscle contraction
NOTCH1Notch 1190198Associated with bicuspid aortic valveDevelopmental
SKIv-SKI sarcoma oncogene homolog164780Shprintzen-Goldberg syndromeTGFβ signaling
SLC2A10Glucose transporter type 10606145Arterial tortuosity syndromeTGFβ signaling
SMAD4SMAD family member 4600993Juvenile polyposis syndrome/hereditary hemorrhagic telangiectasia syndromeTGFβ signaling
EFEMP2Fibulin 4604633Cutis laxa type 1BExtracellular matrix
Category C: Limited Gene-Disease Association (Diagnosis Primarily Based on Non-Vascular Features)
CBSCystathionine beta-synthase613381HomocystinuriaMiscellaneous/Unknown
COL4A5Collagen 4-alpha5303630X-linked Alport syndromeCollagen
PKD1Polycystin 1601313Polycystic kidney disease with intracranial aneurysmsMiscellaneous/Unknown
PKD2Polycystin 2173910Polycystic kidney disease with intracranial aneurysmsMiscellaneous/Unknown
Category D: No Clinical Evidence for Gene-Disease Association
ACVRL1Activin receptor-like kinase 1601284Hereditary hemorrhagic telangiectasia syndrome, type 2TGFβ signaling
ADAMTS10A disintegrin and metalloproteinase with thrombospondin motifs 10608990Weill-Marchesani syndromeMiscellaneous/Unknown
B3GAT3Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3606374Larsen-like syndromeExtracellular matrix
COL11A1Collagen 11 alpha-1120280Stickler syndrome, type 2/Marshall syndromeCollagen
COL18A1Collagen 18 alpha-1120328Knobloch syndromeCollagen
COL1A1Collagen 1 alpha-1120150Ehlers-Danlos syndrome, type 7A, osteogenesis imperfectaCollagen
COL1A2Collagen 1 alpha-2120160Ehlers-Danlos syndrome, type 7B, osteogenesis imperfectaCollagen
COL4A1Collagen 4 alpha-1120130HANACCollagen
COL5A1Collagen 5 alpha-1120215Ehlers-Danlos syndrome, type 1–2Collagen
COL5A2Collagen 5 alpha-2120190Ehlers-Danlos syndrome, type 1–2Collagen
COL9A1Collagen 9 alpha-1120210Multiple epiphyseal dysplasiaCollagen
COL9A2Collagen 9 alpha-2120260Multiple epiphyseal dysplasiaCollagen
EMILIN1Elastin microfibril interfacer 1130660Miscellaneous/Unknown
ENGEndoglin131195Hereditary hemorrhagic telangiectasia syndromeTGFβ signaling
GATA5GATA binding protein 5611496Associated with bicuspid aortic valveMiscellaneous/Unknown
GJA1Connexin-43121014Associated with hypoplastic left heart syndromeMiscellaneous/Unknown
JAG1Jaggard-1601920Alagille syndromeDevelopmental
MED12Mediator of RNA polymerase II transcription, subunit 12 homolog300188Lujan-Fryns syndromeMiscellaneous/Unknown
PLOD1Lysyl hydroxylase 1153454Ehlers-Danlos syndrome, type VIExtracellular matrix
PLOD3Lysyl hydroxylase 3603066Bone fragility, contractures, arterial rupture, deafnessExtracellular matrix
SMAD6SMAD family member 6602931TGFβ signaling
UPF3BRegulator of nonsense transcripts 3b300298Miscellaneous/Unknown
VCANVersican118661Miscellaneous/Unknown
LOX*Lysyl oxidase153455Extracellular matrix
PRKG1*Protein kinase, cGMP-dependent, type 1176894Cytoskeletal/smooth muscle contraction
Recent Genes
BGNBiglycan301870Meester-Loeys syndromeExtracellular matrix
FOXE3Forkhead box 3601094Miscellaneous/Unknown
HCN4Hyperpolarization activated cyclic nucleotide gated potassium channel 4605206Miscellaneous/Unknown
MAT2AMethionine adenosyltransferase II, alpha601468Extracellular matrix
MFAP5Microfibril-associated glycoprotein 2601103Extracellular matrix
SMAD2SMAD family member 2601366TGFβ signaling
TGFB3Transforming growth factor beta 3190230Loeys-Dietz syndrome, type 5TGFβ signaling

[i] *Subsequent accumulated genetic evidence since 2018 has strongly causally implicated LOX and PRKG1 in thoracic aortic disease.

Table 3

Comparison of loci identified in three or more genome-wide association studies (GWAS) studies.

NEAREST GENETCHEANDJIEU ET AL., 202240NEKOUI ET AL., 202241KLARIN ET AL., 202339PIRRUCCELLO ET AL., 202142FRANCIS ET AL., 202243,*
ELN✓✓✓✓✓
FBN1✓✓✓✓✓
PRDM6✓✓✓✓✓
SMG6✓✓✓✓✓
TBX20✓✓✓✓✓
THSD4✓✓✓✓✓
ULK4✓✓✓✓✓
ADAMTS8×✓✓✓✓
AIG1✓✓×✓✓
ANGPT1✓✓×✓✓
CBFA2T3✓✓×✓✓
CDH13×✓✓✓✓
EDN1✓✓×✓✓
FGD5✓✓×✓✓
FLNB✓✓×✓✓
GATA2✓✓×✓✓
HAS2✓✓×✓✓
TNRC6B✓✓×✓✓
USP15✓✓×✓✓
WWP2✓✓×✓✓
ANO1✓✓×✓×
COL6A3×✓✓✓×
DCDC1×✓×✓✓
DLEU1×✓✓✓×
ESR1×✓×✓✓
FGGY×✓×✓✓
GNAO1×✓×✓✓
MASP1✓××✓✓
NOC3 L✓××✓✓
OSR1×✓✓✓×
SLX4IP×✓×✓✓
SPSB1××✓✓✓
ZNF827×✓✓×✓

[i] *For Francis et al., 2022, multiple GWAS were conducted. Genes relating to loci identified in the GWAS for maximum ascending aortic diameter are considered in this table.

Table 4

Select thoracic aortic aneurysm polygenic risk factor studies. GWAS: genome wide association studies; MRI: magnetic resonance imaging; PRS: polygenic risk score

STUDYPRIMARY BIOBANK/DATASETOUTCOME OF INTERESTFINDINGS
High Heritability of Ascending Aortic Diameter and Trans-Ancestry Prediction of Thoracic Aortic Disease (Tcheandjieu et al., 2022)40UK BiobankAscending aortic diameter, TAA, surgical intervention for TAA

  • A GWAS study of ascending aortic diameter extracted from cardiac MRI using machine learning revealed 56 loci of interest.

  • An increase of one standard deviation in the PRS was associated with 0.64 mm increase in ascending aortic diameter, 1.5 times higher odds of TAA, and 1.44 times higher odds of surgical intervention for TAA, which was replicated across additional biobanks with diverse populations.

Spatially Distinct Genetic Determinants of Aortic Dimensions Influence Risks of Aneurysm and Stenosis (Nekoui et al., 2022)41UK BiobankLeft ventricular outflow tract, aortic root, and ascending aorta diameter

  • A GWAS study of the diameter of the left ventricular outflow tract, aortic root, and six aortic segments extracted from cardiac MRI using machine learning revealed 79 loci of interest.

  • The PRS for the diameter 13 mm from the sinotubular junction was most strongly associated with TAA.

  • A one standard deviation increase in the PRS was associated with 1.42 times higher hazard of TAA.

Genome-Wide Association Study of Thoracic Aortic Aneurysm and Dissection in the Million Veteran Program (Klarin et al., 2023)39Million Veteran ProgramTAA/thoracic aortic dissection

  • A GWAS study identified 21 risk loci for TAA/thoracic dissection and further selected nine candidate causal genes based on gene expression in single cell RNA sequencing data from aortic tissue (THSD4, LRP1, CDH13, ADAMTS8, SCAI, TCF7 L2, COL6A3, PRDM6, NOC3 L).

  • Patients in the top 5% of the novel PRS were 2.5 times more likely to experience an incident TAA/thoracic dissection event and > 4.0 times as likely to experience TAA/thoracic dissection-related mortality.

The AORTA Gene Score for Detection and Risk Stratification of Ascending Aortic Dilation (Pirruccello et al., 2024)44UK BiobankAscending aortic diameter

  • A combined model containing polygenic information and clinical risk factors explained 34.9–41.8% of the variation in ascending aortic diameter while a model containing only clinical risk factors explained 28.9–33.0% of the variation in ascending aortic diameter. The combined model also improved prediction of aortic events.

Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions (Misra et al., 2026)45Mass General Brigham BiobankTAA

  • Patients with high-risk PRS scores (81–100th percentile) had 1.7 times higher odds of TAA compared to those at average risk (21–80th percentile).

  • Among patients ≤ 50 years, high-risk PRS was associated with 2.42 times higher odds of TAA.

DOI: https://doi.org/10.14797/mdcvj.1908 | Journal eISSN: 1947-6108
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Language: English
Page range: 87 - 101
Submitted on: Jun 27, 2026
Accepted on: Aug 18, 2026
Published on: Sep 15, 2026
Published by: Houston Methodist DeBakey Heart & Vascular Center
In partnership with: Paradigm Publishing Services
Keywords:
thoracic aortic aneurysm,
cardiovascular genetics,
aortopathy,
polygenic risk scores

© 2026 Rachel E. Wittenberg, Mark E. Lindsay, published by Houston Methodist DeBakey Heart & Vascular Center
This work is licensed under the Creative Commons Attribution-NonCommercial 4.0 License.

Volume 22 (2026): Issue 4
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