Familial thoracic aortic aneurysm and aortic dissection: genes and variants

Genes linked to Familial thoracic aortic aneurysm and aortic dissection

• FBN1: Fibrillin-1

  Its fibrillin-1 microfibrils provide mechanical support to elastic tissues and regulate local availability of growth factors such as TGF-beta. Pathogenic variants cause Marfan syndrome and related fibrillinopathies affecting the aorta, skeleton, eyes, skin, and lungs.

  406 disease-causing and 1,198 uncertain variants in FBN1 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• TGFBR2: TGF-beta receptor type-2

  It binds TGF-beta ligands and activates TGFBR1 to initiate canonical and noncanonical signaling. Germline pathogenic variants cause Loeys-Dietz syndrome type 2, while somatic loss can remove growth-suppressive TGF-beta responses in cancer.

  78 disease-causing and 451 uncertain variants in TGFBR2 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• COL3A1: Collagen alpha-1(III) chain

  Its type III collagen fibrils provide tensile support in arteries, bowel, uterus, skin, and other distensible connective tissues. Pathogenic variants cause vascular Ehlers-Danlos syndrome with marked arterial and hollow-organ fragility.

  57 disease-causing and 528 uncertain variants in COL3A1 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• SMAD3: SMAD family member 3

  It carries TGF-beta receptor signals into the nucleus to control extracellular-matrix, differentiation, and growth programs. Heterozygous loss-of-function variants cause Loeys-Dietz syndrome type 3 with arterial aneurysm and dissection risk and often early osteoarthritis.

  28 disease-causing and 307 uncertain variants in SMAD3 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• TGFBR1: TGF-beta receptor type-1

  After activation by the ligand-bound receptor complex, it phosphorylates SMAD2 and SMAD3 to propagate TGF-beta signals. Germline pathogenic variants cause Loeys-Dietz syndrome type 1 with arterial aneurysm and dissection and variable craniofacial or skeletal features.

  23 disease-causing and 355 uncertain variants in TGFBR1 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• SMAD4: SMAD family member 4

  It forms transcriptional complexes with activated receptor-regulated SMADs and is the central nuclear mediator shared by TGF-beta and BMP pathways. Germline loss-of-function variants cause juvenile polyposis or combined juvenile-polyposis-HHT, while specific gain-of-function variants cause Myhre syndrome.

  12 disease-causing and 500 uncertain variants in SMAD4 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• ACTA2: Actin, aortic smooth muscle

  Its smooth-muscle actin filaments generate contractile force in arteries and visceral organs and help maintain vascular-wall structure. Pathogenic variants are an important cause of familial thoracic aortic aneurysm and dissection and can also produce occlusive vascular disease.

  8 disease-causing and 139 uncertain variants in ACTA2 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• SLC2A10: Solute carrier family 2, facilitated glucose transporter member 10

  5 disease-causing and 165 uncertain variants in SLC2A10 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• TGFB2: Transforming growth factor beta-2 proprotein

  Its secreted signaling regulates extracellular matrix, cell differentiation, proliferation, and cardiovascular development. Haploinsufficiency causes a Loeys-Dietz-spectrum connective-tissue disorder with increased risk of thoracic aortic aneurysm and dissection.

  5 disease-causing and 115 uncertain variants in TGFB2 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• COL5A1: Collagen alpha-1(V) chain

  It helps nucleate and regulate type I collagen fibril assembly, controlling fibril diameter and connective-tissue architecture. Haploinsufficiency or structural variants are a major cause of classical Ehlers-Danlos syndrome, with skin hyperextensibility, atrophic scarring, and joint hypermobility.

  3 disease-causing and 293 uncertain variants in COL5A1 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• MYH11: Myosin-11

  Its smooth-muscle myosin motor generates contractile force in arteries and visceral organs. Pathogenic variants can impair aortic smooth-muscle mechanics and cause familial thoracic aortic aneurysm and dissection, sometimes with patent ductus arteriosus.

  2 disease-causing and 1,255 uncertain variants in MYH11 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• NOTCH1: Neurogenic locus notch homolog protein 1

  Ligand-dependent cleavage releases an intracellular domain that directly controls transcriptional programs governing cell fate and differentiation. Pathogenic variants can cause congenital aortic-valve disease and left-sided heart defects, while activating or inactivating somatic changes contribute to several cancers.

  2 disease-causing and 863 uncertain variants in NOTCH1 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• FLNA: Filamin-A

  It crosslinks actin and connects the cytoskeleton to membrane receptors and signaling proteins during cell migration and tissue morphogenesis. Pathogenic variants cause a broad spectrum including periventricular nodular heterotopia and several skeletal or connective-tissue disorders.

  2 disease-causing and 160 uncertain variants in FLNA are linked to Familial thoracic aortic aneurysm and aortic dissection.

• MYLK: Myosin light chain kinase, smooth muscle

  It phosphorylates myosin regulatory light chains to initiate smooth-muscle contraction in blood vessels and visceral tissues. Pathogenic loss-of-function variants can reduce arterial contractile integrity and cause familial thoracic aortic aneurysm and dissection.

  1 disease-causing and 682 uncertain variants in MYLK are linked to Familial thoracic aortic aneurysm and aortic dissection.

• PRKG1: cGMP-dependent protein kinase 1

  It transduces cyclic-GMP signals from nitric oxide and natriuretic peptides to promote vascular smooth-muscle relaxation and regulate vascular tone. A recurrent activating variant causes highly penetrant familial thoracic aortic aneurysm and dissection.

  1 disease-causing and 135 uncertain variants in PRKG1 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• LOX: Protein-lysine 6-oxidase

  It oxidatively initiates covalent crosslinking of collagen and elastin, strengthening arteries and other extracellular matrices. Pathogenic loss-of-function variants can weaken the aortic wall and predispose to familial thoracic aortic aneurysm and dissection.

  1 disease-causing and 5 uncertain variants in LOX are linked to Familial thoracic aortic aneurysm and aortic dissection.

• FBN2: Fibrillin-2

  It contributes to extracellular microfibrils that guide elastic-fiber formation and tissue organization during development. Heterozygous pathogenic variants cause congenital contractural arachnodactyly, characterized by long limbs and fingers, contractures, and characteristic ear abnormalities.

  0 disease-causing and 5 uncertain variants in FBN2 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• COL5A2: Collagen alpha-2(V) chain

  It partners with COL5A1-derived chains to regulate collagen fibril formation in skin, tendons, and other connective tissues. Pathogenic variants can cause classical Ehlers-Danlos syndrome with tissue fragility, hyperextensible skin, and joint hypermobility.

  0 disease-causing and 192 uncertain variants in COL5A2 are linked to Familial thoracic aortic aneurysm and aortic dissection.

• ELN: Elastin

  Its elastic fibers allow arteries, lungs, skin, and other tissues to stretch and recoil repeatedly without structural failure. Haploinsufficiency causes supravalvular aortic stenosis, while other pathogenic variants can cause autosomal dominant cutis laxa.

  0 disease-causing and 6 uncertain variants in ELN are linked to Familial thoracic aortic aneurysm and aortic dissection.

Weakly linked (only a few uncertain records): GATA5, KMT2D, MTOR and SMAD2.

Where Familial thoracic aortic aneurysm and aortic dissection variants cluster

• TGFBR2 Protein kinase (positions 244–544): 75 of 78 disease-causing changes, 1.8× more than its size predicts.
• SMAD4 MH2 (positions 323–552): 12 of 12 disease-causing changes, 2.4× more than its size predicts.
• TGFBR1 Protein kinase (positions 205–495): 22 of 23 disease-causing changes, 1.6× more than its size predicts.
• FBN1 EGF-like 10 (positions 613–653): 13 of 406 disease-causing changes, 2.2× more than its size predicts.
• FBN1 EGF-like 26 (positions 1487–1527): 13 of 406 disease-causing changes, 2.2× more than its size predicts.

Known disease-causing variants in Familial thoracic aortic aneurysm and aortic dissection

Showing 60 of 634.

Uncertain variants in Familial thoracic aortic aneurysm and aortic dissection that look disease-causing

Which prediction tools work for Familial thoracic aortic aneurysm and aortic dissection

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• AlphaMissense: 98 out of 100
• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 92 out of 100
• CADD: 92 out of 100
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100
• phyloP: 73 out of 100

Same protein, different disease

• Isolated thoracic aortic aneurysm is also caused by FBN1 variants; they fall in the same places as the Familial thoracic aortic aneurysm and aortic dissection variants (12 disease-causing).
• Acromicric dysplasia is also caused by FBN1 variants; they fall partly in the same places as the Familial thoracic aortic aneurysm and aortic dissection variants (6 disease-causing).
• Ectopia lentis 1, isolated, autosomal dominant is also caused by FBN1 variants; they fall in the same places as the Familial thoracic aortic aneurysm and aortic dissection variants (6 disease-causing).
• Geleophysic dysplasia is also caused by FBN1 variants; they fall partly in the same places as the Familial thoracic aortic aneurysm and aortic dissection variants (6 disease-causing).
• Stiff skin syndrome is also caused by FBN1 variants; they fall in the same places as the Familial thoracic aortic aneurysm and aortic dissection variants (3 disease-causing).
• Loeys-Dietz syndrome is also caused by TGFBR2 variants; they fall in the same places as the Familial thoracic aortic aneurysm and aortic dissection variants (49 disease-causing).
• Ehlers-Danlos syndrome is also caused by TGFBR2 variants; they fall in the same places as the Familial thoracic aortic aneurysm and aortic dissection variants (4 disease-causing).
• Ehlers-Danlos syndrome is also caused by COL3A1 variants; they fall partly in the same places as the Familial thoracic aortic aneurysm and aortic dissection variants (196 disease-causing).
• Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome is also caused by COL3A1 variants; they fall mostly in different places as the Familial thoracic aortic aneurysm and aortic dissection variants (6 disease-causing).
• Familial aortopathy is also caused by COL3A1 variants; they fall mostly in different places as the Familial thoracic aortic aneurysm and aortic dissection variants (5 disease-causing).
• Aneurysm-osteoarthritis syndrome is also caused by SMAD3 variants; they fall partly in the same places as the Familial thoracic aortic aneurysm and aortic dissection variants (18 disease-causing).
• Loeys-Dietz syndrome is also caused by TGFBR1 variants; they fall partly in the same places as the Familial thoracic aortic aneurysm and aortic dissection variants (23 disease-causing).
• Juvenile polyposis syndrome is also caused by SMAD4 variants; they fall in the same places as the Familial thoracic aortic aneurysm and aortic dissection variants (18 disease-causing).

Diseases related to Familial thoracic aortic aneurysm and aortic dissection

• Connective tissue disorder, also linked to COL3A1, COL5A1, COL5A2, FBN1 and 5 more
• Ehlers-Danlos syndrome, also linked to COL3A1, COL5A1, COL5A2, SMAD3 and 3 more
• Aortic aneurysm, familial thoracic 7, also linked to ACTA2, LOX, MYH11, MYLK and 1 more
• Familial aortopathy, also linked to ACTA2, COL3A1, FBN1, SLC2A10 and 1 more
• Loeys-Dietz syndrome, also linked to SMAD3, TGFB2, TGFBR1 and TGFBR2
• Marfan syndrome, also linked to FBN1, TGFBR1 and TGFBR2
• Isolated thoracic aortic aneurysm, also linked to ACTA2, FBN1 and MYH11
• Thoracic aortic aneurysm or dissection, also linked to ACTA2, SLC2A10 and TGFB2
• Ehlers-Danlos syndrome, classic type, 1, also linked to COL5A1 and COL5A2
• Marfan syndrome/loeys-dietz syndrome/familial thoracic aortic aneurysms and dissections, also linked to FBN1 and LOX
• Familial hemophagocytic lymphohistiocytosis, also linked to COL3A1 and SLC2A10
• Cutis laxa, also linked to ELN and LOX

Frequently asked questions

Which genes are linked to Familial thoracic aortic aneurysm and aortic dissection?

In CATVariant, Familial thoracic aortic aneurysm and aortic dissection is linked to 19 analyzed proteins: FBN1 (Fibrillin-1), TGFBR2 (TGF-beta receptor type-2), COL3A1 (Collagen alpha-1(III) chain), SMAD3 (SMAD family member 3), TGFBR1 (TGF-beta receptor type-1), SMAD4 (SMAD family member 4) and 13 more.

How many genetic variants are linked to Familial thoracic aortic aneurysm and aortic dissection?

8,525 variants: 634 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 7,355 are of uncertain significance or have conflicting reports.

Which uncertain variants in Familial thoracic aortic aneurysm and aortic dissection look disease-causing?

42 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SMAD3 R243H, COL3A1 G432S, SMAD3 R268H, TGFBR2 F442L and COL5A1 G835S. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Familial thoracic aortic aneurysm and aortic dissection?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 446 disease-causing and 117 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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