Familial aortopathy: genes and variants

Genes linked to Familial aortopathy

• 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.

  5 disease-causing and 0 uncertain variants in ACTA2 are linked to Familial aortopathy.

• 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.

  5 disease-causing and 0 uncertain variants in COL3A1 are linked to Familial aortopathy.

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

  3 disease-causing and 3 uncertain variants in SLC2A10 are linked to Familial aortopathy.

• 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.

  1 disease-causing and 0 uncertain variants in FBN1 are linked to Familial aortopathy.

• 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.

  1 disease-causing and 0 uncertain variants in TGFBR1 are linked to Familial aortopathy.

Weakly linked (only a few uncertain records): COL5A2, LOX and SMAD3.

Known disease-causing variants in Familial aortopathy

Which prediction tools work for Familial aortopathy

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

• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Aortic aneurysm, familial thoracic 7 is also caused by ACTA2 variants; they fall mostly in different places as the Familial aortopathy variants (20 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by ACTA2 variants; they fall mostly in different places as the Familial aortopathy variants (8 disease-causing).
• Multisystemic smooth muscle dysfunction syndrome is also caused by ACTA2 variants; they fall partly in the same places as the Familial aortopathy variants (6 disease-causing).
• Ehlers-Danlos syndrome is also caused by COL3A1 variants; they fall mostly in different places as the Familial aortopathy variants (196 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by COL3A1 variants; they fall mostly in different places as the Familial aortopathy variants (57 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 aortopathy variants (6 disease-causing).
• Arterial tortuosity syndrome is also caused by SLC2A10 variants; they fall mostly in different places as the Familial aortopathy variants (12 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by SLC2A10 variants; they fall mostly in different places as the Familial aortopathy variants (5 disease-causing).
• Marfan syndrome is also caused by FBN1 variants; they fall mostly in different places as the Familial aortopathy variants (434 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by FBN1 variants; they fall mostly in different places as the Familial aortopathy variants (406 disease-causing).
• Isolated thoracic aortic aneurysm is also caused by FBN1 variants; they fall mostly in different places as the Familial aortopathy variants (12 disease-causing).
• Marfan syndrome/loeys-dietz syndrome/familial thoracic aortic aneurysms and dissections is also caused by FBN1 variants; they fall mostly in different places as the Familial aortopathy variants (10 disease-causing).
• Acromicric dysplasia is also caused by FBN1 variants; they fall mostly in different places as the Familial aortopathy variants (6 disease-causing).
• Loeys-Dietz syndrome is also caused by TGFBR1 variants; they fall mostly in different places as the Familial aortopathy variants (23 disease-causing).
• Familial thoracic aortic aneurysm and aortic dissection is also caused by TGFBR1 variants; they fall mostly in different places as the Familial aortopathy variants (23 disease-causing).

Diseases related to Familial aortopathy

• Familial thoracic aortic aneurysm and aortic dissection, also linked to ACTA2, COL3A1, FBN1, SLC2A10 and 1 more
• Marfan syndrome, also linked to FBN1 and TGFBR1
• Ehlers-Danlos syndrome, also linked to COL3A1 and TGFBR1
• Connective tissue disorder, also linked to COL3A1 and FBN1
• Isolated thoracic aortic aneurysm, also linked to ACTA2 and FBN1
• Familial hemophagocytic lymphohistiocytosis, also linked to COL3A1 and SLC2A10
• Thoracic aortic aneurysm or dissection, also linked to ACTA2 and SLC2A10
• Loeys-Dietz syndrome, also linked to TGFBR1
• Aortic aneurysm, familial thoracic 7, also linked to ACTA2
• Perrault syndrome, also linked to FBN1
• Arterial tortuosity syndrome, also linked to SLC2A10
• Marfan syndrome/loeys-dietz syndrome/familial thoracic aortic aneurysms and dissections, also linked to FBN1

Frequently asked questions

Which genes are linked to Familial aortopathy?

In CATVariant, Familial aortopathy is linked to 5 analyzed proteins: ACTA2 (Actin, aortic smooth muscle), COL3A1 (Collagen alpha-1(III) chain), SLC2A10 (Solute carrier family 2, facilitated glucose transporter member 10), FBN1 (Fibrillin-1) and TGFBR1 (TGF-beta receptor type-1).

How many genetic variants are linked to Familial aortopathy?

21 variants: 15 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 6 are of uncertain significance or have conflicting reports.

Which uncertain variants in Familial aortopathy look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

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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