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Condition report · Cardiovascular

Aortic Aneurysm

Whole genome sequencing identifies FBN1, TGFBR1, MYH11, and other vascular gene variants, enabling surveillance protocols and informed surgical planning for heritable aortic disease.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

A localized, pathological dilatation of the aorta caused by a weakening of its wall, posing a risk of rupture. Around 20-30% of incidents are related to hereditary predisposition.

Heritable thoracic aortic disease encompasses a group of conditions predisposing to thoracic aortic aneurysm and dissection (TAAD), a life-threatening emergency where the aortic wall tears and causes massive bleeding. Approximately 20% of thoracic aortic aneurysms have a familial basis. FBN1 variants cause Marfan syndrome (prevalence approximately 1 in 5,000), which affects the aorta, eyes, and skeleton. TGFBR1 variants cause Loeys-Dietz syndrome, characterized by aggressive early-onset aortic disease, craniofacial features, and tissue friability. MYH11 variants cause familial non-syndromic TAAD, often with patent ductus arteriosus. All three follow autosomal dominant inheritance. Aortic dissection can occur without warning at aortic diameters considered safe in the general population, particularly in Loeys-Dietz syndrome, where aggressive aortic dilation and dissection can occur at relatively small aortic diameters.

FBN1 encodes fibrillin-1, a major structural component of extracellular matrix microfibrils; pathogenic variants weaken connective tissue and dysregulate transforming growth factor beta (TGF-β) signaling, causing progressive aortic root dilation. Over 3,000 FBN1 variants have been catalogued. TGFBR1 encodes a TGF-β type I receptor; loss-of-function variants paradoxically increase TGF-β signaling in the aortic wall, driving more aggressive aneurysm formation. MYH11 encodes smooth muscle myosin heavy chain; variants impair vascular smooth muscle cell contraction, compromising aortic wall integrity. Eleven genes total have confirmed high-penetrance TAAD risk, but three (FBN1, TGFBR1, and MYH11) account for the majority of heritable cases.

Confirming a heritable aortic disease diagnosis transforms management into aggressive prevention. For FBN1-related disease, regular imaging (echocardiography or CT/MRI) monitors aortic root diameter; beta-blockers or angiotensin II receptor antagonists slow aortic dilation and delay dissection. Prophylactic aortic root replacement is offered when the aortic root reaches a diameter-specific threshold: typically 5.0-5.5 cm for FBN1, but much smaller (~5.0 cm) for TGFBR1 because dissection risk is higher at smaller diameters. Gene-specific thresholds are critical: using the wrong criterion delays necessary surgery and increases sudden death risk. Identifying a pathogenic variant enables cascade testing of relatives, informing imaging surveillance and surgical planning. Activity restriction (avoiding strenuous sports) is advised.

FBN1, TGFBR1, and MYH11 variants have distinct phenotypes and surgery thresholds: FBN1 typically milder, TGFBR1 more aggressive with lower dissection threshold, MYH11 non-syndromic TAAD.

The 4 conditions we analyse

Aortic Aneurysm

An aneurysm formed in the wall of the proximal portion of the descending aorta proceeding from the arch of the aorta.

What a diagnosis changes

Beta-blockers, angiotensin II receptor antagonists, prophylactic aortic root replacement, activity restriction

Genes analysed

Also known as

ruptured abdominal aortic aneurysm; aortic aneurysm (disease); aortic aneurysm of unspecified site, ruptured; ruptured thoracic aneurysm; ruptured thoracic aortic aneurysm; ruptured thoracoabdominal aortic aneurysm; thoracic aortic aneurysm which HAS ruptured

Includes 7 related subtypes ↓
  • abdominal aortic aneurysm
  • aortic aneurysm, familial abdominal, 1
  • aortic aneurysm, familial abdominal, 2
  • aortic aneurysm, familial abdominal, 3
  • aortic aneurysm, familial abdominal, 4
  • familial abdominal aortic aneurysm
  • thoracic aortic aneurysm
MONDO:0005160MedGen 362

Familial Thoracic Aortic Aneurysm and Dissection

Autosomal dominant

Inherited widening and tearing of the thoracic aorta, caused by changes in genes such as ACTA2, MYH11, MYLK, LOX, PRKG1, MFAP5 and THSD4.

What a diagnosis changes

Knowing about it supports regular aortic imaging, blood pressure control and timely preventive surgery, and screening of relatives.

Genes analysed

Also known as

Erdheim disease; familial aortic dissection; familial non-syndromic TAAD; familial TAAD; FTAAD; nonsyndromic familial thoracic aortic aneurysm and dissection; nonsyndromic heritable thoracic aortic disease; nonsyndromic HTAD; ns-FTAAD; nsHTAD

Includes 11 related subtypes ↓
  • aortic aneurysm, familial thoracic 1
  • aortic aneurysm, familial thoracic 10
  • aortic aneurysm, familial thoracic 12
  • aortic aneurysm, familial thoracic 2
  • aortic aneurysm, familial thoracic 4
  • aortic aneurysm, familial thoracic 6
  • aortic aneurysm, familial thoracic 7
  • aortic aneurysm, familial thoracic 8
  • aortic aneurysm, familial thoracic 9
  • Loeys-Dietz syndrome 1
  • Loeys-Dietz syndrome 2
MONDO:0019625Orphanet 91387MedGen 1644766

Multisystemic Smooth Muscle Dysfunction Syndrome

Autosomal dominant

A range of conditions caused by changes in ACTA2 that can affect the aorta, brain arteries, pupils, gut and bladder.

What a diagnosis changes

Knowing about it supports aortic and brain blood vessel imaging.

Genes analysed

Also known as

ACTA2-related smooth muscle dysfunction syndrome; congenital mydriasis, patent ductus arteriosus, thoracic aortic aneurysm, and vasculopathy

Includes 2 related subtypes ↓
  • aortic aneurysm, familial thoracic 6
  • Moyamoya disease 5
MONDO:0013452OMIM 613834Orphanet 404463MedGen 462551

Familial Thoracic Aortic Aneurysm 11 Susceptibility

Autosomal dominant

An inherited susceptibility to thoracic aortic aneurysm and dissection linked to changes in FOXE3.

Genes analysed

Also known as

AAT11

MONDO:0044301OMIM 617349MedGen 1377970

Why whole genome sequencing

Standard TAAD panels test 11-20 genes but identify mutations in only ~30% of familial non-syndromic thoracic aortic disease.

Most familial thoracic aortic disease remains genetically unresolved

TAAD panels typically test 11-20 genes associated with heritable aortic disease. However, identifiable mutations in known genes account for only approximately 30% of familial non-syndromic TAAD. FBN1 and Loeys-Dietz genes (TGFBR1, TGFBR2) together account for only approximately 10% of familial TAAD. ACTA2 (smooth muscle alpha-actin) accounts for 12 to 21%; MYH11 and others for smaller fractions. The majority of familial TAAD remains genetically unexplained, suggesting undiscovered genes, oligogenic inheritance, or polygenic contributions. Whole genome sequencing enables both rare variant detection and genome-wide risk score calculation.

A finding determines surgical thresholds and prevents dissection

When a pathogenic aortic disease variant is confirmed, gene-specific surgical thresholds become critical for preventing sudden death. FBN1-related disease typically warrants prophylactic surgery at aortic root diameter 5.0-5.5 cm; Loeys-Dietz syndrome (TGFBR1) warrants prophylactic surgery at much smaller diameters (~5.0 cm or even smaller) because of higher dissection risk at smaller sizes. Using the wrong threshold (basing surgery decisions on general population guidelines rather than gene-specific criteria) delays necessary intervention. Cascade testing identifies at-risk relatives before their first imaging study, enabling lifelong surveillance and preventing sudden aortic dissection through preventive surgery.

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