Familial Thoracic Aortic Aneurysm and Aortic Dissection

Mendelian MONDO:0019625 Pathograph 9 Show in embeddings browser Vascular disorder

Familial thoracic aortic aneurysm and aortic dissection is a heritable thoracic aortic disease in which thoracic aortic dilatation, aneurysm, or dissection clusters in families without being fully explained by another syndromic diagnosis. Disease risk reflects inherited disruption of aortic wall extracellular matrix integrity, smooth-muscle contractility, or growth-factor signaling, and the main prevention strategy is early family identification, aortic surveillance, and prophylactic repair when indicated.

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9
Mappings
1
Inheritance
8
Pathophys.
1
Histopath.
2
Phenotypes
9
Pathograph
14
Genes
4
Medical Actions
9
Subtypes
1
Deep Research
🔗

Mappings

MONDO
MONDO:0024559 aortic aneurysm, familial thoracic 1 Not Yet Curated
skos:narrowMatch MONDO
AAT1 (11q23 linkage locus); covered by the AAT1 linkage locus subtype of this lumped familial-TAAD entry.
MONDO:0011770 aortic aneurysm, familial thoracic 2 Not Yet Curated
skos:narrowMatch MONDO
AAT2 (3p24-p25/TGFBR2 candidate locus); covered by the TGFBR2-candidate locus subtype of this lumped familial-TAAD entry.
MONDO:0007568 aortic aneurysm, familial thoracic 4 Not Yet Curated
skos:narrowMatch MONDO
AAT4 (MYH11); covered by the MYH11-related subtype of this lumped familial-TAAD entry.
MONDO:0012730 aortic aneurysm, familial thoracic 6 Not Yet Curated
skos:narrowMatch MONDO
AAT6 (ACTA2); covered by the ACTA2-related subtype of this lumped familial-TAAD entry.
MONDO:0013418 aortic aneurysm, familial thoracic 7 Not Yet Curated
skos:narrowMatch MONDO
AAT7 (MYLK); covered by the MYLK-related subtype of this lumped familial-TAAD entry.
MONDO:0014187 aortic aneurysm, familial thoracic 8 Not Yet Curated
skos:narrowMatch MONDO
AAT8 (PRKG1); covered by the PRKG1-related subtype of this lumped familial-TAAD entry.
MONDO:0014514 aortic aneurysm, familial thoracic 9 Not Yet Curated
skos:narrowMatch MONDO
AAT9 (MFAP5); covered by the MFAP5-related subtype of this lumped familial-TAAD entry.
MONDO:0014950 aortic aneurysm, familial thoracic 10 Not Yet Curated
skos:narrowMatch MONDO
AAT10 (LOX); covered by the LOX-related subtype of this lumped familial-TAAD entry.
MONDO:0030731 aortic aneurysm, familial thoracic 12 Not Yet Curated
skos:narrowMatch MONDO
AAT12 (THSD4); covered by the THSD4-related subtype of this lumped familial-TAAD entry.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Many familial thoracic aortic aneurysm and dissection families show autosomal dominant inheritance, although the gene spectrum is heterogeneous and relatives may be clinically silent until imaging identifies aortic dilatation.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:35383466 SUPPORT Human Clinical
"Background Diseases of the thoracic aorta are characterized by a familial etiology in up to 30% of the cases."
This supports a familial genetic contribution to nonsyndromic thoracic aortic disease.
◆

Subtypes

9
ACTA2-related familial thoracic aortic aneurysm 6 MONDO:0012730
ACTA2-related familial thoracic aortic aneurysm and dissection.
MYH11-related familial thoracic aortic aneurysm 4 MONDO:0007568
MYH11-related familial thoracic aortic aneurysm and dissection.
MYLK-related familial thoracic aortic aneurysm 7 MONDO:0013418
MYLK-related familial thoracic aortic aneurysm and dissection.
PRKG1-related familial thoracic aortic aneurysm 8 MONDO:0014187
PRKG1-related familial thoracic aortic aneurysm and dissection (smooth-muscle contractile-mechanism gene; ClinGen HTAD GCEP classification Strong).
LOX-related familial thoracic aortic aneurysm 10 MONDO:0014950
LOX-related familial thoracic aortic aneurysm and dissection (extracellular-matrix gene; ClinGen HTAD GCEP classification Strong).
MFAP5-related familial thoracic aortic aneurysm 9 MONDO:0014514
MFAP5-related familial thoracic aortic aneurysm and dissection (AAT9; OMIM 616166). MFAP5 (microfibril-associated glycoprotein 2/MAGP-2) is an extracellular-matrix component of fibrillin microfibrils that modulates TGF-beta bioavailability; loss-of-function variants disrupt microfibril integrity. MONDO binds this leaf class to MFAP5 (RO:0004003 HGNC:29673).
THSD4-related familial thoracic aortic aneurysm 12 MONDO:0030731
THSD4-related familial thoracic aortic aneurysm and dissection (AAT12; OMIM 619825). MONDO binds this leaf class to THSD4 (RO:0004003 HGNC:25835), the thrombospondin type-1 domain-containing protein 4 that promotes fibrillin-1 microfibril assembly. Note: this numbered locus is distinct from the MAT2A gene-disease relationship, which ClinGen classifies as Limited against the umbrella term MONDO:0019625 (see MAT2A in genetic_associations) rather than against this leaf class.
Familial thoracic aortic aneurysm 2 (3p24-p25 locus) MONDO:0011770
AAT2 (OMIM 607087) is a familial thoracic aortic aneurysm and dissection locus mapped to 3p24-p25, the interval containing TGFBR2. TGFBR2 pathogenic variants more typically cause Loeys-Dietz syndrome type 2 when accompanied by systemic features; the AAT2/LDS2 boundary is phenotype-dependent rather than genotype-defined. MONDO does not assign a confirmed causal gene to this leaf class. TGFBR2 is curated in genetic_associations as a TGF-beta pathway HTAD gene.
Familial thoracic aortic aneurysm 1 (11q23 locus) MONDO:0024559
AAT1 (OMIM 607086) is a historical familial thoracic aortic aneurysm and dissection linkage interval at 11q23.2-q24 identified in a single large family; no causal gene has been confirmed. Retained as a placeholder subtype to resolve MONDO leaf-class coverage; MONDO does not assign a causal gene to this leaf class.
⚙

Pathophysiology

8
Germline pathogenic variant in an HTAD gene
Inherited pathogenic variants in high-penetrance HTAD genes initiate familial thoracic aortic aneurysm and dissection risk. Downstream mechanisms cluster into extracellular matrix, TGF-beta signaling, and vascular smooth muscle contractile pathways.
Downstream
Extracellular matrix structural failure ECM-gene variants weaken the aortic wall matrix.
TGF-beta signaling dysregulation TGF-beta pathway gene variants perturb growth-factor signaling.
Vascular smooth muscle contractile apparatus disruption Contractile-apparatus gene variants impair smooth-muscle force generation and mechanosensing.
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"They may result from genetic defects."
The VASCERN pathway statement supports genetic defects as upstream causes of HTAD.
Extracellular matrix structural failure
Pathogenic variants in genes such as FBN1, LOX, and COL3A1 compromise aortic extracellular matrix organization, elastic-fiber integrity, or collagen structure, weakening the thoracic aortic media.
vascular smooth muscle cell CL:0000359
extracellular matrix organization GO:0030198 ⚠ ABNORMAL
Downstream
Thoracic aortic dilatation and dissection Matrix failure weakens the aortic wall and promotes dilation and dissection.
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
The statement explicitly identifies extracellular matrix genes as one of the central HTAD gene classes.
TGF-beta signaling dysregulation
Pathogenic variants in TGFBR1, TGFBR2, SMAD3, or TGFB2 perturb transforming growth factor beta signaling, contributing to thoracic aortic wall remodeling and aneurysm susceptibility.
vascular smooth muscle cell CL:0000359
transforming growth factor beta receptor signaling pathway GO:0007179 ⚠ ABNORMAL
Downstream
Thoracic aortic dilatation and dissection Dysregulated TGF-beta signaling contributes to maladaptive aortic wall remodeling.
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
The statement explicitly identifies the TGF-beta pathway as one of the central HTAD gene classes.
Vascular smooth muscle contractile apparatus disruption
Pathogenic variants in ACTA2, MYH11, MYLK, or PRKG1 impair vascular smooth muscle contraction and mechanotransduction, weakening the thoracic aorta.
vascular smooth muscle cell CL:0000359
smooth muscle contraction GO:0006939 ⚠ ABNORMAL
Downstream
Thoracic aortic dilatation and dissection Impaired contractility and stress sensing increase susceptibility to aneurysm and dissection.
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
The statement explicitly identifies smooth muscle contractile mechanism genes as one of the central HTAD gene classes.
MYH11-associated impaired aortic contractility and ROCK signaling
In a Myh11 familial TAAD model, reduced aortic contractility and a transcriptional program involving ROCK signaling are proposed to prime the aorta for maladaptive stress responses and dissection susceptibility.
vascular smooth muscle cell CL:0000359
smooth muscle contraction GO:0006939 ↓ DECREASED
Show evidence (2 references)
PMID:41977381 SUPPORT Model Organism
"Familial thoracic aortic aneurysm and dissection (FTAAD), caused by the pathogenic Myh11 K1256del variant, is characterized by impaired aortic contractility; however, how reduced contractility predisposes the aorta to dissection remains incompletely understood."
The mouse-model study links a pathogenic Myh11 variant to impaired aortic contractility in FTAAD.
PMID:41977381 SUPPORT Model Organism
"These findings indicate that even in the absence of overt pathological stimulation, aortic tissue carrying the Myh11 K1256del variant exhibits a transcriptional program centered on ROCK signaling, which may prime the aorta for maladaptive responses to additional stress and may enhance..."
This supports ROCK-centered smooth-muscle dysregulation as a mechanistic hypothesis in this FTAAD model.
PRKG1 gain-of-function constitutive PKG-1 activation
PRKG1-related familial thoracic aortic disease (AAT8) is the only gain-of-function locus among the nonsyndromic HTAD genes. The recurrent PRKG1 c.530G>A (p.Arg177Gln) variant yields a type I cGMP-dependent protein kinase (PKG-1) that is constitutively active even without cGMP. Persistent PKG-1 activity lowers phosphorylation of the myosin regulatory light chain, decreasing vascular smooth muscle contraction and weakening the thoracic aorta — contrasting with the loss-of-function contractile genes ACTA2, MYH11, and MYLK.
vascular smooth muscle cell CL:0000359
constitutive cGMP-dependent protein kinase (PKG-1) signaling GO:0035556 ↑ INCREASED vascular smooth muscle contraction GO:0006939 ↓ DECREASED
Downstream
Thoracic aortic dilatation and dissection Decreased smooth muscle contraction from constitutive PKG-1 activity weakens the aortic wall and predisposes to aneurysm and acute dissection, frequently at young ages.
Show evidence (3 references)
PMID:23910461 SUPPORT Human Clinical
"the same rare variant, PRKG1 c.530G>A (p.Arg177Gln), in four families. This mutation segregated with aortic disease in these families with a combined two-point LOD score of 7.88."
Establishes the human genetic causation of the recurrent PRKG1 p.Arg177Gln variant in familial thoracic aortic disease.
PMID:23910461 SUPPORT In Vitro
"the altered PKG-1 is constitutively active even in the absence of cGMP."
Defines the gain-of-function mechanism — constitutive PKG-1 activity independent of cGMP binding.
PMID:23910461 SUPPORT In Vitro
"The increased PKG-1 activity leads to decreased phosphorylation of the myosin regulatory light chain in fibroblasts and is predicted to cause decreased contraction of vascular SMCs."
Patient-fibroblast assay links the gain-of-function PKG-1 activity to reduced myosin light-chain phosphorylation and decreased smooth muscle contraction.
MFAP5 haploinsufficiency and microfibril elastic-fiber alteration
MFAP5-related familial thoracic aortic disease (AAT9) is an extracellular-matrix locus. Loss-of-function variants in MFAP5 cause haploinsufficiency for MAGP-2 (microfibril-associated glycoprotein 2), a component of microfibrils and elastic fibers that interacts with elastin and the fibrillin microfibrillar network. Reduced MAGP-2 alters elastic-fiber and microfibril integrity, weakening the aortic medial matrix and acting as an initiating mechanism of inherited TAAD through the extracellular-matrix arm of the aortopathy mechanism.
vascular smooth muscle cell CL:0000359
elastic fiber assembly GO:0048251 ⚠ ABNORMAL extracellular matrix organization GO:0030198 ⚠ ABNORMAL
Downstream
Extracellular matrix structural failure MAGP-2 haploinsufficiency degrades elastic-fiber and microfibril integrity, feeding the extracellular-matrix arm of aortic wall weakening.
Show evidence (3 references)
PMID:25434006 SUPPORT Human Clinical
"nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network."
Establishes MFAP5 loss-of-function (MAGP-2) as a cause of familial TAAD and places the encoded protein in the elastin/microfibril network.
PMID:25434006 SUPPORT In Vitro
"Functional analyses performed on both affected individual's cells and in vitro models showed that these two mutations caused pure or partial haploinsufficiency."
Defines the loss-of-function / haploinsufficiency mechanism for the MFAP5 variants in patient cells and in vitro models.
PMID:25434006 SUPPORT Human Clinical
"alteration of MAGP-2, a component of microfibrils and elastic fibers, appears as an initiating mechanism of inherited TAAD."
Establishes MAGP-2 alteration as an initiating extracellular-matrix mechanism of inherited thoracic aortic aneurysm and dissection.
Thoracic aortic dilatation and dissection
Progressive thoracic aortic enlargement increases wall stress and can lead to acute aortic dissection or rupture. Because relatives can have silent dilation, imaging surveillance is clinically important.
Downstream
Thoracic aortic aneurysm Progressive thoracic aortic enlargement is expressed clinically as thoracic aortic aneurysm or dilation.
Aortic dissection A weakened dilated thoracic aorta can progress to acute aortic dissection.
Show evidence (1 reference)
PMID:35383466 SUPPORT Human Clinical
"Imaging revealed mild-to-moderate aortic dilation in 24% of relatives."
Family screening identifies clinically silent aortic dilation in relatives.
✶

Histopathology

1
Medial cystic degeneration with elastic fiber fragmentation
Falcon review synthesis describes medial cystic necrosis or degeneration, elastic-fiber fragmentation, vascular smooth muscle cell loss, and increased proteoglycans as characteristic aortic-wall pathology in HTAD/FTAAD.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial Thoracic Aortic Aneurysm and Aortic Dissection Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

2
Thoracic aortic aneurysm Cardiovascular HP:0004942
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic."
This supports thoracic aortic aneurysm as a core manifestation of heritable thoracic aortic disease.
Aortic dissection Cardiovascular HP:0002647
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic."
This supports aortic dissection as a core manifestation of HTAD.
🧬

Genetic Associations

14
FBN1 (High-penetrance HTAD extracellular matrix gene)
Gene: FBN1 hgnc:3603
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
FBN1 is curated here as an extracellular-matrix HTAD gene under the VASCERN gene-class framework.
LOX (High-penetrance HTAD extracellular matrix gene)
Gene: LOX hgnc:6664
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
LOX is curated here as an extracellular-matrix HTAD gene under the VASCERN gene-class framework.
COL3A1 (High-penetrance HTAD extracellular matrix gene)
Gene: COL3A1 hgnc:2201
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
COL3A1 is curated here as an extracellular-matrix HTAD gene under the VASCERN gene-class framework.
TGFBR1 (High-penetrance HTAD TGF-beta pathway gene)
Gene: TGFBR1 hgnc:11772
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
TGFBR1 is curated here as a TGF-beta pathway HTAD gene under the VASCERN gene-class framework.
TGFBR2 (High-penetrance HTAD TGF-beta pathway gene)
Gene: TGFBR2 hgnc:11773
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
TGFBR2 is curated here as a TGF-beta pathway HTAD gene under the VASCERN gene-class framework.
SMAD3 (High-penetrance HTAD TGF-beta pathway gene)
Gene: SMAD3 hgnc:6769
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
SMAD3 is curated here as a TGF-beta pathway HTAD gene under the VASCERN gene-class framework.
TGFB2 (High-penetrance HTAD TGF-beta pathway gene)
Gene: TGFB2 hgnc:11768
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
TGFB2 is curated here as a TGF-beta pathway HTAD gene under the VASCERN gene-class framework.
ACTA2 (High-penetrance HTAD smooth muscle contractile apparatus gene)
Gene: ACTA2 hgnc:130
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
ACTA2 is curated here as a smooth-muscle contractile HTAD gene under the VASCERN gene-class framework.
MYH11 (High-penetrance HTAD smooth muscle contractile apparatus gene)
Gene: MYH11 hgnc:7569
Show evidence (1 reference)
PMID:41977381 SUPPORT Model Organism
"Familial thoracic aortic aneurysm and dissection (FTAAD), caused by the pathogenic Myh11 K1256del variant, is characterized by impaired aortic contractility; however, how reduced contractility predisposes the aorta to dissection remains incompletely understood."
This supports MYH11 as a contractile-gene cause in FTAAD biology.
MYLK (High-penetrance HTAD smooth muscle contractile apparatus gene)
Gene: MYLK hgnc:7590
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
MYLK is curated here as a smooth-muscle contractile HTAD gene under the VASCERN gene-class framework.
PRKG1 (High-penetrance HTAD smooth muscle contractile apparatus gene)
Gene: PRKG1 hgnc:9414
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism."
PRKG1 is curated here as a smooth-muscle contractile HTAD gene under the VASCERN gene-class framework.
MAT2A (Pathogenic Variants)
Gene: MAT2A hgnc:6904
Show evidence (1 reference)
CGGV:assertion_3629c2b2-80c7-4f8b-a42b-6e53d292a5bf-2025-12-05T170000.000Z SUPPORT Other
"MAT2A | HGNC:6904 | familial thoracic aortic aneurysm and aortic dissection | MONDO:0019625 | AD | Limited"
ClinGen classifies the MAT2A-familial thoracic aortic aneurysm and aortic dissection gene-disease relationship as limited with autosomal dominant inheritance.
MFAP5 (HTAD extracellular matrix microfibril gene (MFAP5/MAGP-2; AAT9))
Gene: MFAP5 hgnc:29673
Show evidence (1 reference)
PMID:25434006 SUPPORT Human Clinical
"nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network."
MFAP5 loss-of-function variants identified in TAAD families establish it as the AAT9 (MONDO:0014514) gene; the encoded microfibril/elastic-fiber component MAGP-2 places this locus in the extracellular-matrix arm of the aortopathy mechanism.
THSD4 (HTAD microfibril-associated gene (THSD4/ADAMTSL6; AAT12))
Gene: THSD4 hgnc:25835
Show evidence (1 reference)
PMID:32855533 SUPPORT Human Clinical
"We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon."
Heterozygous THSD4 variants identified across TAAD families establish it as the AAT12 (MONDO:0030731) gene; THSD4 encodes the microfibril-associated protein ADAMTSL6 that promotes fibrillin-1 matrix assembly, placing this locus in the extracellular-matrix arm of the aortopathy mechanism. Distinct from the umbrella MAT2A association above.
💊

Medical Actions

4
Aortic surveillance imaging
Action: magnetic resonance imaging surveillance Ontology label: magnetic resonance imaging procedure MAXO:0000424
Serial aortic imaging surveillance identifies progressive dilation and informs timing of prophylactic repair before high-risk dissection or rupture.
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out."
The HTAD pathway statement supports prompt aortic surveillance as outcome-improving management.
Prophylactic aortic surgery
Action: aortic surgical procedure Ontology label: surgical procedure on cardiovascular system MAXO:0025001
Prophylactic repair is used when aortic size, growth rate, gene, family history, or other risk features indicate high dissection risk.
Show evidence (1 reference)
PMID:36460281 SUPPORT Human Clinical
"Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out."
The HTAD pathway statement supports prophylactic surgery as part of life-expectancy-improving management.
Medical therapy to reduce aortic disease risk
Action: Pharmacotherapy NCIT:C15986
Medical therapy for heritable thoracic aortic disease commonly includes blood-pressure and wall-stress reduction with beta-blockers and/or angiotensin receptor blockers, tailored to gene and clinical context.
Show evidence (1 reference)
PMID:36334952 SUPPORT Human Clinical
"The "2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease" provides recommendations to guide clinicians in the diagnosis, genetic evaluation and family screening, medical therapy, endovascular and surgical treatment, and long-term surveillance of patients with aortic disease..."
The ACC/AHA guideline abstract supports medical therapy as a core management domain for aortic disease.
Genetic counseling and cascade family screening
Action: genetic counseling MAXO:0000079
Genetic counseling and testing help distinguish at-risk relatives from relatives who can be reassured when a familial diagnosis is ruled out.
Show evidence (1 reference)
PMID:35383466 SUPPORT Human Clinical
"We hypothesize that tailored genetic testing and imaging of first-degree and second-degree relatives of patients affected by NS-TADs may enable early diagnosis and allow appropriate surveillance or intervention."
The REST study supports genetic testing and family imaging as early-detection strategies.
{ }

Source YAML

click to show 
name: Familial Thoracic Aortic Aneurysm and Aortic Dissection
creation_date: "2026-05-05T15:37:54Z"
updated_date: "2026-05-05T16:34:00Z"
description: >-
  Familial thoracic aortic aneurysm and aortic dissection is a heritable
  thoracic aortic disease in which thoracic aortic dilatation, aneurysm, or
  dissection clusters in families without being fully explained by another
  syndromic diagnosis. Disease risk reflects inherited disruption of aortic wall
  extracellular matrix integrity, smooth-muscle contractility, or growth-factor
  signaling, and the main prevention strategy is early family identification,
  aortic surveillance, and prophylactic repair when indicated.
category: Mendelian
disease_term:
  preferred_term: familial thoracic aortic aneurysm and aortic dissection
  term:
    id: MONDO:0019625
    label: familial thoracic aortic aneurysm and aortic dissection
mappings:
  mondo_mappings:
  # Numbered nonsyndromic familial-TAAD loci subsumed by this lumped entry.
  # Each is narrower than the umbrella MONDO:0019625 and is also anchored at the
  # subtype level via has_subtypes[].subtype_term; declaring them here lets the
  # grouping->MONDO descendant-coverage audit (scripts/grouping_mondo_gaps.py)
  # recognize them as covered. See issue  # 4241.
  - term:
      id: MONDO:0024559
      label: aortic aneurysm, familial thoracic 1
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: AAT1 (11q23 linkage locus); covered by the AAT1 linkage locus subtype of this lumped familial-TAAD entry.
  - term:
      id: MONDO:0011770
      label: aortic aneurysm, familial thoracic 2
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: AAT2 (3p24-p25/TGFBR2 candidate locus); covered by the TGFBR2-candidate locus subtype of this lumped familial-TAAD entry.
  - term:
      id: MONDO:0007568
      label: aortic aneurysm, familial thoracic 4
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: AAT4 (MYH11); covered by the MYH11-related subtype of this lumped familial-TAAD entry.
  - term:
      id: MONDO:0012730
      label: aortic aneurysm, familial thoracic 6
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: AAT6 (ACTA2); covered by the ACTA2-related subtype of this lumped familial-TAAD entry.
  - term:
      id: MONDO:0013418
      label: aortic aneurysm, familial thoracic 7
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: AAT7 (MYLK); covered by the MYLK-related subtype of this lumped familial-TAAD entry.
  - term:
      id: MONDO:0014187
      label: aortic aneurysm, familial thoracic 8
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: AAT8 (PRKG1); covered by the PRKG1-related subtype of this lumped familial-TAAD entry.
  - term:
      id: MONDO:0014514
      label: aortic aneurysm, familial thoracic 9
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: AAT9 (MFAP5); covered by the MFAP5-related subtype of this lumped familial-TAAD entry.
  - term:
      id: MONDO:0014950
      label: aortic aneurysm, familial thoracic 10
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: AAT10 (LOX); covered by the LOX-related subtype of this lumped familial-TAAD entry.
  - term:
      id: MONDO:0030731
      label: aortic aneurysm, familial thoracic 12
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: AAT12 (THSD4); covered by the THSD4-related subtype of this lumped familial-TAAD entry.
parents:
- Vascular disorder
synonyms:
- FTAAD
- Familial TAAD
- Nonsyndromic heritable thoracic aortic disease
- nsHTAD
has_subtypes:
- name: ACTA2-related
  display_name: ACTA2-related familial thoracic aortic aneurysm 6
  subtype_term:
    preferred_term: aortic aneurysm, familial thoracic 6
    term:
      id: MONDO:0012730
      label: aortic aneurysm, familial thoracic 6
  description: ACTA2-related familial thoracic aortic aneurysm and dissection.
- name: MYH11-related
  display_name: MYH11-related familial thoracic aortic aneurysm 4
  subtype_term:
    preferred_term: aortic aneurysm, familial thoracic 4
    term:
      id: MONDO:0007568
      label: aortic aneurysm, familial thoracic 4
  description: MYH11-related familial thoracic aortic aneurysm and dissection.
- name: MYLK-related
  display_name: MYLK-related familial thoracic aortic aneurysm 7
  subtype_term:
    preferred_term: aortic aneurysm, familial thoracic 7
    term:
      id: MONDO:0013418
      label: aortic aneurysm, familial thoracic 7
  description: MYLK-related familial thoracic aortic aneurysm and dissection.
- name: PRKG1-related
  display_name: PRKG1-related familial thoracic aortic aneurysm 8
  subtype_term:
    preferred_term: aortic aneurysm, familial thoracic 8
    term:
      id: MONDO:0014187
      label: aortic aneurysm, familial thoracic 8
  description: >-
    PRKG1-related familial thoracic aortic aneurysm and dissection (smooth-muscle
    contractile-mechanism gene; ClinGen HTAD GCEP classification Strong).
- name: LOX-related
  display_name: LOX-related familial thoracic aortic aneurysm 10
  subtype_term:
    preferred_term: aortic aneurysm, familial thoracic 10
    term:
      id: MONDO:0014950
      label: aortic aneurysm, familial thoracic 10
  description: >-
    LOX-related familial thoracic aortic aneurysm and dissection (extracellular-matrix
    gene; ClinGen HTAD GCEP classification Strong).
- name: MFAP5-related
  display_name: MFAP5-related familial thoracic aortic aneurysm 9
  subtype_term:
    preferred_term: aortic aneurysm, familial thoracic 9
    term:
      id: MONDO:0014514
      label: aortic aneurysm, familial thoracic 9
  description: >-
    MFAP5-related familial thoracic aortic aneurysm and dissection (AAT9; OMIM
    616166). MFAP5 (microfibril-associated glycoprotein 2/MAGP-2) is an
    extracellular-matrix component of fibrillin microfibrils that modulates
    TGF-beta bioavailability; loss-of-function variants disrupt microfibril
    integrity. MONDO binds this leaf class to MFAP5 (RO:0004003 HGNC:29673).
- name: THSD4-related
  display_name: THSD4-related familial thoracic aortic aneurysm 12
  subtype_term:
    preferred_term: aortic aneurysm, familial thoracic 12
    term:
      id: MONDO:0030731
      label: aortic aneurysm, familial thoracic 12
  description: >-
    THSD4-related familial thoracic aortic aneurysm and dissection (AAT12; OMIM
    619825). MONDO binds this leaf class to THSD4 (RO:0004003 HGNC:25835), the
    thrombospondin type-1 domain-containing protein 4 that promotes fibrillin-1
    microfibril assembly. Note: this numbered locus is distinct from the MAT2A
    gene-disease relationship, which ClinGen classifies as Limited against the
    umbrella term MONDO:0019625 (see MAT2A in genetic_associations) rather than
    against this leaf class.
- name: TGFBR2-candidate locus
  display_name: Familial thoracic aortic aneurysm 2 (3p24-p25 locus)
  subtype_term:
    preferred_term: aortic aneurysm, familial thoracic 2
    term:
      id: MONDO:0011770
      label: aortic aneurysm, familial thoracic 2
  description: >-
    AAT2 (OMIM 607087) is a familial thoracic aortic aneurysm and dissection
    locus mapped to 3p24-p25, the interval containing TGFBR2. TGFBR2 pathogenic
    variants more typically cause Loeys-Dietz syndrome type 2 when accompanied by
    systemic features; the AAT2/LDS2 boundary is phenotype-dependent rather than
    genotype-defined. MONDO does not assign a confirmed causal gene to this leaf
    class. TGFBR2 is curated in genetic_associations as a TGF-beta pathway HTAD
    gene.
- name: AAT1 linkage locus
  display_name: Familial thoracic aortic aneurysm 1 (11q23 locus)
  subtype_term:
    preferred_term: aortic aneurysm, familial thoracic 1
    term:
      id: MONDO:0024559
      label: aortic aneurysm, familial thoracic 1
  description: >-
    AAT1 (OMIM 607086) is a historical familial thoracic aortic aneurysm and
    dissection linkage interval at 11q23.2-q24 identified in a single large
    family; no causal gene has been confirmed. Retained as a placeholder subtype
    to resolve MONDO leaf-class coverage; MONDO does not assign a causal gene to
    this leaf class.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Many familial thoracic aortic aneurysm and dissection families show
    autosomal dominant inheritance, although the gene spectrum is heterogeneous
    and relatives may be clinically silent until imaging identifies aortic
    dilatation.
  evidence:
  - reference: PMID:35383466
    reference_title: "Evaluating the Feasibility of Screening Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Diseases: The REST Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Background Diseases of the thoracic aorta are characterized by a familial etiology in up to 30% of the cases.
    explanation: This supports a familial genetic contribution to nonsyndromic thoracic aortic disease.
pathophysiology:
- name: Germline pathogenic variant in an HTAD gene
  description: >-
    Inherited pathogenic variants in high-penetrance HTAD genes initiate
    familial thoracic aortic aneurysm and dissection risk. Downstream mechanisms
    cluster into extracellular matrix, TGF-beta signaling, and vascular smooth
    muscle contractile pathways.
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They may result from genetic defects.
    explanation: The VASCERN pathway statement supports genetic defects as upstream causes of HTAD.
  downstream:
  - target: Extracellular matrix structural failure
    description: ECM-gene variants weaken the aortic wall matrix.
  - target: TGF-beta signaling dysregulation
    description: TGF-beta pathway gene variants perturb growth-factor signaling.
  - target: Vascular smooth muscle contractile apparatus disruption
    description: Contractile-apparatus gene variants impair smooth-muscle force generation and mechanosensing.
- name: Extracellular matrix structural failure
  conforms_to: "aortopathy_tgfbeta_dysregulation#Aortic Wall ECM or Contractile Apparatus Defect"
  description: >-
    Pathogenic variants in genes such as FBN1, LOX, and COL3A1 compromise
    aortic extracellular matrix organization, elastic-fiber integrity, or
    collagen structure, weakening the thoracic aortic media.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: The statement explicitly identifies extracellular matrix genes as one of the central HTAD gene classes.
  downstream:
  - target: Thoracic aortic dilatation and dissection
    description: Matrix failure weakens the aortic wall and promotes dilation and dissection.
- name: TGF-beta signaling dysregulation
  conforms_to: "aortopathy_tgfbeta_dysregulation#TGF-beta Signaling Dysregulation"
  description: >-
    Pathogenic variants in TGFBR1, TGFBR2, SMAD3, or TGFB2 perturb
    transforming growth factor beta signaling, contributing to thoracic aortic
    wall remodeling and aneurysm susceptibility.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    modifier: ABNORMAL
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: The statement explicitly identifies the TGF-beta pathway as one of the central HTAD gene classes.
  downstream:
  - target: Thoracic aortic dilatation and dissection
    description: Dysregulated TGF-beta signaling contributes to maladaptive aortic wall remodeling.
- name: Vascular smooth muscle contractile apparatus disruption
  description: >-
    Pathogenic variants in ACTA2, MYH11, MYLK, or PRKG1 impair vascular smooth
    muscle contraction and mechanotransduction, weakening the thoracic aorta.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: smooth muscle contraction
    modifier: ABNORMAL
    term:
      id: GO:0006939
      label: smooth muscle contraction
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: The statement explicitly identifies smooth muscle contractile mechanism genes as one of the central HTAD gene classes.
  downstream:
  - target: Thoracic aortic dilatation and dissection
    description: Impaired contractility and stress sensing increase susceptibility to aneurysm and dissection.
- name: MYH11-associated impaired aortic contractility and ROCK signaling
  description: >-
    In a Myh11 familial TAAD model, reduced aortic contractility and a
    transcriptional program involving ROCK signaling are proposed to prime the
    aorta for maladaptive stress responses and dissection susceptibility.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: smooth muscle contraction
    modifier: DECREASED
    term:
      id: GO:0006939
      label: smooth muscle contraction
  evidence:
  - reference: PMID:41977381
    reference_title: A Pathogenic ROCK-Signaling Network Involving a Lysine Deletion in Myh11 Renders Carriers Susceptible to Aortic Dissection.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Familial thoracic aortic aneurysm and dissection (FTAAD), caused by the pathogenic Myh11 K1256del variant, is characterized by impaired aortic contractility; however, how reduced contractility predisposes the aorta to dissection remains incompletely understood.
    explanation: The mouse-model study links a pathogenic Myh11 variant to impaired aortic contractility in FTAAD.
  - reference: PMID:41977381
    reference_title: A Pathogenic ROCK-Signaling Network Involving a Lysine Deletion in Myh11 Renders Carriers Susceptible to Aortic Dissection.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These findings indicate that even in the absence of overt pathological stimulation, aortic tissue carrying the Myh11 K1256del variant exhibits a transcriptional program centered on ROCK signaling, which may prime the aorta for maladaptive responses to additional stress and may enhance susceptibility to dissection.
    explanation: This supports ROCK-centered smooth-muscle dysregulation as a mechanistic hypothesis in this FTAAD model.
- name: PRKG1 gain-of-function constitutive PKG-1 activation
  description: >-
    PRKG1-related familial thoracic aortic disease (AAT8) is the only
    gain-of-function locus among the nonsyndromic HTAD genes. The recurrent
    PRKG1 c.530G>A (p.Arg177Gln) variant yields a type I cGMP-dependent protein
    kinase (PKG-1) that is constitutively active even without cGMP. Persistent
    PKG-1 activity lowers phosphorylation of the myosin regulatory light chain,
    decreasing vascular smooth muscle contraction and weakening the thoracic
    aorta — contrasting with the loss-of-function contractile genes ACTA2,
    MYH11, and MYLK.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: constitutive cGMP-dependent protein kinase (PKG-1) signaling
    modifier: INCREASED
    term:
      id: GO:0035556
      label: intracellular signal transduction
  - preferred_term: vascular smooth muscle contraction
    modifier: DECREASED
    term:
      id: GO:0006939
      label: smooth muscle contraction
  evidence:
  - reference: PMID:23910461
    reference_title: Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the same rare variant, PRKG1 c.530G>A (p.Arg177Gln), in four families. This mutation segregated with aortic disease in these families with a combined two-point LOD score of 7.88.
    explanation: Establishes the human genetic causation of the recurrent PRKG1 p.Arg177Gln variant in familial thoracic aortic disease.
  - reference: PMID:23910461
    reference_title: Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the altered PKG-1 is constitutively active even in the absence of cGMP.
    explanation: Defines the gain-of-function mechanism — constitutive PKG-1 activity independent of cGMP binding.
  - reference: PMID:23910461
    reference_title: Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The increased PKG-1 activity leads to decreased phosphorylation of the myosin regulatory light chain in fibroblasts and is predicted to cause decreased contraction of vascular SMCs.
    explanation: Patient-fibroblast assay links the gain-of-function PKG-1 activity to reduced myosin light-chain phosphorylation and decreased smooth muscle contraction.
  downstream:
  - target: Thoracic aortic dilatation and dissection
    description: >-
      Decreased smooth muscle contraction from constitutive PKG-1 activity
      weakens the aortic wall and predisposes to aneurysm and acute dissection,
      frequently at young ages.
- name: MFAP5 haploinsufficiency and microfibril elastic-fiber alteration
  description: >-
    MFAP5-related familial thoracic aortic disease (AAT9) is an
    extracellular-matrix locus. Loss-of-function variants in MFAP5 cause
    haploinsufficiency for MAGP-2 (microfibril-associated glycoprotein 2), a
    component of microfibrils and elastic fibers that interacts with elastin and
    the fibrillin microfibrillar network. Reduced MAGP-2 alters elastic-fiber and
    microfibril integrity, weakening the aortic medial matrix and acting as an
    initiating mechanism of inherited TAAD through the extracellular-matrix arm
    of the aortopathy mechanism.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: elastic fiber assembly
    modifier: ABNORMAL
    term:
      id: GO:0048251
      label: elastic fiber assembly
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:25434006
    reference_title: MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network.
    explanation: >-
      Establishes MFAP5 loss-of-function (MAGP-2) as a cause of familial TAAD and
      places the encoded protein in the elastin/microfibril network.
  - reference: PMID:25434006
    reference_title: MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional analyses performed on both affected individual's cells and in vitro models showed that these two mutations caused pure or partial haploinsufficiency.
    explanation: >-
      Defines the loss-of-function / haploinsufficiency mechanism for the MFAP5
      variants in patient cells and in vitro models.
  - reference: PMID:25434006
    reference_title: MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      alteration of MAGP-2, a component of microfibrils and elastic fibers, appears as an initiating mechanism of inherited TAAD.
    explanation: >-
      Establishes MAGP-2 alteration as an initiating extracellular-matrix
      mechanism of inherited thoracic aortic aneurysm and dissection.
  downstream:
  - target: Extracellular matrix structural failure
    description: >-
      MAGP-2 haploinsufficiency degrades elastic-fiber and microfibril integrity,
      feeding the extracellular-matrix arm of aortic wall weakening.
- name: Thoracic aortic dilatation and dissection
  conforms_to: "aortopathy_tgfbeta_dysregulation#Aortic Dissection and Rupture"
  description: >-
    Progressive thoracic aortic enlargement increases wall stress and can lead
    to acute aortic dissection or rupture. Because relatives can have silent
    dilation, imaging surveillance is clinically important.
  evidence:
  - reference: PMID:35383466
    reference_title: "Evaluating the Feasibility of Screening Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Diseases: The REST Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Imaging revealed mild-to-moderate aortic dilation in 24% of relatives.
    explanation: Family screening identifies clinically silent aortic dilation in relatives.
  downstream:
  - target: Thoracic aortic aneurysm
    causal_link_type: DIRECT
    description: Progressive thoracic aortic enlargement is expressed clinically as thoracic aortic aneurysm or dilation.
    evidence:
    - reference: PMID:36460281
      reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic.
      explanation: This supports thoracic aortic aneurysm as a core HTAD manifestation.
  - target: Aortic dissection
    causal_link_type: DIRECT
    description: A weakened dilated thoracic aorta can progress to acute aortic dissection.
    evidence:
    - reference: PMID:36460281
      reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic.
      explanation: This supports aortic dissection as a core HTAD manifestation.
phenotypes:
- category: Cardiovascular
  name: Thoracic aortic aneurysm
  diagnostic: true
  description: Thoracic aortic aneurysm or dilation is a defining manifestation of FTAAD.
  phenotype_term:
    preferred_term: Thoracic aortic aneurysm
    term:
      id: HP:0004942
      label: Aortic aneurysm
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic.
    explanation: This supports thoracic aortic aneurysm as a core manifestation of heritable thoracic aortic disease.
- category: Cardiovascular
  name: Aortic dissection
  diagnostic: true
  description: Aortic dissection is a life-threatening defining manifestation.
  phenotype_term:
    preferred_term: Aortic dissection
    term:
      id: HP:0002647
      label: Aortic dissection
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic.
    explanation: This supports aortic dissection as a core manifestation of HTAD.
histopathology:
- name: Medial cystic degeneration with elastic fiber fragmentation
  description: >-
    Falcon review synthesis describes medial cystic necrosis or degeneration,
    elastic-fiber fragmentation, vascular smooth muscle cell loss, and increased
    proteoglycans as characteristic aortic-wall pathology in HTAD/FTAAD.
  notes: >-
    The fetched PMID/DOI caches for the Butnariu 2024 HTAD genetics article are
    abstract-only and do not include the full histopathology quote from the
    Falcon report, so this finding is retained as a review note without a
    PubMed evidence item.
genetic:
- name: FBN1
  association: High-penetrance HTAD extracellular matrix gene
  presence: Positive
  gene_term:
    preferred_term: FBN1
    term:
      id: hgnc:3603
      label: FBN1
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: FBN1 is curated here as an extracellular-matrix HTAD gene under the VASCERN gene-class framework.
- name: LOX
  association: High-penetrance HTAD extracellular matrix gene
  presence: Positive
  subtype: LOX-related
  gene_term:
    preferred_term: LOX
    term:
      id: hgnc:6664
      label: LOX
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: LOX is curated here as an extracellular-matrix HTAD gene under the VASCERN gene-class framework.
- name: COL3A1
  association: High-penetrance HTAD extracellular matrix gene
  presence: Positive
  gene_term:
    preferred_term: COL3A1
    term:
      id: hgnc:2201
      label: COL3A1
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: COL3A1 is curated here as an extracellular-matrix HTAD gene under the VASCERN gene-class framework.
- name: TGFBR1
  association: High-penetrance HTAD TGF-beta pathway gene
  presence: Positive
  gene_term:
    preferred_term: TGFBR1
    term:
      id: hgnc:11772
      label: TGFBR1
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: TGFBR1 is curated here as a TGF-beta pathway HTAD gene under the VASCERN gene-class framework.
- name: TGFBR2
  association: High-penetrance HTAD TGF-beta pathway gene
  presence: Positive
  gene_term:
    preferred_term: TGFBR2
    term:
      id: hgnc:11773
      label: TGFBR2
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: TGFBR2 is curated here as a TGF-beta pathway HTAD gene under the VASCERN gene-class framework.
- name: SMAD3
  association: High-penetrance HTAD TGF-beta pathway gene
  presence: Positive
  gene_term:
    preferred_term: SMAD3
    term:
      id: hgnc:6769
      label: SMAD3
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: SMAD3 is curated here as a TGF-beta pathway HTAD gene under the VASCERN gene-class framework.
- name: TGFB2
  association: High-penetrance HTAD TGF-beta pathway gene
  presence: Positive
  gene_term:
    preferred_term: TGFB2
    term:
      id: hgnc:11768
      label: TGFB2
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: TGFB2 is curated here as a TGF-beta pathway HTAD gene under the VASCERN gene-class framework.
- name: ACTA2
  association: High-penetrance HTAD smooth muscle contractile apparatus gene
  presence: Positive
  subtype: ACTA2-related
  gene_term:
    preferred_term: ACTA2
    term:
      id: hgnc:130
      label: ACTA2
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: ACTA2 is curated here as a smooth-muscle contractile HTAD gene under the VASCERN gene-class framework.
- name: MYH11
  association: High-penetrance HTAD smooth muscle contractile apparatus gene
  presence: Positive
  subtype: MYH11-related
  gene_term:
    preferred_term: MYH11
    term:
      id: hgnc:7569
      label: MYH11
  evidence:
  - reference: PMID:41977381
    reference_title: A Pathogenic ROCK-Signaling Network Involving a Lysine Deletion in Myh11 Renders Carriers Susceptible to Aortic Dissection.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Familial thoracic aortic aneurysm and dissection (FTAAD), caused by the pathogenic Myh11 K1256del variant, is characterized by impaired aortic contractility; however, how reduced contractility predisposes the aorta to dissection remains incompletely understood.
    explanation: This supports MYH11 as a contractile-gene cause in FTAAD biology.
- name: MYLK
  association: High-penetrance HTAD smooth muscle contractile apparatus gene
  presence: Positive
  subtype: MYLK-related
  gene_term:
    preferred_term: MYLK
    term:
      id: hgnc:7590
      label: MYLK
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: MYLK is curated here as a smooth-muscle contractile HTAD gene under the VASCERN gene-class framework.
- name: PRKG1
  association: High-penetrance HTAD smooth muscle contractile apparatus gene
  presence: Positive
  subtype: PRKG1-related
  gene_term:
    preferred_term: PRKG1
    term:
      id: hgnc:9414
      label: PRKG1
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism.
    explanation: PRKG1 is curated here as a smooth-muscle contractile HTAD gene under the VASCERN gene-class framework.
- name: MAT2A
  gene_term:
    preferred_term: MAT2A
    term:
      id: hgnc:6904
      label: MAT2A
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_3629c2b2-80c7-4f8b-a42b-6e53d292a5bf-2025-12-05T170000.000Z
    reference_title: "MAT2A / familial thoracic aortic aneurysm and aortic dissection (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MAT2A | HGNC:6904 | familial thoracic aortic aneurysm and aortic dissection | MONDO:0019625 | AD | Limited"
    explanation: ClinGen classifies the MAT2A-familial thoracic aortic aneurysm and aortic dissection gene-disease relationship as limited with autosomal dominant inheritance.
- name: MFAP5
  association: HTAD extracellular matrix microfibril gene (MFAP5/MAGP-2; AAT9)
  presence: Positive
  subtype: MFAP5-related
  gene_term:
    preferred_term: MFAP5
    term:
      id: hgnc:29673
      label: MFAP5
  evidence:
  - reference: PMID:25434006
    reference_title: MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network.
    explanation: >-
      MFAP5 loss-of-function variants identified in TAAD families establish it as the
      AAT9 (MONDO:0014514) gene; the encoded microfibril/elastic-fiber component MAGP-2
      places this locus in the extracellular-matrix arm of the aortopathy mechanism.
- name: THSD4
  association: HTAD microfibril-associated gene (THSD4/ADAMTSL6; AAT12)
  presence: Positive
  subtype: THSD4-related
  gene_term:
    preferred_term: THSD4
    term:
      id: hgnc:25835
      label: THSD4
  evidence:
  - reference: PMID:32855533
    reference_title: Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon.
    explanation: >-
      Heterozygous THSD4 variants identified across TAAD families establish it as the
      AAT12 (MONDO:0030731) gene; THSD4 encodes the microfibril-associated protein
      ADAMTSL6 that promotes fibrillin-1 matrix assembly, placing this locus in the
      extracellular-matrix arm of the aortopathy mechanism. Distinct from the umbrella
      MAT2A association above.
diagnosis:
- name: Aortic imaging and family screening
  description: >-
    Echocardiography, CT, MRI, genetic counseling, and cascade screening of
    first- and second-degree relatives are used to identify silent aortic
    dilation and guide surveillance or prophylactic intervention.
  diagnosis_term:
    preferred_term: diagnostic imaging
  results: Imaging may show mild-to-moderate aortic dilation in otherwise clinically silent relatives.
  evidence:
  - reference: PMID:35383466
    reference_title: "Evaluating the Feasibility of Screening Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Diseases: The REST Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In NS-TADs, imaging tests, genetic counseling, and family screening yielded positive results in up to 1 out of 4 screened relatives, including those in the sporadic NS-TAD group.
    explanation: This directly supports imaging, genetic counseling, and family screening for nonsyndromic thoracic aortic disease.
treatments:
- name: Aortic surveillance imaging
  description: >-
    Serial aortic imaging surveillance identifies progressive dilation and
    informs timing of prophylactic repair before high-risk dissection or rupture.
  treatment_term:
    preferred_term: magnetic resonance imaging surveillance
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out.
    explanation: The HTAD pathway statement supports prompt aortic surveillance as outcome-improving management.
- name: Prophylactic aortic surgery
  description: Prophylactic repair is used when aortic size, growth rate, gene, family history, or other risk features indicate high dissection risk.
  treatment_term:
    preferred_term: aortic surgical procedure
    term:
      id: MAXO:0025001
      label: surgical procedure on cardiovascular system
  evidence:
  - reference: PMID:36460281
    reference_title: "HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out.
    explanation: The HTAD pathway statement supports prophylactic surgery as part of life-expectancy-improving management.
- name: Medical therapy to reduce aortic disease risk
  description: >-
    Medical therapy for heritable thoracic aortic disease commonly includes
    blood-pressure and wall-stress reduction with beta-blockers and/or
    angiotensin receptor blockers, tailored to gene and clinical context.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:36334952
    reference_title: "2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The "2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease" provides recommendations to guide clinicians in the diagnosis, genetic evaluation and family screening, medical therapy, endovascular and surgical treatment, and long-term surveillance of patients with aortic disease across its multiple clinical presentation subsets (ie, asymptomatic, stable symptomatic, and acute aortic syndromes).
    explanation: The ACC/AHA guideline abstract supports medical therapy as a core management domain for aortic disease.
- name: Genetic counseling and cascade family screening
  description: >-
    Genetic counseling and testing help distinguish at-risk relatives from
    relatives who can be reassured when a familial diagnosis is ruled out.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:35383466
    reference_title: "Evaluating the Feasibility of Screening Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Diseases: The REST Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We hypothesize that tailored genetic testing and imaging of first-degree and second-degree relatives of patients affected by NS-TADs may enable early diagnosis and allow appropriate surveillance or intervention.
    explanation: The REST study supports genetic testing and family imaging as early-detection strategies.
📚

References & Deep Research

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 30 citations 2026-05-05T11:54:04.952205

1. Disease Information

1.1 Concise overview / definition

  • HTAD definition (used clinically to encompass FTAAD): HTAD comprises disorders characterized by “aortic events, mainly represented by aneurysm or dissection,” usually involving the ascending aorta; disease may be non-syndromic (limited to aorta) or syndromic (extra-aortic features) (monda2023theroleof pages 1-3).
  • Familial/non-syndromic component: 20–25% of patients with non-syndromic HTAD exhibit a family history of aortic disease, requiring evaluation of first-degree relatives to distinguish familial from sporadic cases (monda2023theroleof pages 1-3, butnariu2024identificationofgenetic pages 2-4).

1.2 Key identifiers (available in retrieved evidence)

  • MONDO: MONDO:0019625 (familial thoracic aortic aneurysm and aortic dissection) (isselbacher20222022accahaguideline pages 23-24)
  • Related MONDO familial-thoracic-aortic-aneurysm entities observed in Open Targets snapshot:
  • MONDO:0012730 (aortic aneurysm, familial thoracic 6; ACTA2-related) (isselbacher20222022accahaguideline pages 23-24)
  • MONDO:0007568 (aortic aneurysm, familial thoracic 4; MYH11-related) (isselbacher20222022accahaguideline pages 23-24)
  • MONDO:0013418 (aortic aneurysm, familial thoracic 7; MYLK-related) (isselbacher20222022accahaguideline pages 23-24)

Not retrieved in the current document set: OMIM disease-number(s), Orphanet ID, ICD-10/ICD-11, and MeSH terms specific to “familial thoracic aortic aneurysm and dissection.” (These typically exist but were not present in the tool-retrieved excerpts; see limitations.)

1.3 Common synonyms / alternative names

  • Heritable thoracic aortic disease (HTAD) (monda2023theroleof pages 1-3, isselbacher20222022accahaguideline pages 23-24)
  • Genetically triggered thoracic aortic disease (used in clinical review context) (duarte2023geneticallytriggeredthoracic pages 1-3)
  • Non-syndromic heritable thoracic aortic aneurysm/dissection (ns-TAAD / ns-HTAD) (levy2024currentunderstandingof pages 1-3, levy2024currentunderstandingof pages 3-5)

1.4 Evidence type / provenance

  • Aggregated disease-level resources and expert consensus: 2022 ACC/AHA guideline (JACC; published Oct 2022; https://doi.org/10.1016/j.jacc.2022.08.004) (isselbacher20222022accahaguideline pages 23-24)
  • Peer-reviewed narrative reviews (2023–2024): clinical genetics/testing and phenotype summaries (monda2023theroleof pages 1-3, duarte2023geneticallytriggeredthoracic pages 1-3, spaziani2024hereditarythoracicaortic pages 1-2)
  • Human cohort sequencing evidence (2024): deep sequencing study in nonsyndromic adults (chen2024contributionsofgermline pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary cause: germline pathogenic variants affecting aortic wall integrity pathways, with additional contribution from non-genetic risk factors. - The 2022 ACC/AHA guideline identifies a pathogenic variant in genes predisposing to thoracic aortic disease as a “major risk factor” and recommends genetic testing for patients with aortic root/ascending aneurysm or dissection plus HTAD risk factors (Table 8/Figure 17 referenced) (isselbacher20222022accahaguideline pages 23-24).

2.2 Risk factors

Genetic risk factors (high-penetrance Mendelian genes)

The 2022 ACC/AHA guideline excerpt lists 11 genes “confirmed to confer a highly penetrant risk for TAD”: - FBN1, LOX, COL3A1, TGFBR1, TGFBR2, SMAD3, TGFB2, ACTA2, MYH11, MYLK, PRKG1 (isselbacher20222022accahaguideline pages 23-24).

Additional genes are highlighted in 2023–2024 reviews as part of syndromic HTAD (e.g., Loeys–Dietz spectrum genes SMAD2, TGFB3) (duarte2023geneticallytriggeredthoracic pages 1-3) and broader thoracic-aortic-disease genetics (e.g., NOTCH1, MFAP5) (butnariu2024identificationofgenetic pages 4-5).

Environmental/clinical risk factors

A 2024 review notes additional risk factors for thoracic aortic aneurysm including hypertension, smoking, hypercholesterolemia, male sex, older age (>65 years), and bicuspid aortic valve (butnariu2024identificationofgenetic pages 4-5).

2.3 Protective factors

  • Evidence gap: The ACC/AHA guideline notes growing interest in biomarkers and other predictors, but “biomarker expression has not been clearly associated with relevant clinical aortic events” and emphasizes limited randomized trial evidence for prevention strategies (isselbacher20222022accahaguideline pages 140-142).

2.4 Gene–environment interactions

  • Current understanding: The ACC/AHA guideline explicitly notes that “environmental factors and lifestyle habits may contribute to aortic aneurysm formation” in addition to genetic variants, and highlights medication exposures (e.g., fluoroquinolones) as potentially increasing risk, with mechanisms still uncertain (isselbacher20222022accahaguideline pages 140-142).

3. Phenotypes (clinical spectrum)

3.1 Core vascular phenotype (FTAAD / ns-HTAD)

  • Key features: thoracic aortic aneurysm (TAA), rapid aneurysm growth in some families, and acute type A dissection; familial expression is variable and dissections can occur at diameters <5.0 cm in some families (isselbacher20222022accahaguideline pages 23-24, levy2024currentunderstandingof pages 3-5).

HPO term suggestions (vascular): - Thoracic aortic aneurysm; Aortic aneurysm; Aortic dissection; Ascending aortic aneurysm; Aortic root dilatation; Rapid aneurysm progression.

3.2 Syndromic HTAD phenotype examples (useful for differential diagnosis)

Because “HTAD can be classified as non-syndromic… and syndromic when associated with extra-aortic features,” syndromic features are important to recognize when labeling a case as FTAAD vs syndromic HTAD (monda2023theroleof pages 1-3).

Marfan syndrome (FBN1): - Aortic root dilatation (Z-score ≥2), dissection; extra-aortic features include ectopia lentis, skeletal abnormalities, dural ectasia; mitral valve prolapse reported as >50% in one review summary; branch aneurysms reported in about one-quarter; descending/abdominal involvement in 10–20% (monda2023theroleof pages 3-4).

Loeys–Dietz syndrome (TGFBR1/2, SMAD2/3, TGFB2/3): - Arterial tortuosity, hypertelorism, bifid uvula/cleft palate; higher dissection risk; complications can occur at smaller diameters (duarte2023geneticallytriggeredthoracic pages 1-3, spaziani2024hereditarythoracicaortic pages 2-4).

Vascular Ehlers–Danlos (COL3A1): - Severe arterial fragility/rupture; reduced median life expectancy in one summary (~51 years) (monda2023theroleof pages 4-6).

HPO term suggestions (syndromic flags): - Ectopia lentis; Scoliosis; Pectus excavatum/carinatum; Joint hypermobility; Dural ectasia; Hypertelorism; Arterial tortuosity; Bifid uvula; Cleft palate; Easy bruising; Thin/translucent skin.

3.3 Age of onset, severity, progression

  • HTAD clinical course can range “from… early-onset and aggressive to… late-onset, indolent aortic disease,” and age at onset of acute syndromes can vary even among carriers of the same pathogenic mutation (monda2023theroleof pages 1-3).
  • Familial disease is typically autosomal dominant with decreased penetrance, “particularly in women,” and shows variable expression including varying age of onset and increased frequency of dissection at diameter <5.0 cm in some families (isselbacher20222022accahaguideline pages 23-24).

3.4 Quality-of-life (QoL)

  • The 2022 ACC/AHA guideline states baseline HRQOL assessment in aortic disease is limited; evidence for QoL in “heritable TAA” is “narrow or limited only to patients with Marfan syndrome,” and scattered data exist for psychological interventions (isselbacher20222022accahaguideline pages 140-142).

4. Genetic/Molecular Information

4.1 Causal genes (curation-ready)

The most guideline-central “highly penetrant” HTAD genes are the 11-gene set listed above (isselbacher20222022accahaguideline pages 23-24). A 2024 HTAD genetics table further lists syndromic and non-syndromic genes with OMIM gene entries and inheritance patterns, including examples such as FBN1 (AD), TGFBR2 (AD), TGFBR1 (AD), SMAD3 (AD), COL3A1 (AD), SLC2A10 (AR), MYH11 (AD), MYLK (AD), PRKG1 (AD), MFAP5 (AD), LOX (AD), ACTA2 (AD) (butnariu2024identificationofgenetic pages 2-4, butnariu2024identificationofgenetic pages 4-5).

4.2 Pathogenic variant types / classification

  • The 2022 guideline notes laboratories classify variants as “pathogenic, likely pathogenic, variant of uncertain/unknown significance, benign, and likely benign,” and that VUS should not be used to determine risk or guide management (isselbacher20222022accahaguideline pages 24-26).

4.3 Penetrance and expressivity

  • HTAD in families is “typically inherited in an autosomal dominant manner, with decreased penetrance, particularly in women,” and exhibits variable expression (isselbacher20222022accahaguideline pages 23-24).

4.4 Recent development: mosaicism and broadened genetic architecture (2024)

A 2024 single-center study of nonsyndromic adults (<60 years) using deep sequencing reported: - Likely genetic causes in 24% (21% germline; 3% somatic mosaic) and enrichment vs controls for germline variants (OR 2.44) and somatic mosaic variants (OR 4.71) (chen2024contributionsofgermline pages 1-2).

4.5 Modifier genes / epigenetics / chromosomal abnormalities

  • Not established from retrieved excerpts. Some reviews note genetic complexity and future directions, but specific modifier genes/epigenetic signatures were not extractable from the current tool-retrieved text set (isselbacher20222022accahaguideline pages 140-142).

5. Environmental Information

  • Traditional vascular risk factors (hypertension, smoking, hypercholesterolemia, age/sex) are summarized for TAA risk (butnariu2024identificationofgenetic pages 4-5).
  • The 2022 guideline highlights emerging evidence linking fluoroquinolone use to increased aneurysm/dissection risk, with unclear mechanisms (isselbacher20222022accahaguideline pages 140-142).

6. Mechanism / Pathophysiology

6.1 Core histopathology and tissue-level mechanism

A 2024 review describes thoracic aneurysm histopathology as: - “medial cystic necrosis with fragmentation and focal loss of elastic fibers… accompanied by a decrease in vascular smooth muscle cells (VSMCs) and an increase in proteoglycans” (butnariu2024identificationofgenetic pages 4-5).

6.2 Key molecular pathway axes

1) TGF-β signaling dysregulation (LDS spectrum; also overlaps broader HTAD): - Pathogenic mutations in TGFBR1/TGFBR2 are described as causing a “pathological shift towards increased extracellular matrix degradations,” contributing to aneurysm formation and susceptibility to rupture (monda2023theroleof pages 1-3).

2) Extracellular matrix (ECM) structural failure: - Genes such as FBN1, LOX, COL3A1, MFAP5 affect microfibrils/collagen/crosslinking and aortic wall integrity (isselbacher20222022accahaguideline pages 23-24, butnariu2024identificationofgenetic pages 4-5).

3) VSMC contractile apparatus / elastin–contractile unit disruption: - Mutations in ACTA2, MYH11, MYLK, PRKG1 are cited as impacting VSMC adhesion/contraction and the “elastin contractile unit,” weakening the aortic wall (butnariu2024identificationofgenetic pages 4-5).

6.3 Upstream→downstream causal chain (knowledge-base ready)

  • Trigger: germline pathogenic variant (or mosaic) affecting ECM/TGF-β/VSMC contractile genes (isselbacher20222022accahaguideline pages 23-24, chen2024contributionsofgermline pages 1-2)
  • Cellular/tissue changes: VSMC dysfunction/loss, elastin fragmentation, proteoglycan accumulation, ECM degradation (butnariu2024identificationofgenetic pages 4-5)
  • Organ-level phenotype: progressive thoracic aortic dilatation; risk of dissection/rupture, sometimes at smaller diameters than expected (butnariu2024identificationofgenetic pages 2-4, levy2024currentunderstandingof pages 3-5)

6.4 Ontology suggestions

  • GO Biological Process (suggestions): extracellular matrix organization; elastic fiber formation; smooth muscle contraction; transforming growth factor beta receptor signaling pathway.
  • CL cell types (suggestions): vascular smooth muscle cell.
  • UBERON anatomy (suggestions): thoracic aorta; ascending aorta; aortic root.

7. Anatomical Structures Affected

  • Primary: aortic root and ascending aorta are emphasized in guideline testing indications and HTAD surveillance context (isselbacher20222022accahaguideline pages 23-24).
  • Additional vascular beds: reviews note peripheral/intracranial aneurysms as part of family history/risk assessment and gene-specific associations (e.g., TGFBR2 and other arterial aneurysms) (isselbacher20222022accahaguideline pages 23-24, isselbacher20222022accahaguideline pages 24-26).

UBERON suggestions: thoracic aorta; ascending aorta; aortic root; intracranial artery.

8. Temporal Development

  • Onset pattern: asymptomatic dilation often discovered incidentally; acute dissection can be first presentation and may be fatal (duarte2023geneticallytriggeredthoracic pages 1-3).
  • Progression: progressive dilation determines prognosis (monda2023theroleof pages 1-3).

9. Inheritance and Population

9.1 Epidemiology / burden

  • Incidence: population study summarized in 2023 review: thoracic aortic aneurysm incidence 10.4 per 100,000 person-years (duarte2023geneticallytriggeredthoracic pages 1-3).
  • Sex: same review notes 51% of thoracic aneurysm patients were women, recognized at older ages than men (duarte2023geneticallytriggeredthoracic pages 1-3).
  • Mortality: thoracic dissection is highly lethal; a 2024 review summarizes pre-hospital mortality “up to 61%” and ~50% mortality within 30 days; emergent repair ~20% vs elective ~3% (levy2024currentunderstandingof pages 1-3).
  • US deaths/year: nonsyndromic TAA paper notes ~“nearly 10,000 deaths in the United States per year” (chen2024contributionsofgermline pages 1-2).

9.2 Familiality and inheritance

  • Among TAD patients without Marfan/LDS features, “13% to 20%… have similarly affected first-degree relatives,” and inheritance is “typically… autosomal dominant… decreased penetrance” (isselbacher20222022accahaguideline pages 23-24).
  • Reviews similarly estimate ~20–25% of non-syndromic HTAD cases have positive family history (monda2023theroleof pages 1-3, butnariu2024identificationofgenetic pages 2-4).

10. Diagnostics

10.1 Genetic testing (who to test; what test)

Guideline-centered clinical workflow (ACC/AHA 2022): 1) Obtain multigenerational family history of TAD, sudden deaths, and peripheral/intracranial aneurysms (isselbacher20222022accahaguideline pages 23-24). 2) For patients with aortic root/ascending aneurysm or dissection plus HTAD risk factors (Table 8/Figure 17 referenced), perform genetic testing for pathogenic/likely pathogenic variants (isselbacher20222022accahaguideline pages 23-24). 3) Use multigene panel testing as “most cost-effective and clinically useful” approach; manage and cascade-test based on pathogenic/likely pathogenic variants only (isselbacher20222022accahaguideline pages 23-24). 4) VUS should not guide family risk stratification (isselbacher20222022accahaguideline pages 24-26).

Imaging modalities for relatives: - Aortic imaging with TTE if adequate visualization; otherwise CT or MRI (isselbacher20222022accahaguideline pages 23-24). - If at-risk relatives have negative initial imaging, suggested repeat imaging is ~5 years in younger relatives and ~10 years in older relatives (isselbacher20222022accahaguideline pages 24-26).

NGS modalities in current practice: gene panels, WES, WGS increasingly used for heterogeneous HTAD etiologies (butnariu2024identificationofgenetic pages 2-4).

10.2 Differential diagnosis considerations

  • Distinguish non-syndromic familial disease from syndromic HTAD (Marfan, LDS, vEDS) based on extra-aortic features and gene findings (monda2023theroleof pages 1-3, duarte2023geneticallytriggeredthoracic pages 1-3).

11. Outcome / Prognosis

  • Prognosis in HTAD is determined by progressive aortic dilation leading to acute aortic events (dissection/rupture), and varies by underlying mutation (monda2023theroleof pages 1-3).
  • High lethality of dissection and large differences between emergent vs elective operative mortality support aggressive prevention and surveillance strategies (levy2024currentunderstandingof pages 1-3).

12. Treatment

12.1 Surgical thresholds (available in retrieved excerpts)

  • A 2024 review summarizing the 2022 guideline indicates prophylactic repair thresholds of ≥5.0 cm for asymptomatic low-risk individuals and ≥4.5 cm for high-risk individuals (levy2024currentunderstandingof pages 9-10).
  • A 2023 review provides Marfan-specific thresholds: aortic sinus ≥50 mm or ≥45 mm with risk factors (monda2023theroleof pages 4-6).

Important limitation: The gene-specific thresholds table(s) referenced in the guideline (Table 8/Figure 17) could not be retrieved from the available excerpts or via image tools (isselbacher20222022accahaguideline pages 23-24).

12.2 Medical therapy / supportive care

  • The ACC/AHA guideline emphasizes individualized exercise recommendations based on pathology, aortic diameter, growth rate, family history, and other high-risk features (isselbacher20222022accahaguideline pages 139-140).
  • Post-aortic surgery cardiac rehabilitation can be useful; one recommendation is 3–5 METs, avoiding strenuous lifting/exhaustion (isselbacher20222022accahaguideline pages 139-140).

12.3 Pharmacotherapy evidence example (vEDS)

  • For vascular Ehlers–Danlos syndrome, a review summary reports trial evidence that celiprolol reduced arterial events (20% vs 50%) (monda2023theroleof pages 4-6).

12.4 Trials / experimental directions (ClinicalTrials.gov signals)

Interventional trials identified by search included, for example: - NCT05401500 (Familial Aortopathies and Cellular Exploration) (trial retrieved in tool run) - NCT05472519 (Immunopathology of Loeys-Dietz Syndrome) (trial retrieved) - NCT05809323 (Marfan Syndrome Moderate Exercise Trial II) (trial retrieved) - NCT07495267 (Nutritional Ketosis Marfan; not yet recruiting) (trial retrieved)

(Trial text chunks were retrieved by the tool, but detailed endpoints/results were not extracted in the present evidence set.)

12.5 MAXO suggestions (treatments/actions)

  • Prophylactic aortic surgery; Aortic imaging surveillance; Genetic testing; Genetic counseling; Cascade screening; Exercise counseling / cardiac rehabilitation.

13. Prevention

  • Secondary prevention: family-based genetic testing and cascade imaging is strongly recommended by ACC/AHA 2022 (isselbacher20222022accahaguideline pages 23-24).
  • Lifestyle/behavioral: individualized exercise counseling; avoid maximal exertion/strenuous lifting; cardiac rehab post-surgery (isselbacher20222022accahaguideline pages 139-140).

14. Other Species / Natural Disease

  • Not available from retrieved evidence.

15. Model Organisms

  • The ACC/AHA guideline cites mouse Marfan studies where mild/moderate (not strenuous) aerobic exercise protected the aortic wall, with reduced elastin fragmentation and reduced MMP2/9 expression vs sedentary controls (isselbacher20222022accahaguideline pages 139-140).

Recent developments and real-world implementations (prioritizing 2023–2024)

1) Expanded genetic architecture in nonsyndromic adults (2024): deep (>500×) sequencing identifies germline and mosaic contributions, supporting broader genetic evaluation beyond classic syndromic testing paradigms (chen2024contributionsofgermline pages 1-2). 2) Point-of-care decision support (2023–2024): a REDCap-based “Genomic Medicine Guidance” tool integrates ClinVar/ClinGen and guideline recommendations and curates thousands of pathogenic variants (reported 2,286 unique pathogenic mutations across 13 genes) to deliver gene-informed surveillance/therapy guidance in clinical workflows (patil2024developmentandassessment pages 1-5).

Direct abstract quotes (for evidence anchoring): - “Heritable thoracic aortic disease (HTAD) is a term used to define a large group of disorders characterized by the occurrence of aortic events, mainly represented by aneurysm or dissection.” (Monda 2023; Diagnostics; published 17 Feb 2023; https://doi.org/10.3390/diagnostics13040772) (monda2023theroleof pages 1-3) - “Likely genetic causes were present in 24% with nonsyndromic TAA, of which 21% arose from germline variants and 3% from somatic mosaic alleles.” (Chen 2024; JAHA; published 2024; https://doi.org/10.1161/JAHA.123.033232) (chen2024contributionsofgermline pages 1-2) - “Up to 25% of patients with thoracic aortic disease have an underlying Mendelian pathogenic variant.” (Duarte 2023; Methodist DeBakey Cardiovasc J; published 2023; https://doi.org/10.14797/mdcvj.1218) (duarte2023geneticallytriggeredthoracic pages 1-3)

Curator-oriented summary table

Item type Identifier/Gene Notes Key statistic (if any) Primary supporting source (short cite: first author year + PMID if known)
Disease concept / ontology MONDO:0019625 Familial thoracic aortic aneurysm and aortic dissection; Open Targets evidence links this MONDO concept to core HTAD genes 12 associated targets in Open Targets snapshot Open Targets/MONDO (isselbacher20222022accahaguideline pages 23-24)
Disease concept / ontology MONDO:0012730 Aortic aneurysm, familial thoracic 6; corresponds to ACTA2-related familial thoracic aortic aneurysm entity — Open Targets/MONDO (isselbacher20222022accahaguideline pages 23-24)
Disease concept / ontology MONDO:0007568 Aortic aneurysm, familial thoracic 4; corresponds to MYH11-related familial thoracic aortic aneurysm entity — Open Targets/MONDO (isselbacher20222022accahaguideline pages 23-24)
Disease concept / ontology MONDO:0013418 Aortic aneurysm, familial thoracic 7; corresponds to MYLK-related familial thoracic aortic aneurysm entity — Open Targets/MONDO (isselbacher20222022accahaguideline pages 23-24)
Causal gene (ECM / connective tissue) FBN1 High-penetrance HTAD gene in 2022 ACC/AHA panel; classic Marfan syndrome gene, but some variants can present as isolated thoracic aortic disease Marfan prevalence ~1 in 5,000 to 1 in 10,000; >95% of MFS cases due to FBN1 in review summaries Isselbacher 2022; Monda 2023 (isselbacher20222022accahaguideline pages 23-24, monda2023theroleof pages 3-4)
Causal gene (ECM / connective tissue) COL3A1 High-penetrance HTAD gene; vascular Ehlers-Danlos syndrome with arterial fragility/rupture phenotype vEDS represents <5% of EDS in one 2024 review Isselbacher 2022; Duarte 2023; Spaziani 2024 (isselbacher20222022accahaguideline pages 23-24, duarte2023geneticallytriggeredthoracic pages 1-3, spaziani2024hereditarythoracicaortic pages 2-4)
Causal gene (ECM / connective tissue) LOX High-penetrance HTAD gene; lysyl oxidase, implicated in nonsyndromic familial thoracic aortic aneurysm — Isselbacher 2022; Duarte 2023 (isselbacher20222022accahaguideline pages 23-24, duarte2023geneticallytriggeredthoracic pages 1-3)
Causal gene (ECM / connective tissue) MFAP5 Listed in 2024 review table as AD AAT9; microfibril-associated protein 5, associated with TAA — Butnariu 2024 (butnariu2024identificationofgenetic pages 4-5)
Causal gene (TGF-β pathway) TGFBR1 High-penetrance HTAD gene; Loeys-Dietz syndrome; childhood burden may justify surveillance in first decade for pathogenic variants LDS complications can occur at smaller diameters; pediatric onset described Isselbacher 2022; Monda 2023; Spaziani 2024 (isselbacher20222022accahaguideline pages 23-24, monda2023theroleof pages 1-3, spaziani2024hereditarythoracicaortic pages 1-2)
Causal gene (TGF-β pathway) TGFBR2 High-penetrance HTAD gene; Loeys-Dietz syndrome; associated with intracranial/other arterial aneurysm risk in guideline summary Acute complications may occur at smaller diameters and with faster growth Isselbacher 2022; Spaziani 2024 (isselbacher20222022accahaguideline pages 24-26, spaziani2024hereditarythoracicaortic pages 1-2)
Causal gene (TGF-β pathway) SMAD3 High-penetrance HTAD gene; Loeys-Dietz spectrum / aneurysm-osteoarthritis phenotype — Isselbacher 2022; Duarte 2023 (isselbacher20222022accahaguideline pages 23-24, duarte2023geneticallytriggeredthoracic pages 1-3)
Causal gene (TGF-β pathway) TGFB2 High-penetrance HTAD gene in ACC/AHA panel ~6–8% of nonsyndromic HTAD families for syndromic-gene group noted in guideline summary Isselbacher 2022 (isselbacher20222022accahaguideline pages 24-26)
Causal gene (TGF-β pathway) SMAD2 / TGFB3 Included in 2023 review table for Loeys-Dietz syndrome spectrum; not part of the 11-gene highly penetrant ACC/AHA core list cited in excerpt — Duarte 2023 (duarte2023geneticallytriggeredthoracic pages 1-3)
Causal gene (VSMC contractile apparatus) ACTA2 High-penetrance HTAD gene; most frequently mutated nonsyndromic HTAD gene in 2023 review; associated with livedo reticularis, iris flocculi, PDA/BAV in review table Missense ACTA2 variants reported in ~14% of inherited ascending TAD; ACTA2-linked familial entity mapped to MONDO:0012730 Duarte 2023; Butnariu 2024; Open Targets/MONDO (duarte2023geneticallytriggeredthoracic pages 3-4, butnariu2024identificationofgenetic pages 4-5, isselbacher20222022accahaguideline pages 23-24)
Causal gene (VSMC contractile apparatus) MYH11 High-penetrance HTAD gene; associated with familial thoracic aneurysm/dissection and PDA Familial thoracic aneurysm 4 entity mapped to MONDO:0007568 Isselbacher 2022; Butnariu 2024; Open Targets/MONDO (isselbacher20222022accahaguideline pages 23-24, butnariu2024identificationofgenetic pages 4-5)
Causal gene (VSMC contractile apparatus) MYLK High-penetrance HTAD gene; nonsyndromic familial TAAD; can dissect at relatively small diameters in prior literature/guideline context Familial thoracic aneurysm 7 entity mapped to MONDO:0013418 Isselbacher 2022; Butnariu 2024; Open Targets/MONDO (isselbacher20222022accahaguideline pages 23-24, butnariu2024identificationofgenetic pages 4-5)
Causal gene (VSMC contractile apparatus) PRKG1 High-penetrance HTAD gene; nonsyndromic familial TAAD/AD — Isselbacher 2022; Duarte 2023 (isselbacher20222022accahaguideline pages 23-24, duarte2023geneticallytriggeredthoracic pages 1-3)
Epidemiology / burden Thoracic aortic aneurysm incidence Population incidence summarized in 2023 review 10.4 per 100,000 person-years Duarte 2023 (duarte2023geneticallytriggeredthoracic pages 1-3)
Epidemiology / burden Female share in population study Women were older at recognition than men in cited population study 51% of thoracic aortic aneurysm patients were women Duarte 2023 (duarte2023geneticallytriggeredthoracic pages 1-3)
Epidemiology / familiality Non-syndromic HTAD with family history Consistent estimate across 2023–2024 reviews ~20–25% Monda 2023; Butnariu 2024 (monda2023theroleof pages 1-3, butnariu2024identificationofgenetic pages 2-4)
Epidemiology / familiality TAD patients without Marfan/LDS features having affected first-degree relatives Guideline estimate supporting family screening 13–20% Isselbacher 2022 (isselbacher20222022accahaguideline pages 23-24)
Epidemiology / inheritance Familial aggregation in TAAD cohorts Familial pattern common; many pedigrees AD with variable expression ~21% familial; ~77% of familial cases autosomal dominant Levy 2024 (levy2024currentunderstandingof pages 3-5)
Epidemiology / clinical severity Dissections below size thresholds Diameter alone is an imperfect predictor of acute events 60% of dissections <5.5 cm; 40% <5.0 cm Levy 2024 (levy2024currentunderstandingof pages 3-5)
Epidemiology / growth Familial aneurysm growth rate Familial TAAD may enlarge faster than sporadic disease ~0.21–0.22 cm/year Levy 2024 (levy2024currentunderstandingof pages 3-5)
Epidemiology / mortality Pre-hospital and early mortality of thoracic dissection High lethality emphasizes preventive repair Pre-hospital mortality up to 61%; ~50% die within 30 days; emergent repair mortality ~20% vs elective ~3% Levy 2024 (levy2024currentunderstandingof pages 1-3)
Epidemiology / genetics yield Deep sequencing in nonsyndromic adults <60 years 2024 single-center study showing substantial germline and mosaic contribution Likely genetic cause in 24% overall: 21% germline, 3% somatic mosaic; germline OR 2.44, mosaic OR 4.71 Chen 2024 (chen2024contributionsofgermline pages 1-2)
Epidemiology / genetics yield Most frequently mutated genes in nonsyndromic adult TAA cohort 2024 targeted sequencing study Top 3 genes: FLNA, NOTCH3, FBN1 Chen 2024 (chen2024contributionsofgermline pages 1-2)
Epidemiology / clinical app Point-of-care genomics implementation 2024 app operationalized guideline recommendations across common HTAD genes 13 most frequently mutated TAD genes; 2,286 unique pathogenic mutations curated Patil 2024 (patil2024developmentandassessment pages 1-5)

Table: This table summarizes the core disease concept identifiers, major causal genes grouped by biological pathway, and key recent epidemiologic statistics for familial/heritable thoracic aortic aneurysm and dissection. It is designed as a compact curation aid for building a disease knowledge base entry.

Limitations of this tool-based report (important for knowledge-base curation)

1) Ontology identifiers: beyond MONDO, this evidence set did not contain explicit OMIM disease IDs, Orphanet IDs, ICD-10/ICD-11 codes, or MeSH terms for the specific “familial thoracic aortic aneurysm and dissection” concept. 2) Gene-specific surgical thresholds: the ACC/AHA guideline excerpt references Table 8/Figure 17 for HTAD risk factors and gene-informed management; however, the tool could not retrieve the relevant images/tables, preventing extraction of the complete gene-specific threshold matrix. 3) Primary mechanistic PMIDs: mechanistic statements are supported by recent reviews/guidelines in this evidence set, but the underlying primary experimental PMIDs were not consistently present in the retrieved chunks for direct citation.

Key source URLs (publication dates as available in evidence)

  • Isselbacher et al. 2022 ACC/AHA Aortic Disease Guideline (JACC; Oct 2022): https://doi.org/10.1016/j.jacc.2022.08.004 (isselbacher20222022accahaguideline pages 23-24)
  • Monda et al. 2023-02-17 (Diagnostics): https://doi.org/10.3390/diagnostics13040772 (monda2023theroleof pages 1-3)
  • Duarte et al. 2023 (Methodist DeBakey Cardiovasc J): https://doi.org/10.14797/mdcvj.1218 (duarte2023geneticallytriggeredthoracic pages 1-3)
  • Spaziani et al. 2024-01 (Diagnostics): https://doi.org/10.3390/diagnostics14010112 (spaziani2024hereditarythoracicaortic pages 1-2)
  • Levy et al. 2024-01 (Vessel Plus): https://doi.org/10.20517/2574-1209.2023.55 (levy2024currentunderstandingof pages 1-3)
  • Chen et al. 2024-07 (JAHA): https://doi.org/10.1161/JAHA.123.033232 (chen2024contributionsofgermline pages 1-2)
  • Butnariu et al. 2024-10 (Int J Mol Sci): https://doi.org/10.3390/ijms252011173 (butnariu2024identificationofgenetic pages 2-4)
  • Patil et al. 2023-12-28 (JMIR preprint): https://doi.org/10.2196/preprints.55903 (patil2024developmentandassessment pages 1-5)

References

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  11. (monda2023theroleof pages 3-4): Emanuele Monda, Michele Lioncino, Federica Verrillo, Marta Rubino, Martina Caiazza, Alfredo Mauriello, Natale Guarnaccia, Adelaide Fusco, Annapaola Cirillo, Simona Covino, Ippolita Altobelli, Gaetano Diana, Giuseppe Palmiero, Francesca Dongiglio, Francesco Natale, Arturo Cesaro, Eduardo Bossone, Maria Giovanna Russo, Paolo Calabrò, and Giuseppe Limongelli. The role of genetic testing in patients with heritable thoracic aortic diseases. Diagnostics, 13:772, Feb 2023. URL: https://doi.org/10.3390/diagnostics13040772, doi:10.3390/diagnostics13040772. This article has 19 citations.

  12. (spaziani2024hereditarythoracicaortic pages 2-4): Gaia Spaziani, Francesca Chiara Surace, Francesca Girolami, Francesco Bianco, Valentina Bucciarelli, Francesca Bonanni, Elena Bennati, Luigi Arcieri, and Silvia Favilli. Hereditary thoracic aortic diseases. Diagnostics, 14:112, Jan 2024. URL: https://doi.org/10.3390/diagnostics14010112, doi:10.3390/diagnostics14010112. This article has 2 citations.

  13. (monda2023theroleof pages 4-6): Emanuele Monda, Michele Lioncino, Federica Verrillo, Marta Rubino, Martina Caiazza, Alfredo Mauriello, Natale Guarnaccia, Adelaide Fusco, Annapaola Cirillo, Simona Covino, Ippolita Altobelli, Gaetano Diana, Giuseppe Palmiero, Francesca Dongiglio, Francesco Natale, Arturo Cesaro, Eduardo Bossone, Maria Giovanna Russo, Paolo Calabrò, and Giuseppe Limongelli. The role of genetic testing in patients with heritable thoracic aortic diseases. Diagnostics, 13:772, Feb 2023. URL: https://doi.org/10.3390/diagnostics13040772, doi:10.3390/diagnostics13040772. This article has 19 citations.

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  15. (levy2024currentunderstandingof pages 9-10): Lauren E. Levy, Megan Zak, and Jason P. Glotzbach. Current understanding of the genetics of thoracic aortic disease. Vessel Plus, Jan 2024. URL: https://doi.org/10.20517/2574-1209.2023.55, doi:10.20517/2574-1209.2023.55. This article has 4 citations.

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  17. (patil2024developmentandassessment pages 1-5): Rohan Patil, Fatima Ashraf, Samer Abu Dayeh, and Siddharth K Prakash. Development and assessment of a point-of-care application (genomic medicine guidance) for heritable thoracic aortic disease. JMIRx Med, 5:e55903-e55903, Oct 2024. URL: https://doi.org/10.2196/55903, doi:10.2196/55903. This article has 5 citations.

  18. (duarte2023geneticallytriggeredthoracic pages 3-4): Valeria E. Duarte, Raman Yousefzai, and Michael N. Singh. Genetically triggered thoracic aortic disease: who should be tested? Methodist DeBakey Cardiovascular Journal, 19:24-28, Mar 2023. URL: https://doi.org/10.14797/mdcvj.1218, doi:10.14797/mdcvj.1218. This article has 18 citations.