Renard M, Francis C, Ghosh R, Scott AF, Witmer PD, Adès LC, Andelfinger GU, Arnaud P, Boileau C, Callewaert BL, Guo D, Hanna N, Lindsay ME, Morisaki H, Morisaki T, Pachter N, Robert L, Van Laer L, Dietz HC, Loeys BL, Milewicz DM, De Backer J. Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection. J Am Coll Cardiol. 2018;72(6):605-615. PMID 30071989¶
One-paragraph summary¶
Thoracic aortic aneurysms progressively enlarge and predispose to acute dissection, and up to 25% of individuals with thoracic aortic disease harbour an underlying Mendelian pathogenic variant — so which genes to test is a consequential question that had been answered by accretion rather than by assessment. This study applied the Clinical Genome Resource (ClinGen) semiquantitative framework to 53 candidate genes and their presumed relationships to heritable thoracic aortic aneurysm and dissection (HTAAD). Every gene–disease assertion was evaluated by a pre-defined curator–expert pair and then discussed with an expert panel. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable — that is, if identifying them should trigger routine aortic surveillance, intervention, and family cascade screening. The result was a five-tier classification plus a second axis stratifying genes by severity of associated aortic disease and risk of progression.
Key findings¶
Strength-of-association classification across 53 candidate genes:
| Tier | Genes |
|---|---|
| Definitive | 9 |
| Strong | 2 |
| Moderate | 4 |
| Limited | 15 |
| No reported evidence | 23 |
- 11 genes (definitive + strong) were designated "HTAAD genes" — category A, the actionable set.
- A second axis stratified by severity and progression risk: 8 genes category B (unlikely to be progressive) and 4 genes category C (low risk).
- The remainder were recent genes with uncertain classification or genes with no evidence of HTAAD association.
- Conclusion: the ClinGen framework is usable for semiquantitative assessment of HTAAD gene–disease relationships, and the resulting categories should inform clinical laboratories in developing panels, interpreting results, and communicating clinical implications.
Per-gene assignments (verified from the full text, retrieved 2026-08-28):
| Category | Genes |
|---|---|
| A — "HTAAD genes" (definitive) | ACTA2, COL3A1, FBN1, MYH11, MYLK, SMAD3, TGFB2, TGFBR1, TGFBR2 |
| A — "HTAAD genes" (strong) | LOX, PRKG1 |
| B — aortic enlargement, no evidence of progression to dissection | EFEMP2 (moderate); ELN, FBN2, FLNA, NOTCH1, SLC2A10, SMAD4, SKI (limited) |
| C — low-risk "risk alleles"; disease diagnosed on non-vascular (renal/metabolic) features | COL4A5, PKD1, PKD2, CBS |
| Uncertain (recent) — insufficient publications to classify | BGN, FOXE3, HCN4, MAT2A, MFAP5, SMAD2, TGFB3 |
| D — no clinical evidence | 23 genes, including B3GAT3 (downgraded from limited by the expert panel: no published case with an isolated aortic aneurysmal phenotype) |
Process details worth keeping: category A is subdivided A1/A2 by whether variants primarily cause isolated TAAD (A1) or often syndromic presentations (A2) — COL3A1 sits in A1 because vEDS patients can present with acute aortic dissection despite low (<5%) aortic penetrance. Scores of 1–7 = limited, 8–12 = moderate, 13–18 = strong; "definitive" requires strong plus replication (≥2 convincing publications over ≥3 years). Expert review changed the biocurator classification for only 5 of 53 genes (90.5% concordance): MYLK moved moderate → strong (and, being replicated since 2010, stands in the definitive nine); B3GAT3 moved limited → no evidence; MAT2A, FOXE3 and HCN4 moved moderate → limited.
Limitations¶
- Curation reflects the evidence available in 2018; genes classified "limited" or "no reported evidence" may have accrued evidence since, and the classification requires periodic re-curation to stay valid.
- The ClinGen framework is semiquantitative and expert-adjudicated; it formalises judgement rather than eliminating it, and different expert panels could reach different tier assignments at the margins.
- Restricting "causative for HTAAD" to genes associated with isolated thoracic aortic disease is a defensible but consequential design choice: it will down-weight genes whose aortic disease is real but always syndromic.
- The actionability criterion embeds current management practice into a genetic classification; if thresholds or surveillance strategies change, the category boundaries move with them.
- The classification says nothing about the pathogenicity of any individual variant within a valid gene — the two are routinely conflated in practice.
Why it matters¶
This paper drew the line between "a gene reported in association with aortic disease" and "a gene whose result should change what you do to a patient." That distinction had become urgent: commercial panels were expanding faster than evidence, and 38 of 53 assessed genes turned out to have limited or no evidence — meaning the majority of candidate content on a maximally inclusive panel was not clinically interpretable. Because a positive HTAAD result can lower a surgical threshold and commit an entire family to cascade screening, a false-positive gene assignment is not a benign inefficiency. The paper is therefore the reference point for panel design, for how variant reports should be worded, and for the standing warning that a pathogenic-looking variant in a limited-evidence gene is not an actionable finding. It also quantified the field's headline number — up to 25% of thoracic aortic disease being Mendelian — in a source designed to be citable.
Cited by wiki pages¶
- genetics of TAA