In 3746 patients in the Yale Aortic Institute Database, thoracic aortic aneurysm and dissection (TAAD) showed strongly familial and genetically mediated patterns, even in non-syndromic cases, supporting vigorous family investigation and application of whole exome sequencing.
Key Findings
Results
Syndromic TAAD patients had a much higher rate of 'proven' family history and a much lower rate of no family history than non-syndromic patients.
Family history and connective tissue status could be determined for 3113 of 3746 patients: 109 (3.5%) syndromic and 3004 (96.5%) non-syndromic.
'Proven' family history: 42.2% in syndromic vs. 19.5% in non-syndromic; 'none': 16.5% vs. 48.1% (p < 0.001).
Methodology: retrospective review of charts and electronic medical records; 'proven' meant a relative's aneurysm or dissection confirmed by imaging, surgery, or postmortem examination.
Results
Family history distribution in the syndromic group: 42.2% proven, 5.5% likely, 3.7% possible, 16.5% none, 32.1% unknown.
Of 109 syndromic patients, 46 had 'proven', 6 'likely', 4 'possible', and 18 'none' family history.
For 35 patients (32.1%) family history was unknown.
'Likely' was defined as sudden death in a relative at age ≤50 (males) or ≤60 (females); 'possible' as sudden death at any age.
Results
Among non-syndromic TAAD patients, roughly half had no family history, while about 31% had proven, likely, or possible family history.
Syndromic patients presented at a significantly younger age than non-syndromic or sporadic patients.
Mean age at presentation was 41.2 years in syndromic vs. 63.3 (non-syndromic familial) or 63.6 (sporadic) years (p < 0.001).
Results
Age at presentation did not differ between familial non-syndromic and sporadic TAAD patients.
Familial non-syndromic (proven, likely, possible) mean age 63.3 vs. sporadic 63.6 years (p = 0.64).
Results
Whole exome sequencing in 631 patients identified 170 disease-causing or suspicious variants in 141 patients (22.3%).
WES was performed in 25 syndromic, 552 non-syndromic, and 54 patients of unknown status.
Variants: 13 pathogenic, 16 likely pathogenic, 7 not classified, 134 variants of uncertain significance (VUS).
Variant carriers: 12 syndromic, 103 non-syndromic, and 26 of unknown connective tissue status.
Results
Patients with a family history were more likely to have a variant found on WES than patients without a family history.
Seventy (49.6%) of the 141 patients with variants had a 'proven' family history.
Familial TAAD patients with a variant vs. patients without family history with a variant: 70 vs. 26 (p < 0.001).
Conclusions
The authors conclude that TAAD is strongly familial and genetically mediated, including in non-syndromic cases, supporting family screening and WES.
They state that recognizing familial patterns encourages intensive investigation of family members to detect silent TAA disease.
They advocate vigorous family investigation when a new TAA patient is diagnosed and vigorous application of WES for these families.
What This Means
This study reviewed records of 3746 patients treated for thoracic aortic aneurysm or dissection (a bulging or tearing of the body's main artery in the chest) at the Yale Aortic Institute. The researchers looked at whether patients had relatives with similar problems and whether they had syndromes that affect other parts of the body, such as connective tissue disorders. Patients with such syndromes were much more likely to have a confirmed family history (42% vs. 20%) and were diagnosed much younger (about 41 vs. 63 years).
Even among patients without a syndrome, about 31% had a proven, likely, or possible family history, and about half had none. Those with a family history were diagnosed at about the same age as those without (about 63 years). Genetic testing of the protein-coding portion of the genome (whole exome sequencing) in 631 patients found suspicious or disease-causing variants in 22% of them. Variants were found more often in patients with a family history, and about half of those with variants had a confirmed family history.
This research suggests that thoracic aortic disease often runs in families, even without obvious syndromic features. The authors argue that this supports checking relatives of newly diagnosed patients, since silent aneurysms could be found, and using genetic sequencing in affected families. Many variants found were of uncertain significance, and this was a retrospective single-center study, so the findings should be interpreted with that in mind.
Harling L, Zafar M, Changez M, Papanikolaou D, Celik N, Grewal N, et al.. (2026). Genetic Patterns in Familial Thoracic Aortic Aneurysm Disease.. Genes. https://doi.org/10.3390/genes17101205