Genetic Patterns in Familial Thoracic Aortic Aneurysm Disease

Background and Aims: We examined familial patterns and phenotypes of thoracic aortic aneurysms and dissections (TAAD) in the 3746 patients currently populating our Yale Aortic Institute Database. Methods: Patient charts and electronic medical records were retrospectively reviewed for the entire cohort. TAAD disease was categorized as syndromic (with extra-aortic manifestations) or non-syndromic (without) for each patient. Family patterns and whole exome sequencing results were assessed. Family history was considered ‘proven’ when a patient’s relative(s) had an arterial aneurysm or dissection confirmed by an imaging study, surgical treatment, or postmortem examination. Family history was termed ‘likely’ when at least one relative suffered sudden death at ages ≤50 for males and ≤60 for females, and ‘possible’ with a history of sudden death at any age. Results: Of the 3746 patients in the database, family history of aneurysm or dissection and connective tissue status was able to be determined for 3113 patients, divided into 109 (3.5%) syndromic and 3004 (96.5%) non-syndromic TAAD patients. Findings were as follows: (1) In the syndromic group, 46 (42.2%) patients had a ‘proven’ family history, 6 (5.5%) had a ‘likely’ family history, 4 (3.7%) had a ‘possible’ family history, and 18 (16.5%) had ‘none’. For 35 patients (32.1%) their family history was unknown. (2) In the non-syndromic group, 587 (19.5%) patients had ‘proven’ family history, 147 (4.9%) had ‘likely’ family history, 210 (7.0%) had ‘possible’ family history and 1444 (48.1%) had no family history, thus representing sporadic TAAD. A total of 616 (20.5%) had an unknown family history. (3) There was a significant difference between the rate for ‘proven’ and ‘none’ family history between the syndromic and non-syndromic groups (42.2% vs. 19.5% and 16.5% vs. 48.1%, respectively; p < 0.001). (4) Syndromic patients presented at a significantly younger age than non-syndromic or sporadic patients (41.2 vs. 63.3 or 63.6; p < 0.001). (5) There was no significant difference in age of presentation between familial non-syndromic (patients with ‘proven’, ‘likely’, and ‘possible’ family history) and sporadic patients (63.3 vs. 63.6; p = 0.64). (6) Overall, of the 3746 patients in the database, 631 patients (25 syndromic, 552 non-syndromic, and 54 with unknown status) underwent Whole Exome Sequencing (WES). Sequencing revealed 170 disease-causing or suspicious variants [13 pathogenic, 16 likely pathogenic, 7 not classified, and 134 Variants of Uncertain Significance (VUS)] found in the exomes of 141 (22.3%) patients (12 syndromic, 103 non-syndromic TAAD patients plus a remaining 26 of unknown connective tissue status). Seventy (49.6%) of these patients had a ‘proven’ family history. (7) Familial TAAD patients were more likely to find a variant in their WES result than patients without a family history (70 vs. 26; p < 0.001). Recognition of these strong familial patterns, even in non-syndromic cases, encourages intensive investigation of family in order to save lives by detecting silent TAA disease. Conclusions: Our large-scale, clinical and sequencing-based study clearly demonstrates the strongly familial and genetically mediated nature of thoracic aortic disease. We vividly demonstrate and characterize this familial nature of TAAD, both clinically and by genetic sequencing. Our findings strongly support vigorous family investigation when a new patient is diagnosed with thoracic aortic aneurysm, as well as vigorous application of whole exome sequencing for these families.