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Levy et al. Vessel Plus 2024;8:4 https://dx.doi.org/10.20517/2574-1209.2023.55 Page 11 of 15

youngest case of complication in the family. Transthoracic echocardiography and CT or MRI axial imaging
are the preferred screening modalities. Similar to the AHA/ACC guidelines, individuals lacking a genetic
variant in ns-TAAD families with baseline normal screening should have repeat screening every five years.

A recent systematic review of 53 studies aimed to quantify the effectiveness of screening tests (via genetic
testing and imaging) in relatives of both familial and sporadic ns-TAAD cases . A total of 2,696 relatives
[74]
underwent screening, including genetic testing in 49%, imaging studies in 11%, and a combination of
genetic testing and imaging in the remaining 40%. First-, second-, and third-degree relatives were all
included. Benefits of routine screening in both first- and second-degree relatives were indicated, with a
possible benefit in third-degree relatives. They identified a total of 695 second-degree relatives who were
screened and found 24% to be newly diagnosed compared to 33% of 893 first-degree relatives. This study
supports screening for first- and second-degree relatives as well as the need for individualized screening,
although they do recognize that diagnostic yield in various screening techniques is unknown. Moreover,
Robertson et al. examined 216 relatives of newly diagnosed sporadic ns-TAAD cases (no known family
history of TAAD) . Screening of relatives from these probands yielded a new diagnosis in 86 additional
[22]
relatives (40%), altering the hereditary pattern of diagnosed individuals from sporadic to familial ns-TAAD.

FUTURE RESEARCH OPPORTUNITIES
Four overarching aims define areas of future research in ns-TAAD: (1) refining understanding of
heritability patterns; (2) identifying novel pathogenic genes; (3) investigating the epigenetic contribution to
aortic pathophysiology; and (4) individualizing screening and treatment algorithms. High-quality evidence
in these areas is lacking, largely due to the phenotypic inconsistencies. However, recent strides have been
made in verifying the importance of family history and screening for first and second- degree relatives. To
further investigate heritability risk and genetics, whole population studies will be beneficial. The majority of
published literature on these topics is from a few specialized centers and is subject to referral bias. A whole
population study focused on delineating heritability patterns would include those individuals who are
unaware they are at risk or aware of risk but choose not to pursue treatment, thereby decreasing the risk of
selection bias. Additionally, broadening the inclusion net to a whole population sample could identify new
heritability patterns and provide a better foundation for future genetic research in genetic linkage analyses
and genome-wide association studies to discover the impact of significant polygenic and epigenetic factors.
Stratifying familial risk of inheritance and genetic factors will advance developments in individualized
screening algorithms.

CONCLUSION
Thoracic aortic dissection is a feared complication of aortic aneurysm due to its high mortality rates, but it
is preventable through prophylactic surgical intervention. With advances in genomics and the emergence of
a personalized medicine paradigm for the diagnosis and treatment of aortic disease, there is a greater focus
on understanding the biochemical underpinnings of ns-TAAD to better inform patient care. The purpose of
this review article is to summarize the foundation of knowledge in ns-TAAD heritability and outline recent
genetic research developments. Non-syndromic individuals are at particular risk for dissection due to the
difficulty of diagnosing asymptomatic aneurysms without associated clinical features as well as variable
penetrance and phenotypic expression of mutations that lack classical Mendelian inheritance patterns. This
complexity has made the development of screening and intervention guidelines for ns-TAAD challenging.
Current guidelines emphasize the importance of genetic testing, serial imaging, and prophylactic thoracic
aortic replacement for individuals in high-risk ns-TAAD families. However, these guidelines still lack the
specificity present for s-TAAD and other cardiac diseases, convoluting the recommended shared decision
making between surgeons and patients. Avenues of future research involve risk stratification of relatives