Routine genetic testing for thoracic aortic disease may levy high costs to patients with little benefit

A disease spectrum best described as ‘silent killers’ are thoracic aortic aneurysms and dissections (TAADs). Numerous studies throughout the past two and a half decades have implicated familial clustering of TAADs; notably, that the prevalence in patients with a positive family history of TAADs is significantly higher compared to sporadic counterparts. Many genetic disorders are significantly associated with the development of TAADs including Marfan syndrome, Ehlers–Danlos syndrome, Loeys–Dietz syndrome (LDS), and large vessel vasculitides such as Takayasu’s arteritis, giant cell arteritis, polyarteritis nodosa and Behçet’s disease. However, there is also an environmental component to the development of TAADs including thoracic trauma, previous cardiac surgery and catheterization, and the sequela of late stage diseases including long-standing aortic valve insufficiency or uncontrolled hypertension. Given that TAADs are ‘not problems until they are problems’, Carino and colleagues set out to establish a role for genetic testing in the detection and early management of familial clustering of TAADs.1 Presently in the United States, there are no established guidelines for the utilization of genetic testing on established or questionable familial clustering of TAAD patients. Significant advances have led to the discovery of 29 proteins that play a role in familial clustering of TAADs which function physiologically in vascular smooth muscle contraction, extracellular matrix composition, and in transforming growth factor beta (TGF-β) signaling.2 As previously stated, familial clustering of TAADs typically exists as part of a disease syndrome which can account for approximately 20% of all TAADs diagnosed but this can be broken down further into syndromic and non-syndromic manifestations of familial clustering of TAADs.3 Point mutations in a few key proteins comprise the non-syndromic category of familial clustering of TAADs with manifestations of the disease isolated strictly to the aorta. Previous studies have shown that patients with TAADs caused by a familial component develop pathological lesions significantly earlier in life and have a more rapid annual growth rate of these lesions.3 Most importantly, it has been shown that familial clustering of TAAD lesions treated by both endovascular stenting and traditional open repair have significantly greater late complications compared to sporadic TAADs repaired in similar manners. Carino et al.1 put forth a straightforward flow chart in their suggested decision-making for offering whole exome sequencing (WES) to the general population. Briefly, after confirming the diagnosis of TAAD, a thorough family history must be taken. Given familial clustering of TAADs manifests much earlier in life compared to sporadic cases, the authors suggest genetic testing in established patients with a positive family history aged less than 60 years without cardiovascular risk factors. A single center study from 2015 demonstrated a possible role for echocardiography in identifying familial clustering of TAAD patients.4 Hannuksela and colleagues4 demonstrated two problems in a cohort of 119 patients (13 with known aortic disease and 106 with only family history-positive disease). The first being that none of the patients were found to have underlying genetic defects at the time of testing and the second being that only 19 patients in the family history-positive group were found to have imaging evidence of aortic dilation. This highlights a glaring issue with shotgun genetic testing in patients with possible familial clustering of TAADs. WES is an expensive and time-consuming test within the United States and is covered by insurance after a family member is found to be positive for an insulting gene with evidence of familial inheritability. The cohort of Hannuksela et al. was screened under the caveat that most genetic causes of familial clustering of TAADs follow an autosomal dominant inheritance. In their group of 106 patients, the expected number of identified patients utilizing their screening protocol should be approximately 10. Hannuksela and colleagues failed to identify a single patient in this cohort, demonstrating a great amount of cost to the patients without benefit. Although identification of patients at a molecular level may assist in determining who to screen for TAADs, current radiological screening guidelines may fail to identify patients at an early stage. It is not known at what age range any of the familial clustering of TAAD diseases occurs other than generally manifesting before sporadic TAADs. This fact further complicates the issue in that changes in genetic penetrance and variable expressivity of each disease-causing genetic change will require consistent and regular radiological screening in order to identify all at-risk patients, further exacerbating the cost.5 Presently, the American Heart Association’s only guidelines for thoracic aortic disease screening is from a 2010 report stating that routine echocardiographic screening should be offered to all patients diagnosed with Marfan syndrome at the time of diagnosis, with annual screening continuing based on maximal aortic diameter.6 In addition, patients with LDS or a confirmed genetic mutation to genes known to cause TAADs (TGFBR1, TGFBR2, FBN1, ACTA2, MYH11 are referenced specifically) should undergo similar screening protocols to their Marfan peers with the exception that LDS patients be followed with annual magnetic resonance imaging of the circulatory system from the cerebrovascular circulation to the pelvis. The last of their class I evidence includes Turner syndrome patients undergoing routine screening for any aortic or valvular disease and reduction of screening to every 5–10 years if no anatomical abnormalities are seen and initial imaging shows normal maximal aortic diameter. It appears both radiological and genetic screening are intertwined regarding the management of familial clustering of TAADs. Genetic evidence of familial clustering of TAADs does not dictate the expected age of onset of radiological or clinical manifestations of disease. The frequent use of WES has implications of creating high cost to patients with little benefit given limitations in familial clustering of TAADs radiological screening with echocardiography. More detailed work regarding cost and benefit to potential patients is warranted prior to formal guideline adaption for the genetic diagnosis of familial clustering of TAADs. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.