O0012: Role and Yield of Clinical Genetic Testing Among Patients with Bicuspid Aortic Valve and Aortic Dilation

Background: Bicuspid aortic valve (BAV) is one of the most common causes of aortic dilation among children, adolescent and young adults. BAV can also occur in concomitance with other heritable thoracic aortic diseases like Loeys-Dietz syndrome, Marfan syndrome and Ehler-Danlos syndrome. Therefore it is critical to rule out these concomitant heritable thoracic aortic diseases among patients with BAV to guide an optimal medical therapy, surgical decision making, risk stratification and prognostication. There is limited guidance regarding the role of genetic testing in this context.

Methods: We retrospectively identified 125 patients with BAV, without a known genetic association, who were referred to the Cardiovascular Genetics clinic at Texas Children Hospital between Jan 2010 to Dec 2021 for further evaluation. We subsequently identified 83 patients with BAV and aortic dilation, where the primary referral question was evaluation for a concomitant heritable thoracic aortic disease.

Results: Among 83 patients with BAV and aortic dilation, 71 (86%) underwent genetic testing after detailed phenotypic evaluation based on the clinical concern for presence of a concomitant heritable thoracic aortic disease or other genetic conditions. The predominant form of initial testing was a panel of genes associated with aortopathy or connective tissue conditions in 59 patients (83%), while whole exome sequencing (WES) was done in 8 (11%) patients and other miscellaneous testing in 4 (6%) patients. A total of 16 (19%) patients underwent chromosomal microarray (CMA) irrespective of other genetic testing and 4 patients underwent WES after negative initial testing with a total of 12 (17%) patients undergoing WES. Overall yield of genetic testing relevant to the clinical phenotype of patients including variants of uncertain significance was 24% (17/71). After meticulous interpretation of the results in these 17 patients, the final diagnostic yield of genetic testing in terms of pathogenic/likely pathogenic variants and clinically actionable findings was 13% (9/71) as reported in Table 1. The remaining 11 % (8/71) patients had a variant of uncertain significance associated with the phenotype with probable clinical impact, but lacking enough evidence to be classified as pathogenic or likely pathogenic (Figure 1).

Conclusion: Genetic testing among patients with BAV and aortic dilation, guided by a detailed phenotypic evaluation for heritable thoracic aortic diseases or associated genetic conditions, can provide a considerable clinically relevant and actionable diagnostic yield.