Clinical implications of identifying pathogenic variants in aortic dissection patients with whole exome sequencing

Abstract

1Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine 2 screening for genetic variants causing thoracic aortic dissection is not currently performed for 3 patients or their family members. 4 Methods:We performed whole exome sequencing of 240 patients with thoracic aortic dissection 5 (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-6 control status, we annotated variants in 11 genes for pathogenicity. 7Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, 8 TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. 9Among dissection cases, we compared those with pathogenic variants to those without and found 10 that pathogenic variant carriers had significantly earlier onset of dissection (41 vs. 57 years), higher 11 rates of root aneurysm (54% vs. 30%), less hypertension (15% vs. 57%), lower rates of smoking 12 (19% vs. 45%), and greater incidence of aortic disease in family members. Multivariable logistic 13 regression showed significant risk factors associated with pathogenic variants are age <50 [odds 14 ratio (OR) = 5.5; 95% CI: 1.6-19.7], no history of hypertension (OR=5.6; 95% CI: 1.4-22.3) and 15 family history of aortic disease (mother: OR=5.7; 95% CI: 1.4-22.3, siblings: OR=5.1; 95% CI 16 1.1-23.9, children: OR=6.0; 95% CI: 1.4-26.7). 17 Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should 18 be considered in patients with aortic dissection, followed by cascade screening of family 19 members, especially in patients with age-of-onset of aortic dissection <50 years old, family 20 history of aortic disease, and no history of hypertension. 21 22 23 Keywords: thoracic aortic dissection, aortic rupture, gene sequencing, precision health 24 Dianna M. Milewicz (Dianna.M.Milewicz@uth.tmc.edu) has no conflicts of interest to disclose. 1 Cristen J. Willer (cristen@med.umich.edu) has no conflicts of interest to disclose. 2 Bo Yang (boya@med.umich.edu) has no conflicts of interest to disclose. 3 4 AUTHORS 5