Abstract 16643: Clinical Implications of Identifying Pathogenic Variants in Aortic Dissection Patients With Whole Exome

Introduction: Aortic dissection is a life threatening condition due to associated complications, such as aortic rupture, end-organ malperfusion and failure with high mortality of surgical treatment. It is not known how to manage family members of patient’s that suffer from aortic dissection, and routine cascade genetic screening of first-degree family members is not regularly practiced. Hypothesis: Clinical genetic testing for patients and cascade screening would identify pathogenic variants facilitating the management of patients with aortic dissection and families. Methods: From August 2012 to December 2015, 265 patients with aortic dissection had whole exome sequencing (WES), including Stanford type A and B or rupture, at Michigan Medicine with age-, sex-, and ancestry-matched controls (n=265). After quality control, 249 non-trauma dissection cases and 258 controls were retained. Annotation of variants in 11 known genes lead to heritable thoracic aortic disease (HTAD) was performed by experts in the field blinded to sample’s case or control status. Non-pathogenic variants were identified in 223 patients and pathogenic variants were in 26 patients. Results: Twenty-four pathogenic variants across 6 genes ( COL3A1, FBN1, LOX, PRKG1, SMAD3, TGFBR2 ) were identified in 26 patients representing 10% of aortic patients and 0% of controls. Compared to non-pathogenic group, the pathogenic group was significantly younger (41 vs 57 years, 77% younger than 50 years old), more root aneurysm (54% vs 29%), less hypertension (15% vs. 57%) and smoking history (19% vs. 47%), and more incidence of TAAD in parents, siblings and children. (all p’s<0.05) Conclusion: We recommend clinical genetic testing of known HTAD genes in patients of aortic dissection with subsequent cascade screening of family members, especially the age of onset of aortic dissection younger than 50 years old, with aortic root aneurysm, no history of hypertension and smoking, as well as family members of patients whose causative variants have been identified. If the patient and families are found to have the known pathologic HTAD genes, then surgeons should be more aggressive to perform prophylactic operation on those patients to prevent aortic dissection.