WHOLE EXOME SEQUENCING FOR THORACIC AORTIC ANEURYSM: THE FUTURE IS HERE



John A. Elefteriades, M.D., Yale University School of Medicine, New Haven, CT, USA

Background: Convincing evidence is accumulating that genetics play an important etiologic role in thoracic aortic aneurysm and dissection (TAAD). Multiple genes have been found to cause syndromic and familial TAAD. The current study evaluates the impact of genetic testing via whole exome sequencing (WES) for a panel of genes associated with TAAD as a clinical test performed at a specialized aortic center.

Methods: WES was offered as an ongoing clinical test to 188 patients (mean age 59.2±14.8 years, range 13-85, 131 males (69.7%)) with TAAD. Thirty-four patients were declined testing for insurance reasons. DNA was extracted from saliva samples collected in Oragene kits. DNA exonic fragments were sequenced on the Illumina HiSeq platform. The resulting sequence was analyzed for single nucleotide variants and small insertions and deletions differing from the reference genome (Human Genome 19, HG19). To date, genetic results were available for 102 patients (66.2%).

Results: The panel of tested genes is presented in Figure 1. Three patients (2.9%) had a deleterious mutation identified in the FBN1, COL5A1, and MYLK genes. Twenty patients (19.6%) had suspicious variants of unknown significance (previously unreported) in one or more of these genes: FBN1 (n=5), MYH11 (n=4), ACTA2 (n=2), COL1A1 (n=2), FLNA (n=2), TGFBR1 (n=2), COL3A1 (n=1), COL5A1 (n=1), COL5A2 (n=1), NOTCH1 (n=1), PRKG1 (n= 1), and TGFBR3 (n=1). Identified mutations had implications for clinical management. Seventy-three patients (71.6%) had no medically important genetic alterations.

Conclusion: Routine genetic screening of patients with TAAD provides important information that enables genetically personalized care and permits identification of novel mutations responsible for aortic pathology.