Spontaneous Coronary Artery Dissection and a Family History of Aortic Dissection: A Genetic Association Study

Abstract

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndrome or sudden cardiac death, primarily affecting relatively young women (median age, 51 years) without typical cardiovascular risk factors. SCAD has a genetic component, with genome-wide association studies identifying multiple risk loci. Thoracic aortic dissection (type A) shares some genetic overlap with SCAD, suggesting potential common predispositions.

Methods: We performed genetic screening or whole-genome sequencing of 17 patients with SCAD (94% women) with a first- or second-degree relative (89% men) affected by aortic dissection (AD). We assessed rare variants in candidate genes and genome-wide using the American College of Medical Genetics and Genomics criteria. Polygenic risk scores were calculated to assess genetic risk for SCAD, fibromuscular dysplasia, AD, and abdominal aortic aneurysm in patients with SCAD, relatives with AD, and controls.

Results: Whole-genome sequencing identified pathogenic or likely pathogenic variants in SMAD3, CBS, and COL3A1 in 3 SCAD cases. Additionally, 4 variants of uncertain significance were found in candidate genes. Polygenic risk scores for SCAD were significantly associated with increased odds of SCAD in probands versus controls (odds ratio, 1.79 [95% CI, 1.08-2.99]; P=0.024).

Conclusions: Our study supports a complex genetic landscape underlying SCAD, implicating rare monogenic pathogenic variants and polygenic risk. We identified pathogenic variants in patients with SCAD with a family history of AD, highlighting potential genetic links between these vascular disorders. The findings underscore the importance of genetic screening in patients with SCAD with a history of AD to identify individuals at risk and guide preventive strategies.

Keywords: aortic dissection; pathogenic variants; polygenic risk score; spontaneous coronary artery dissection; whole genome sequencing.

Figure 1. Pedigrees for the SCAD–AD families including affected and sequenced individuals.

Arrowheads indicate probands. Women are represented by circles; men are represented by squares. A slash indicates a deceased individual. Phenotype key listed at the bottom. All SCAD diagnoses are angiographically confirmed. AD diagnosis was confirmed through direct interview or medical records for all participants with AD with a sample ID listed. AD was self‐reported by family history for all other individuals with AD except for the grandmother of 08–28 (cardiologist letter), the father of 11_251 (medical records obtained), and the uncle of 16_309 (meticulous medical history notes compiled by 16_385) for whom additional documentation was available. All samples with sample IDs underwent whole‐genome sequencing, with the exception of 01_13. Participant 01_13 and the parents and sister of proband 15_146 had clinical genetic testing. Individuals 01_13 and 16_385 reported their CTD diagnosis, have the physical features of the condition, and carry predicted damaging variants in genes established to be causative for the condition with autosomal dominant inheritance. + indicates that a family member was tested and is heterozygous for a variant linked to a CTD; ‐ indicates that a family member was tested and does not carry the variant; Family 1 + indicates SMAD3 (p.Met1Val), Family 15 + indicates COL3A1 p.(Ser934llefsTer35), Family 16 + indicates FBN1 (chr15:48780559:A>C, predicted splice donor gain). AD indicates aortic dissection; CTD, connective tissue disorder; NR, not reported; and SCAD, spontaneous coronary artery dissection.