Rare genetic coding variants may predict high-risk SCAD phenotype

September 21, 2022

3 min read


Ganesh and the editorial authors report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

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Approximately one in five adults with spontaneous coronary artery dissection with high-risk features had an increased burden of rare genetic variants on whole-exome sequencing, suggesting testing may be considered, researchers reported.

Spontaneous coronary artery dissection (SCAD), a nonatherosclerotic cause of MI typically seen in young women, has both complex genetic and monogenic influences, Santhof K. Ganesh, MD, associate professor of internal medicine and human genetics at the University of Michigan Medical School, and colleagues wrote in JAMA Cardiology. Current estimates are that approximately 5% of all patients with SCAD have a monogenic etiology involving genes that have been previously implicated in vascular connective tissue diseases, including genes underlying vascular Ehlers-Danlos syndrome, Marfan syndrome, Loeys-Dietz syndrome and fibrillar collagens.

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Whole-exome sequencing

Ganesh and colleagues conducted whole-exome sequencing for subsequent case-control association analyzes and individual variant annotation among 336 adults with high-risk SCAD from May 2014 to August 2018 recruited from the Canadian SCAD registry. The mean age of participants was 53 years; 90% were women and 87.5% were white. Researchers also selected 282 age-, sex- and ancestry-matched healthy controls from the Michigan Genomics Initiative biorepository.

Researchers annotated genetic variants for pathogenicity by in silico analysis of genes previously defined by sequencing for vascular connective tissue diseases and/or SCAD, as well as genes prioritized by genome-wide association study (GWAS) and colocalization of arterial expression quantitative trait loci.

Researchers then compared aggregated variants observed in participants with SCAD with those of the matched controls or the Genome Aggregation Database (gnomAD).

Within the cohort, 94 participants met criteria for a high-risk SCAD phenotype, including eight with peripartum SCAD (2%), 33 with recurrent SCAD (10%) and 65 with family history of arteriopathy (19%).

Researchers identified variants in vascular connective tissue disease genes in 17% of participants with high-risk SCAD; these were enriched when compared with gnomAD data (OR = 2.6; 95% CI, 1.6-4.2; P = 7.8 × 104). Researchers observed leading significant signals in COL3A1 (OR = 13.4; 95% CI, 4.9–36.2; P = 2.8 × 104) and Loeys-Dietz syndrome genes (OR = 7.9; 95% CI, 2.9-21.2; P = 2 × 103).

Variants in GWAS-prioritized genes, observed in 6.4% of participants with high-risk SCAD, were also enriched (OR = 3.6; 95% CI, 1.6-8.2; P = 7.4 × 103). Variants annotated as “likely pathogenic or pathogenic” occurred in four individuals in the COL3A1, TGFBR2 and ADAMTSL4 gene.

The researchers also identified novel associations with peripartum SCAD using genome-wide aggregated variant testing.

“The observation that approximately one in six (approximately 17%) [of] individuals with high-risk SCAD harbored variants from previously reported genes for vascular connective tissue diseases and SCAD suggests that expanded clinical screening may have utility in individuals presenting with SCAD with high-risk features,” the researchers wrote. “However, most variants were annotated as variants of uncertain significance, and whether these variants are pathogenic or modifiers of an underlying arterial predisposition to SCAD remains to be determined.”

Cutting through ‘genetic background noise’

In a related editorial, John R. Giudicessi, MD, PhD, senior associate consultant at the Windland Smith Rice Genetic Heart Rhythm Clinic at Mayo Clinic, and colleagues wrote noted that these variants are “far too common” and currently have limited clinical utility; however, the enrichment of such variants in SCAD should not be completely ignored.

“The statistical enrichment of rare variants in inherited connective tissue disorder/arteriopathy-susceptibility genes suggests that these comparatively more common variants may serve as primary drivers or substantive contributors to oligogenic or polygenic forms of SCAD,” Giudicessi and colleagues wrote. “Therefore, in addition to providing an impetus to better define those SCAD subgroups that could benefit most from clinical genetic testing, this study also provides motivation to explore the collective and likely synergistic contribution of rare and common genetic variants to the genetic susceptibility component of SCAD .”

Giudicessi and colleagues wrote that continued development of SCAD polygenic and/or rare variant genetic risk scores could help “finally cut through the genetic background noise and harness the complex genetic architecture of SCAD,” offering a clinically meaningful tool for clinicians to diagnose and risk stratify the patient.


Giudicesi JR, et al. JAMA Cardiol. 2022; doi:10.1001/jamacardio.2022.2978.