Rare genetic coding variants may predict high-risk SCAD phenotype

September 21, 2022

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Ganesh and the editorial writers report no relevant financial disclosures. The relevant financial information of all other authors can be found in the study.

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About 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 might be considered, the researchers reported.

Spontaneous coronary artery dissection (SCAD), a non-atherosclerotic cause of MI that typically occurs in young women, has both complex genetic and monogenic influences. SanthI K Ganesh, MD associate professor of internal medicine and human genetics at the University of Michigan School of Medicine, and colleagues wrote JAMA Cardiology. Current estimates suggest that approximately 5% of all patients with SCAD have a monogenic etiology that includes genes previously associated with connective tissue vascular disease, including genes encoding Ehlers-Danlos vascular syndrome, Marfan syndrome, underlying Loeys-Dietz syndrome and fibrillar collagens.

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Whole exome sequencing

Ganesh and colleagues performed whole exome sequencing for subsequent case-control association analyzes and individual variant annotations in 336 adults with high-risk SCAD recruited from the Canadian SCAD registry from May 2014 to August 2018. The average age of the participants was 53 years; 90% were women and 87.5% were white. The 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 disease and/or SCAD, as well as genes defined by genome-wide association study (GWAS) and colocalization of arterial expression quantitative traits. loci were prioritized.

Researchers then compared aggregated variants observed in participants with SCAD to 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 a 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 compared to 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).

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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 designated as “probably pathogenic or pathogenic” occurred in four individuals COL3A1, TGFBR2 and ADAMTSL4 genes

Researchers also identified new associations with peripartum SCAD using genome-wide aggregated variant testing.

“The observation that about one in six (about 17%) [of] Individuals with high-risk SCAD harbor variants of previously reported vascular connective tissue disease genes, and SCAD suggest that expanded clinical screening may be beneficial in individuals with SCAD with high-risk traits,” the researchers wrote. “However, most variants have been annotated as variants of uncertain importance, and whether these variants are pathogenic or modifiers of an underlying arterial predisposition to SCAD remains to be determined.”

Cut 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 that these variants are “way too common” and currently have limited clinical utility; however, the enrichment of such variants in SCAD should not be completely ignored.

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“The statistical enrichment of rare variants in inherited connective tissue disease/arteriopathy susceptibility genes suggests that these comparatively more common variants may serve as primary drivers or major contributors to oligogenic or polygenic forms of SCAD,” Giudicessi and colleagues wrote. “Therefore, this study not only provides impetus to better define those SCAD subgroups that might benefit most from clinical genetic testing, but also motivates to examine the collective and likely synergistic contribution of rare and common genetic variants to the genetic susceptibility component of SCAD.” .”

Giudicessi and colleagues wrote that the continued development of polygenic SCAD risk scores and/or genetic variants of rare variants could help “finally break through the genetic background noise and take advantage of the complex genetic architecture of SCAD” and provide clinicians with a clinically useful tool for Provide diagnosis and risk stratification to patients.


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

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