Rare genetic coding variants may predict high-risk SCAD phenotype

September 21, 2022

3 minute read


Ganesh and editorial authors do not report any relevant financial information. Please see the study for relevant financial information from all other authors.

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

Spontaneous coronary artery dissection (SCAD), a non-atherosclerotic cause of myocardial infarction commonly seen in young women, has both complex genetic and monogenic influences, SanthI K Ganesh, medical doctor, associate professor of internal medicine and human genetics at the University of Michigan Medical School, and his 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, Marfan syndrome, 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 annotation in 336 adults with high-risk SCAD from May 2014 to August 2018 recruited from the Canadian Registry of SCAD. The average age of participants was 53; 90% were female 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 prioritized by the system-wide association study. genome (GWAS) and colocalization of arterial expression quantitative trait loci.

The researchers then compared the aggregated variants seen in participants with SCAD with those in matched controls or the Genome Aggregation Database (gnomAD).

Within the cohort, 94 participants met the 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 arterial disease (19%). ).

Researchers identified variants in vascular connective tissue disease genes in 17% of participants with high-risk SCAD; these were enriched with respect to gnomAD data (OR = 2.6; 95% CI, 1.6-4.2; P= 7.8×104). The researchers observed important 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 of priority genes for GWAS, 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 “probably pathogenic or pathogenic” appeared in four individuals in the COL3A1, TGFBR2 and ADAMTSL4 Genoa.

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

“The observation that about one in six (about 17%) [of] people with high-risk SCAD harbored variants of genes previously reported for vascular connective tissue diseases and SCAD suggests that expanded clinical screening may be useful in people with SCAD with high-risk features,” wrote Researchers. “However, most variants have been annotated as variants of uncertain significance, and it remains to be determined whether these variants are pathogenic or alter an underlying arterial predisposition to SCAD.”

Cut the “genetic background noise”

In a related editorial, John R. Giudicessi, MD, PhD, senior associate consultant at Mayo Clinic’s Windland Smith Rice Genetic Heart Rhythm Clinic and colleagues 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.

“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 substantial contributors to oligogenic or polygenic forms of SCAD,” they wrote. writes Giudicessi and his colleagues. “Therefore, in addition to providing an impetus to better define the 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 the continued development of polygenic and/or rare genetic risk scores for SCAD could help “finally reduce genetic background noise and exploit the complex genetic architecture of SCAD”, providing clinicians with a clinically meaningful tool for diagnosing and stratifying risk. the patients.


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

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