A rare gene-coding variant may predict a high-risk SCAD phenotype

September 21, 2022

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Ganesh and editors do not report relevant financial disclosures. See research for relevant financial disclosures of all other authors.

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Approximately 1 in 5 adults with high-risk spontaneous coronary artery dissection have an increased burden of rare genetic mutations with whole-exome sequencing, suggesting testing may be considered. There are, the researchers reported.

Spontaneous coronary artery dissection (SCAD), a non-atherosclerotic cause of myocardial infarction that is typically seen in young women, has both complex and monogenic effects. SansMe K. Ganesh, MD, An associate professor of internal medicine and human genetics at the University of Michigan School of Medicine and a colleague wrote: JAMA cardiology. Current estimates are that approximately 5% of all SCAD patients have previously been implicated in vascular connective tissue disorders, including vascular Ehlers-Danlos syndrome, Marfan syndrome, Loeys-Dietz syndrome, and genes underlying fibrillar collagen. presumed to have a monogenic etiology, including the

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Whole exome sequencing

Ganesh et al. studied 336 adults with high-risk SCAD recruited from the Canadian SCAD registry between May 2014 and August 2018, and whole exomes were analyzed for subsequent case-control association analysis and individual variant annotation. I ran a sequence. The average age of participants he was 53 years old. 90% were female and 87.5% were Caucasian. The researchers also selected her 282 healthy controls, matched for age, sex and ancestry, from the Michigan Genomics Initiative biorepository.

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Researchers prioritized in silico analysis of genes previously defined by sequencing of vascular connective tissue disease and/or SCAD, as well as genome-wide association studies (GWAS) and colocalization of arterial expression quantitative trait loci. Pathogenic genetic variants were annotated by in silico analysis of the ranked genes.

The researchers then compared the aggregated variants observed in SCAD participants to matched controls or variants from the Genome Aggregation Database (gnomAD).

Within the cohort, 94 participants had high-risk SCAD, including 8 (2%) with perinatal SCAD, 33 (10%) with recurrent SCAD, and 65 (19%) with a family history of arterial disease. met the phenotypic criteria.

Researchers identified variants in the vascular connective tissue disease gene in 17% of high-risk SCAD participants. These were enhanced when compared with the gnomAD data (OR = 2.6; 95% CI, 1.6-4.2; P = 7.8×10Four).Researchers Observed Key Significant Signals COL3A1 (OR = 13.4; 95% CI, 4.9–36.2; P = 2.8×10Four) and Loeys-Dietz syndrome genes (OR = 7.9; 95% CI, 2.9–21.2; P = 2×103).

Variants in GWAS-preferred genes were also abundant, observed in 6.4% of participants with high-risk SCAD (OR = 3.6; 95% CI, 1.6-8.2; P = 7.4×103). Variants annotated as “pathogenic or likely pathogenic” COL3A1, TGFBR2 When ADMTSL4 gene.

The researchers also used genome-wide aggregated variant testing to identify novel associations with perinatal SCAD.

“About 1 in 6 (about 17%) [of] High-risk SCAD patients carry previously reported vascular connective tissue disease gene variants, and SCAD may benefit from extended clinical screening for patients presenting with SCAD with high-risk features. It suggests that it is possible,” the researchers wrote. “However, most variants have been annotated as variants of unknown significance, and it remains to be determined whether these variants are pathogenic or modifiers of the arterial predisposition underlying SCAD.” Is not.”

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Cut through the “genetic background noise”

In a related editorial, John R. Judicessi, MD, PhD, Senior Associate Consultant The Windland Smith Rice Genetic Heart Rhythm Clinic at the Mayo Clinic and colleagues say these variants are “too common” and have limited current clinical utility. However, such variant enrichment in SCAD should not be completely ignored.

“Statistical enrichment of rare variants in hereditary connective tissue disorder/arteriopathy susceptibility genes suggests that these relatively common variants act as major drivers or substantial contributors to oligogenic or polygenic forms of SCAD.” suggest that there is potential to do so,” write Giudicessi and colleagues. “Thus, in addition to providing the impetus to better define the SCAD subgroups likely to benefit most from clinical genetic testing, this study provides a rare and common understanding of the genetic susceptibility component of SCAD.” It also provides an incentive to investigate the collective and synergistic contributions of different gene variants.”

Giudicessi and colleagues believe that continued development of genetic risk scores for polygenic and/or rare variants in SCAD will “eventually cut through the genetic background noise and take advantage of the complex genetic makeup of SCAD.” ‘ and may provide clinicians with a clinically meaningful tool for diagnosis and risk stratification. Patience.

reference:

Judy Sessi JR and others JAMA Cardiol. 2022; doi:10.1001/jamacardio.2022.2978.

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