September 21 2022
3 minutes to read
Source / Disclosures
Ganesh and the editorial authors did not make any relevant financial disclosures. Please see the study for all relevant financial disclosures by other authors.
Nearly one in five adults with Spontaneous coronary artery dissection The researchers reported that those with high-risk traits had an increased burden of rare genetic variants on whole-exome sequencing, suggesting that the test could be considered.
Spontaneous coronary artery dissection (SCAD), a non-sclerotic cause of coronary artery disease commonly seen in young women, has complex genetic and monogenic effects, santhI K. Ganesh, MD, Associate Professor of Internal Medicine and Human Genetics at the University of Michigan Medical School, and colleagues write in Heart gamma. Current estimates are that approximately 5% of all patients with SCAD have a monogenic etiology that includes genes that have previously been implicated in vascular connective tissue disease, including genes underlying vascular EDS, Marfan syndromeLouise-Dietz syndrome and fibrous collagen.
Whole exome sequencing
Ganesh and colleagues performed whole-exome sequencing for case- and post-control association analyzes and single-variable annotation among 336 adults with high-risk SCAD from May 2014 to August 2018 recruited from the Canadian SCAD registry. The average age of the participants was 53 years. 90% of women and 87.5% of whites. The researchers also selected 282 healthy, age-, gender- and ancestral-matched controls from the Michigan Genome Initiative Biorepository.
The researchers annotated pathogenicity genetic variants through in silico analysis of genes previously identified by sequencing for vascular connective tissue disease and/or SCAD, as well as genes prioritized by a genome-wide association study (GWAS) and standardization of quantitative expression loci for expression arterial;
The researchers then compared the pooled variants observed in participants with SCAD with those in the matched controls or the Genome Assembly Database (gnomAD).
Within the group, 94 participants fulfilled the criteria for a high-risk SCAD phenotype, including eight with perinatal SCAD (2%), 33 with RCD (10%) and 65 participants with perinatal SCAD A family history of arterial disease (19%).
The researchers identified variants in vascular connective tissue disease genes in 17% of participants with high-risk SCAD. enriched when compared with the gnomAD data (OR = 2.6; 95% CI, 1.6–4.2; q = 7.8 x 104). The researchers observed driving important signals in COL3A1 (OR = 13.4; 95% CI, 4.9-36.2; q = 2.8 x 104) and Loeys-Dietz syndrome genes (OR = 7.9; 95% CI, 2.9-21.2; q = 2 x 103).
Variants were also enriched in GWAS priority genes, which were observed in 6.4% of participants with high-risk SCAD (OR = 3.6; 95% CI, 1.6–8.2; q = 7.4 x 103). Variants annotated as ‘pathogenic or pathogenic’ occurred in four individuals in COL3A1And the TGFBR2 And the ADAMTSL4 genes.
The researchers also identified new associations with perinatal SCAD using genome-wide pooled variant testing.
The observation that one in six (about 17%) [of] The authors write that individuals with high-risk SCAD harbor variants of previously reported genes for vascular connective tissue disease, and SCAD suggests that extended clinical examination may be useful in individuals with SCAD with high-risk traits. “However, most variants have been explained as variants of uncertain significance, and whether these variants are pathogenic or modulators of primary arterial predisposition to SCAD remains to be determined.”
Cut out “genetic background noise”
In a related editorial, John R. Giudicessi, MD, Ph.D., Senior Associate Consultant at Wendland-Smith-Rice and colleagues note that these variants are “very common” and currently have limited clinical utility. However, the enrichment of these variants in SCAD should not be completely ignored.
“Statistical enrichment of rare variants in the heritable genes for connective tissue disorder/arteropathy susceptibility suggests that these relatively more common variants may serve as underlying drivers or intrinsic contributions to oligogenic or polygenic forms of SCAD,” Giudicesi and colleagues write. “Therefore, in addition to providing impetus to better identify SCAD subgroups that could benefit most from clinical genetic testing, this study also provides impetus to explore the collective and potential contribution of rare and common genetic variants to the genetic susceptibility component of SCAD.”
Giudicessi and colleagues write that the ongoing development of genetic risk scores for polygenic and/or rare variants of SCAD could help “finally bypass genetic background noise and harness the complex genetic architecture of SCAD,” providing a clinically meaningful tool for clinicians to diagnose and classify patients’ risk.