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Heart Disease Genes Flagged by Rare Variant Analysis of Spontaneous Coronary Artery Dissection

NEW YORK – By sequencing protein-coding portions of the genome in individuals with clinically high-risk forms of spontaneous coronary artery dissection (SCAD), a team from the US and Canada has tracked down rare variant contributors to the female-centric heart condition, including variants in genes previously associated with SCAD or to related monogenic diseases.

"[W]e identified rare coding variants in known and new genes that are associated with high-risk SCAD phenotypes," co-senior and co-corresponding authors Santhi Ganesh, at the University of Michigan Medical School, and Jacqueline Saw, at the University of British Columbia and Vancouver General Hospital, and their colleagues wrote, noting that the results "provide new biologic insights into the genetic basis of SCAD and support clinical genetic testing considerations for individuals with high-risk SCAD presentations."

As they reported in JAMA Cardiology on Wednesday, the researchers started from 336 SCAD cases from the Canadian SCAD (CanSCAD) genetics project, focusing their subsequent genetic analyses on 94 individuals classified as having high-risk SCAD clinical features. With exome sequencing on these 94 high-risk SCAD cases and 282 unaffected, age-, gender-, and ancestry-matched control individuals from the Michigan Genomics Initiative biorepository, they tracked down nearly two dozen candidate risk genes.

The high-risk SCAD group encompassed 65 cases involving a family history of arteriopathy, 33 cases of recurrent SCAD (R-SCAD), and eight peripartum SCAD (P-SCAD) cases, the team noted.

The analyses suggested that rare variants in at least 10 vascular connective tissue disease (CTD) genes were overrepresented in the individuals with SCAD, the researchers noted, turning up in 17 percent of the cases considered. Across the SCAD cohort, rare variants in CTD genes such as COL3A1 also tended to turn up more frequently than they did in gnomAD.

"Although monogenic variants in vascular CTD genes have been previously understood to affect approximately 5 percent of individuals in general SCAD cohorts, the current report supports a much higher frequency (approximately 17 percent) among individuals with SCAD and high-risk features," the authors reported. "These findings provide new biologic insights into the genetic basis of SCAD and support clinical genetic testing considerations for individuals with high-risk SCAD presentations."

Likewise, the team saw enrichment for rare variants in genes implicated in conditions such as Loeys-Dietz syndrome or Ehlers-Danlos syndrome, and in genes such as ADAMTSL4 and LRP1 that were highlighted in prior genome-wide association studies focused on SCAD.

Within a set of 22 candidate SCAD genes, the investigators narrowed in on three genes containing potentially actionable variants, while their rare variant burden-based analyses led to SCAD-associated variants in the P4HB and HYDIN genes and variants associated with a subset of high-risk SCAD cases classified as P-SCAD.

Based on past research, which has unearthed rare variants in individual genes linked to conditions such as Loeys-Dietz syndrome in a small subset of SCAD cases, "the current consensus is to reserve genetic testing in SCAD for those cases where there is reasonable clinical suspicion for an underlying inherited CTD/arteriopathy," Mayo Clinic cardiovascular medicine researcher Sharonne Hayes and her colleagues noted in a commentary article accompanying the JAMA Cardiology study.

They suggested that the latest exome sequencing results may help in teasing out causative contributors to SCAD and weeding out background variants that do not directly impact risk of the condition, which can lead to myocardial infarction and death.

While causative ties to SCAD are anticipated for pathogenic or likely pathogenic variants in the COL3A1 gene, previously implicated in vascular Ehlers-Danlos syndrome, or in Loeys-Dietz syndrome-causing genes, for example, the commentary authors urged caution when interpreting variants that are predicted to be deleterious in protein-truncating variant-tolerant genes such as ADAMTSL4 that were initially identified with GWAS approaches.

"With the future development of SCAD polygenic and/or rare variant genetic risk scores, the field may finally cut through the genetic background noise and harness the complex genetic architecture of SCAD to provide a clinically meaningful tool to aid in the diagnosis and risk stratification of this enigmatic disease," Hayes and her colleagues wrote.