Spontaneous Coronary Artery Dissection

Abstract

Background - Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture is poorly understood. Here, we aim to better understand the diagnostic yield of rare variant genetic testing among a cohort of SCAD survivors and to identify genes or gene-sets that have a significant enrichment of rare variants. Methods - We sequenced a cohort of 384 SCAD survivors from the UK, alongside 13,722 UK Biobank controls and a validation cohort of 92 SCAD survivors. We performed a research diagnostic screen for pathogenic variants, and exome-wide and gene-set rare variant collapsing analyses. Results - The majority of patients within both cohorts are female, 29% of the study cohort and 14% validation cohort have a remote arteriopathy. Four cases across the two cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in seven genes ( PKD1 , COL3A1 , SMAD3 , TGFB2 , LOX , MYLK , and YY1AP1 ) in 14/384 cases in the study cohort and in 1/92 cases in the validation cohort. In our rare variant collapsing analysis, PKD1 was the highest ranked gene and several functionally plausible genes were enriched for rare variants, although no gene achieved study-wide statistical significance. Gene-set enrichment analysis suggested a role for additional genes involved in renal function. Conclusions - By studying the largest sequenced cohort of SCAD survivors we demonstrate that, based on current knowledge, only a small proportion have a pathogenic variant that could explain their disease. Our findings strengthen the overlap between SCAD and renal and connective tissue disorders and we highlight several new genes for future validation.

The diagnosis and management of spontaneous coronary artery dissection — expert opinion of the Association of Cardiovascular Interventions (ACVI) of Polish Cardiac Society

“…In a very recent British genome sequencing study including 476 SCAD survivors and 13722 controls, pathogenic or likely rare pathogenic variants were detected in 3.5% of SCAD cases in 7 genes (PKD1, COL3A1, SMAD3, TGFB2, LOX, MYLK, and YY1AP1, with the highest association of the PKD1 gene with SCAD [88]. The results strengthen the overlap between SCAD and renal and connective tissue disorders.…”

Differential miRNAs in acute spontaneous coronary artery dissection: Pathophysiological insights from a potential biomarker

“… [40] Very recent data highlight the presence of causal variants in MYLK in SCAD. [41] Whether these biological processes are a cause, or a consequence of SCAD pathophysiology is just prospective. Neither the cells from which these plasma miRNAs are secreted, nor their recipient cells can be elucidated from our results, although both topics are very interesting aspects to address in future investigations.…”

Spontaneous Coronary Artery Dissection as Presenting Feature of Vascular Ehlers-Danlos Syndrome

“…The role of genetic testing in SCAD patients remains to be established. In a recent study, among 384 SCAD survivors from the UK a pathogenic variant was detected in 14 patients (3.6%), including two COL3A1 variants [2]. In many cases, the presence of recognizable skeletal features, age at presentation, or family history will provide additional clues for an underlying genetic disease.…”

“…In addition, SCAD is associated with pregnancy, fibromuscular dysplasia, and vigorous exercise. In approximately 3% of SCAD cases a genetic defect can be identified [2]. Genetic causes include polycystic kidney disease and connective tissue disorders.…”