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. 2020 Dec;13(6):e003030.
doi: 10.1161/CIRCGEN.120.003030. Epub 2020 Oct 30.

Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing

Keren J Carss  1 , Anna A Baranowska  2 , Javier Armisen  1 , Tom R Webb  2 , Stephen E Hamby  2 , Diluka Premawardhana  2 , Abtehale Al-Hussaini  2 , Alice Wood  2 , Quanli Wang  1 , Sri V V Deevi  1 , Dimitrios Vitsios  1 , Samuel H Lewis  1 , Deevia Kotecha  2 , Nabila Bouatia-Naji  3 , Stephanie Hesselson  4 , Siiri E Iismaa  4   5 , Ingrid Tarr  4 , Lucy McGrath-Cadell  5 , David W Muller  4   5 , Sally L Dunwoodie  4   5 , Diane Fatkin  4   5   6 , Robert M Graham  4   5 , Eleni Giannoulatou  4   5 , Nilesh J Samani  2 , Slavé Petrovski  1 , Carolina Haefliger #  1 , David Adlam #  2
Affiliations

Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing

Keren J Carss et al. Circ Genom Precis Med. 2020 Dec.

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 United Kingdom, 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 2 cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in 7 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.

Keywords: coronary artery dissection; dissection; genetics; spontaneous.

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Conflict of interest statement

Dr Carss, Dr Armisen, Q. Wang, Dr Deevi, Dr Vitsios, Dr Lewis, Dr Petrovski, and Dr Haefliger are employees of AstraZeneca. Dr Adlam has received research funding from Abbott vascular inc to support a clinical research fellow and has undertaken unrelated consultancy for GE Inc. The other authors report no conflicts.

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