Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation from Genome Sequencing
journal contribution
posted on 2020-11-23, 10:32 authored by Keren J Carss, Anna A Baranowska, Javier Armisen, Thomas R Webb, Stephen E Hamby, Diluka Premawardhana, Abtehale Al-Hussaini, Alice Wood, Quanli Wang, Sri VV Deevi, Dimitrios Vitsios, Samuel H Lewis, Deevia Kotecha, Nabila Bouatia-Naji, Stephanie Hesselson, Siiri E Iismaa, Ingrid Tarr, Lucy McGrath-Cadell, David W Muller, Sally L Dunwoodie, Diane Fatkin, Robert M Graham, Eleni Giannoulatou, Nilesh J Samani, Slavé Petrovski, Carolina Haefliger, David AdlamBackground - 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.
Funding
Sequencing was funded by AstraZeneca's Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, and grants from the Cardiac Society of Australia and New Zealand, National Health and Medical Research Council, Australia (Grant number APP1161200; SEI & RMG), St Vincent’s Clinic Foundation (RMG), Catholic Archdiocese of Sydney (RMG), Perpetual Philanthropy (RMG), NSW Health CVD Clinician-Scientist Grant (RMG), and SCAD Research Inc. The UK SCAD study was supported by the British Heart Foundation (BHF) PG/13/96/30608, the NIHR rare disease translational collaboration, the Leicester NIHR Biomedical Research Centre and BeatSCAD. NB is supported by a European grant from the European Commission (ERC-Stg-ROSALIND-716628).
History
Citation
Circulation: Genomic and Precision Medicine, 2020, https://doi.org/10.1161/CIRCGEN.120.003030Author affiliation
Department of Cardiovascular SciencesVersion
- AM (Accepted Manuscript)
Published in
Circulation: Genomic and Precision MedicinePublisher
American Heart Associationissn
2574-8300eissn
2574-8300Acceptance date
2020-09-24Copyright date
2020Available date
2020-10-30Publisher DOI
Language
enPublisher version
Usage metrics
Categories
No categories selectedLicence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC