Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing
| Autor: | Sally L. Dunwoodie, Lucy McGrath-Cadell, Abtehale Al-Hussaini, Slavé Petrovski, Eleni Giannoulatou, Sri V V Deevi, Nabila Bouatia-Naji, Keren J Carss, David Adlam, Tom R. Webb, Ingrid S. Tarr, Diluka Premawardhana, Nilesh J. Samani, Stephen E. Hamby, Alice Wood, Carolina Haefliger, David W.M. Muller, Robert M. Graham, Javier Armisen, Samuel H. Lewis, Deevia Kotecha, Quanli Wang, Anna A Baranowska, Dimitrios Vitsios, Diane Fatkin, S. Hesselson, Siiri E. Iismaa |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty Epicardial coronary artery Coronary Vessel Anomalies Dissection (medical) 030204 cardiovascular system & hematology coronary artery dissection DNA sequencing Cohort Studies Machine Learning 03 medical and health sciences Young Adult 0302 clinical medicine Internal medicine Genetic variation Exome Sequencing medicine Polycystic kidney disease Humans genetics Vascular Diseases Artery dissection spontaneous Exome sequencing Aged Models Genetic business.industry Genome Human Genetic Variation General Medicine Original Articles Middle Aged medicine.disease United Kingdom 3. Good health 030104 developmental biology dissection Cardiology ComputingMethodologies_DOCUMENTANDTEXTPROCESSING Female Scad business |
| Zdroj: | Circulation. Genomic and Precision Medicine |
| ISSN: | 2574-8300 |
| Popis: | Supplemental Digital Content is available in the text. 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. |
| Databáze: | OpenAIRE |
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