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Detection of Rare Genomic Variants from Pooled Sequencing Using SPLINTER
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Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing

Keren J Carss1, Anna A Baranowska2, Javier Armisen1

  • 1Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca (K.J.C., J.A., Q.W., S.V.V.D., D.V., S.H.L., S.P., C.H.).

Circulation. Genomic and Precision Medicine
|October 30, 2020
PubMed

Insights

Genetic testing reveals few pathogenic variants in spontaneous coronary artery dissection (SCAD) survivors, suggesting a small genetic contribution. Findings link SCAD to renal and connective tissue disorders, highlighting new genes for research.

Area of Science:

  • Cardiovascular Genetics
  • Genomic Medicine
  • Arterial Diseases

Background:

  • Spontaneous coronary artery dissection (SCAD) is an arterial condition primarily affecting women, often linked to pregnancy and fibromuscular dysplasia.
  • The genetic basis of SCAD is not well understood, although variants in genes associated with connective tissue disorders have been implicated.

Purpose of the Study:

  • To evaluate the diagnostic yield of rare variant genetic testing in SCAD survivors.
  • To identify genes and gene sets with significant rare variant enrichment in SCAD.

Main Methods:

  • Whole exome sequencing of 384 SCAD survivors and 13,722 UK Biobank controls.
  • Research diagnostic screening for pathogenic variants.
  • Exome-wide and gene-set rare variant collapsing analyses were performed.

Main Results:

  • Pathogenic variants were identified in 7 genes (PKD1, COL3A1, SMAD3, TGFB2, LOX, MYLK, YY1AP1) in 14 of 384 SCAD survivors.
  • PKD1 was the highest-ranked gene in rare variant collapsing analysis.
  • Gene-set enrichment analysis suggested a role for genes involved in renal function.

Conclusions:

  • Current genetic testing explains disease in a small proportion of SCAD survivors.
  • Findings reinforce the association between SCAD, renal disorders, and connective tissue disorders.
  • Several novel genes warrant further investigation for their role in SCAD pathogenesis.
Abstract

Keywords:
coronary artery dissectiondissectiongeneticsspontaneous

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