An ABCC9 Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs

Genes (Basel). 2023 Apr 27;14(5):988. doi: 10.3390/genes14050988.

Abstract

Sudden cardiac death in the young (SCDY) is a devastating event that often has an underlying genetic basis. Manchester Terrier dogs offer a naturally occurring model of SCDY, with sudden death of puppies as the manifestation of an inherited dilated cardiomyopathy (DCM). We performed a genome-wide association study for SCDY/DCM in Manchester Terrier dogs and identified a susceptibility locus harboring the cardiac ATP-sensitive potassium channel gene ABCC9. Sanger sequencing revealed an ABCC9 p.R1186Q variant present in a homozygous state in all SCDY/DCM-affected dogs (n = 26). None of the controls genotyped (n = 398) were homozygous for the variant, but 69 were heterozygous carriers, consistent with autosomal recessive inheritance with complete penetrance (p = 4 × 10-42 for the association of homozygosity for ABCC9 p.R1186Q with SCDY/DCM). This variant exists at low frequency in human populations (rs776973456) with clinical significance previously deemed uncertain. The results of this study further the evidence that ABCC9 is a susceptibility gene for SCDY/DCM and highlight the potential application of dog models to predict the clinical significance of human variants.

Keywords: canine; channelopathy; molecular autopsy; sudden cardiac death in the young.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathy, Dilated* / genetics
  • Cardiomyopathy, Dilated* / veterinary
  • Death, Sudden, Cardiac* / etiology
  • Death, Sudden, Cardiac* / veterinary
  • Dog Diseases* / genetics
  • Dogs
  • Genome-Wide Association Study
  • Genotype
  • Mutation, Missense
  • Sulfonylurea Receptors* / genetics

Substances

  • Sulfonylurea Receptors