| Summary: | 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 <i>ABCC9</i>. Sanger sequencing revealed an <i>ABCC9</i> p.R1186Q variant present in a homozygous state in all SCDY/DCM-affected dogs (<i>n</i> = 26). None of the controls genotyped (<i>n</i> = 398) were homozygous for the variant, but 69 were heterozygous carriers, consistent with autosomal recessive inheritance with complete penetrance (<i>p</i> = 4 × 10<sup>−42</sup> for the association of homozygosity for <i>ABCC9</i> 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 <i>ABCC9</i> is a susceptibility gene for SCDY/DCM and highlight the potential application of dog models to predict the clinical significance of human variants.
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