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


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.

SUBMITTER: Furrow E 

PROVIDER: S-EPMC10218235 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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An <i>ABCC9</i> Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs.

Furrow Eva E   Tate Nicole N   Minor Katie K   Martinson Shannon S   Larrabee Shannon S   Anttila Marjukka M   Sleeper Meg M   Henthorn Paula P  

Genes 20230427 5


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>  ...[more]

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