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

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

Eva Furrow  1 , Nicole Tate  1 , Katie Minor  1 , Shannon Martinson  2 , Shannon Larrabee  1 , Marjukka Anttila  3 , Meg Sleeper  4 , Paula Henthorn  5
Affiliations

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

Eva Furrow et al. Genes (Basel). .

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.

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Conflict of interest statement

E.F. and K.M. are members of the University of Minnesota Canine Genetics Laboratory, which offers genetic testing for the ABCC9 variant in dogs; a portion of proceeds supports ongoing research for the laboratory. The other authors (N.T., S.M., S.L., M.A., M.S. and P.H.) declare they have no conflict of interest.

Figures

Figure 1
Figure 1
Right ventricle from a juvenile Manchester Terrier showing patchy regions of pallor in the myocardium (arrows). HE, scale = 200 µm. Upper inset: In these areas, there is myofiber degeneration and loss with replacement by connective tissue and scant mononuclear cells. Degenerate myofibers are present in the upper right half of the inset and are small (attenuated) with flocculent cytoplasm. Normal myofibers are evident at the lower right corner for comparison. HE, scale = 20 µm. Lower inset: Staining with Masson’s trichrome demonstrates collagen deposition (blue) in the affected regions. Scale = 20 µm.
Figure 2
Figure 2
Photographs of two closely related dog breeds affected by sudden cardiac death of the young and dilated cardiomyopathy: (a) Manchester Terrier dog; (b) English Toy Terrier dog.
Figure 3
Figure 3
Manhattan plot of a mixed model genome-wide association study for sudden cardiac death in the young and dilated cardiomyopathy in 12-case and 36-control Manchester Terrier dogs. There is a strong signal on chromosome 27 (p = 5 × 10−17 Wald test) at a locus that harbors genes encoding subunits of an ATP-sensitive cardiac potassium channel (ABCC9 and KCNJ8). Single nucleotide polymorphisms above the black dotted line achieved a p value < 10−8.
Figure 4
Figure 4
Representative Sanger sequencing electropherograms for wild-type, heterozygous, and homozygous affected genotypes for the ABCC9 p.R1186Q variant (ENSCAFT00000043641.4 c.3557G > A) associated with sudden cardiac death in the young and dilated cardiomyopathy in a natural dog model.
See this image and copyright information in PMC

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