An <i>ABCC9</i> Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs
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 as...
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| Format: | Article |
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MDPI AG
2023-04-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/5/988 |
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| author | Eva Furrow Nicole Tate Katie Minor Shannon Martinson Shannon Larrabee Marjukka Anttila Meg Sleeper Paula Henthorn |
| author_facet | Eva Furrow Nicole Tate Katie Minor Shannon Martinson Shannon Larrabee Marjukka Anttila Meg Sleeper Paula Henthorn |
| author_sort | Eva Furrow |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T03:42:35Z |
| format | Article |
| id | doaj.art-59931031f2e24987b23de95889fbc94d |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T03:42:35Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-59931031f2e24987b23de95889fbc94d2023-11-18T01:28:56ZengMDPI AGGenes2073-44252023-04-0114598810.3390/genes14050988An <i>ABCC9</i> Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile DogsEva Furrow0Nicole Tate1Katie Minor2Shannon Martinson3Shannon Larrabee4Marjukka Anttila5Meg Sleeper6Paula Henthorn7College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55455, USACollege of Veterinary Medicine, University of Minnesota, St. Paul, MN 55455, USACollege of Veterinary Medicine, University of Minnesota, St. Paul, MN 55455, USAAtlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE CIA 4P3, CanadaCollege of Veterinary Medicine, University of Minnesota, St. Paul, MN 55455, USAPathology, Finnish Food Authority, 00790 Helsinki, FinlandCollege of Veterinary Medicine, University of Florida, Gainesville, FL 32610, USASchool of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USASudden 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.https://www.mdpi.com/2073-4425/14/5/988channelopathycaninesudden cardiac death in the youngmolecular autopsy |
| spellingShingle | Eva Furrow Nicole Tate Katie Minor Shannon Martinson Shannon Larrabee Marjukka Anttila Meg Sleeper Paula Henthorn An <i>ABCC9</i> Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs Genes channelopathy canine sudden cardiac death in the young molecular autopsy |
| title | An <i>ABCC9</i> Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs |
| title_full | An <i>ABCC9</i> Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs |
| title_fullStr | An <i>ABCC9</i> Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs |
| title_full_unstemmed | An <i>ABCC9</i> Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs |
| title_short | An <i>ABCC9</i> Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs |
| title_sort | i abcc9 i missense variant is associated with sudden cardiac death and dilated cardiomyopathy in juvenile dogs |
| topic | channelopathy canine sudden cardiac death in the young molecular autopsy |
| url | https://www.mdpi.com/2073-4425/14/5/988 |
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