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Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs

Hundreds of genetic variants implicated in Mendelian disease have been characterized in dogs and commercial screening is being offered for most of them worldwide. There is typically limited information available regarding the broader population frequency of variants and uncertainty regarding their f...

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Autores principales: Donner, Jonas, Freyer, Jamie, Davison, Stephen, Anderson, Heidi, Blades, Matthew, Honkanen, Leena, Inman, Laura, Brookhart-Knox, Casey A., Louviere, Annette, Forman, Oliver P., Chodroff Foran, Rebecca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9997962/
https://www.ncbi.nlm.nih.gov/pubmed/36848397
http://dx.doi.org/10.1371/journal.pgen.1010651
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author Donner, Jonas
Freyer, Jamie
Davison, Stephen
Anderson, Heidi
Blades, Matthew
Honkanen, Leena
Inman, Laura
Brookhart-Knox, Casey A.
Louviere, Annette
Forman, Oliver P.
Chodroff Foran, Rebecca
author_facet Donner, Jonas
Freyer, Jamie
Davison, Stephen
Anderson, Heidi
Blades, Matthew
Honkanen, Leena
Inman, Laura
Brookhart-Knox, Casey A.
Louviere, Annette
Forman, Oliver P.
Chodroff Foran, Rebecca
author_sort Donner, Jonas
collection PubMed
description Hundreds of genetic variants implicated in Mendelian disease have been characterized in dogs and commercial screening is being offered for most of them worldwide. There is typically limited information available regarding the broader population frequency of variants and uncertainty regarding their functional and clinical impact in ancestry backgrounds beyond the discovery breed. Genetic panel screening of disease-associated variants, commercially offered directly to the consumer or via a veterinary clinician, provides an opportunity to establish large-scale cohorts with phenotype data available to address open questions related to variant prevalence and relevance. We screened the largest canine cohort examined in a single study to date (1,054,293 representative dogs from our existing cohort of 3.5 million; a total of 811,628 mixed breed dogs and 242,665 purebreds from more than 150 countries) to examine the prevalence and distribution of a total of 250 genetic disease-associated variants in the general population. Electronic medical records from veterinary clinics were available for 43.5% of the genotyped dogs, enabling the clinical impact of variants to be investigated. We provide detailed frequencies for all tested variants across breeds and find that 57% of dogs carry at least one copy of a studied Mendelian disease-associated variant. Focusing on a subset of variants, we provide evidence of full penetrance for 10 variants, and plausible evidence for clinical significance of 22 variants, on diverse breed backgrounds. Specifically, we report that inherited hypocatalasia is a notable oral health condition, confirm that factor VII deficiency presents as subclinical bleeding propensity and verify two genetic causes of reduced leg length. We further assess genome-wide heterozygosity levels in over 100 breeds, and show that a reduction in genome-wide heterozygosity is associated with an increased Mendelian disease variant load. The accumulated knowledge represents a resource to guide discussions on genetic test relevance by breed.
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spelling pubmed-99979622023-03-10 Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs Donner, Jonas Freyer, Jamie Davison, Stephen Anderson, Heidi Blades, Matthew Honkanen, Leena Inman, Laura Brookhart-Knox, Casey A. Louviere, Annette Forman, Oliver P. Chodroff Foran, Rebecca PLoS Genet Research Article Hundreds of genetic variants implicated in Mendelian disease have been characterized in dogs and commercial screening is being offered for most of them worldwide. There is typically limited information available regarding the broader population frequency of variants and uncertainty regarding their functional and clinical impact in ancestry backgrounds beyond the discovery breed. Genetic panel screening of disease-associated variants, commercially offered directly to the consumer or via a veterinary clinician, provides an opportunity to establish large-scale cohorts with phenotype data available to address open questions related to variant prevalence and relevance. We screened the largest canine cohort examined in a single study to date (1,054,293 representative dogs from our existing cohort of 3.5 million; a total of 811,628 mixed breed dogs and 242,665 purebreds from more than 150 countries) to examine the prevalence and distribution of a total of 250 genetic disease-associated variants in the general population. Electronic medical records from veterinary clinics were available for 43.5% of the genotyped dogs, enabling the clinical impact of variants to be investigated. We provide detailed frequencies for all tested variants across breeds and find that 57% of dogs carry at least one copy of a studied Mendelian disease-associated variant. Focusing on a subset of variants, we provide evidence of full penetrance for 10 variants, and plausible evidence for clinical significance of 22 variants, on diverse breed backgrounds. Specifically, we report that inherited hypocatalasia is a notable oral health condition, confirm that factor VII deficiency presents as subclinical bleeding propensity and verify two genetic causes of reduced leg length. We further assess genome-wide heterozygosity levels in over 100 breeds, and show that a reduction in genome-wide heterozygosity is associated with an increased Mendelian disease variant load. The accumulated knowledge represents a resource to guide discussions on genetic test relevance by breed. Public Library of Science 2023-02-27 /pmc/articles/PMC9997962/ /pubmed/36848397 http://dx.doi.org/10.1371/journal.pgen.1010651 Text en © 2023 Donner et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Donner, Jonas
Freyer, Jamie
Davison, Stephen
Anderson, Heidi
Blades, Matthew
Honkanen, Leena
Inman, Laura
Brookhart-Knox, Casey A.
Louviere, Annette
Forman, Oliver P.
Chodroff Foran, Rebecca
Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs
title Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs
title_full Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs
title_fullStr Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs
title_full_unstemmed Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs
title_short Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs
title_sort genetic prevalence and clinical relevance of canine mendelian disease variants in over one million dogs
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9997962/
https://www.ncbi.nlm.nih.gov/pubmed/36848397
http://dx.doi.org/10.1371/journal.pgen.1010651
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