Development and validation of animal variant classification guidelines to objectively evaluate genetic variant pathogenicity in domestic animals
Assessing the pathogenicity of a disease-associated genetic variant in animals accurately is vital, both on a population and individual scale. At the population level, breeding decisions based on invalid DNA tests can lead to the incorrect inclusion or exclusion of animals and compromise the long-te...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Veterinary Science |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fvets.2024.1497817/full |
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| author | Fréderique Boeykens Marie Abitbol Heidi Anderson Iris Casselman Caroline Dufaure de Citres Jessica J. Hayward Jens Häggström Mark D. Kittleson Mark D. Kittleson Elvio Lepri Ingrid Ljungvall Maria Longeri Leslie A. Lyons Åsa Ohlsson Luc Peelman Pascale Smets Tommaso Vezzosi Tommaso Vezzosi Frank G. van Steenbeek Bart J.G. Broeckx Bart J.G. Broeckx |
| author_facet | Fréderique Boeykens Marie Abitbol Heidi Anderson Iris Casselman Caroline Dufaure de Citres Jessica J. Hayward Jens Häggström Mark D. Kittleson Mark D. Kittleson Elvio Lepri Ingrid Ljungvall Maria Longeri Leslie A. Lyons Åsa Ohlsson Luc Peelman Pascale Smets Tommaso Vezzosi Tommaso Vezzosi Frank G. van Steenbeek Bart J.G. Broeckx Bart J.G. Broeckx |
| author_sort | Fréderique Boeykens |
| collection | DOAJ |
| description | Assessing the pathogenicity of a disease-associated genetic variant in animals accurately is vital, both on a population and individual scale. At the population level, breeding decisions based on invalid DNA tests can lead to the incorrect inclusion or exclusion of animals and compromise the long-term health of a population, and at the level of the individual animal, lead to incorrect treatment and even life-ending decisions. Criteria to determine pathogenicity are not standardized, i.e., no guidelines for animal variants are available. Here, we aimed to develop and validate guidelines to be used by the community for Mendelian disorders in domestic animals to classify variants in categories based on standardized criteria. These so-called animal variant classification guidelines (AVCG) were based on those developed for humans by The American College of Medical Genetics and Genomics (ACMG). In a direct comparison, 83% of the pathogenic variants were correctly classified with ACMG, while this increased to 92% with AVCG. We described methods to develop datasets for benchmarking the criteria and identified the most optimal in silico variant effect predictor tools. As the reproducibility was high, we classified 72 known disease-associated variants in cats and 40 other disease-associated variants in eight additional species. |
| format | Article |
| id | doaj-art-b7062e0d95804309901cbbee0b945201 |
| institution | OA Journals |
| issn | 2297-1769 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Veterinary Science |
| spelling | doaj-art-b7062e0d95804309901cbbee0b9452012025-08-20T02:19:10ZengFrontiers Media S.A.Frontiers in Veterinary Science2297-17692024-12-011110.3389/fvets.2024.14978171497817Development and validation of animal variant classification guidelines to objectively evaluate genetic variant pathogenicity in domestic animalsFréderique Boeykens0Marie Abitbol1Heidi Anderson2Iris Casselman3Caroline Dufaure de Citres4Jessica J. Hayward5Jens Häggström6Mark D. Kittleson7Mark D. Kittleson8Elvio Lepri9Ingrid Ljungvall10Maria Longeri11Leslie A. Lyons12Åsa Ohlsson13Luc Peelman14Pascale Smets15Tommaso Vezzosi16Tommaso Vezzosi17Frank G. van Steenbeek18Bart J.G. Broeckx19Bart J.G. Broeckx20Laboratory of Animal Genetics, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, Merelbeke, BelgiumUniv Lyon, VetAgro Sup, 69280 Marcy-l’Etoile, France and Institut NeuroMyoGène INMG-PNMG, CNRS UMR5261, INSERM U1315, Faculté de Médecine, Rockefeller, Université Claude Bernard, Lyon, FranceWisdom Panel, Mars Petcare Science and Diagnostics, Helsinki, FinlandLaboratory of Animal Genetics, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, Merelbeke, BelgiumAntagene—Animal Genomics Laboratory, La Tour de Salvagny, FranceDepartment of Biomedical Sciences and Cornell Veterinary Biobank, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesDepartment of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, SwedenSchool of Veterinary Medicine and Epidemiology, University of California, Davis, Davis, CA, United StatesVeterinary Information Network, 777 West Covell Boulevard, Davis, CA, United StatesDepartment of Veterinary Medicine, University of Perugia, Perugia, ItalyDepartment of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, Sweden0Department of Veterinary Medicine and Animal Sciences, University of Milan, Lodi, Italy1Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, United States2Department of Animal Biosciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, SwedenLaboratory of Animal Genetics, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium3Small Animal Department, Ghent University, Merelbeke, Belgium4Italian Veterinary Observatory for Cardiac Diseases (OVIC), Associazione Cardiologi ed Ecografisti Clinici Veterinari (CARDIEC), Bergamo, Italy5Department of Veterinary Sciences, University of Pisa, Pisa, Italy6Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsLaboratory of Animal Genetics, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium7Centre for Clinical Genetics of Companion Animals, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, Merelbeke, BelgiumAssessing the pathogenicity of a disease-associated genetic variant in animals accurately is vital, both on a population and individual scale. At the population level, breeding decisions based on invalid DNA tests can lead to the incorrect inclusion or exclusion of animals and compromise the long-term health of a population, and at the level of the individual animal, lead to incorrect treatment and even life-ending decisions. Criteria to determine pathogenicity are not standardized, i.e., no guidelines for animal variants are available. Here, we aimed to develop and validate guidelines to be used by the community for Mendelian disorders in domestic animals to classify variants in categories based on standardized criteria. These so-called animal variant classification guidelines (AVCG) were based on those developed for humans by The American College of Medical Genetics and Genomics (ACMG). In a direct comparison, 83% of the pathogenic variants were correctly classified with ACMG, while this increased to 92% with AVCG. We described methods to develop datasets for benchmarking the criteria and identified the most optimal in silico variant effect predictor tools. As the reproducibility was high, we classified 72 known disease-associated variants in cats and 40 other disease-associated variants in eight additional species.https://www.frontiersin.org/articles/10.3389/fvets.2024.1497817/full(clinical) genetic testinggenetic variant datasetsinterpretationreproducibilityin silico variant effect predictor toolsacross-species classification |
| spellingShingle | Fréderique Boeykens Marie Abitbol Heidi Anderson Iris Casselman Caroline Dufaure de Citres Jessica J. Hayward Jens Häggström Mark D. Kittleson Mark D. Kittleson Elvio Lepri Ingrid Ljungvall Maria Longeri Leslie A. Lyons Åsa Ohlsson Luc Peelman Pascale Smets Tommaso Vezzosi Tommaso Vezzosi Frank G. van Steenbeek Bart J.G. Broeckx Bart J.G. Broeckx Development and validation of animal variant classification guidelines to objectively evaluate genetic variant pathogenicity in domestic animals Frontiers in Veterinary Science (clinical) genetic testing genetic variant datasets interpretation reproducibility in silico variant effect predictor tools across-species classification |
| title | Development and validation of animal variant classification guidelines to objectively evaluate genetic variant pathogenicity in domestic animals |
| title_full | Development and validation of animal variant classification guidelines to objectively evaluate genetic variant pathogenicity in domestic animals |
| title_fullStr | Development and validation of animal variant classification guidelines to objectively evaluate genetic variant pathogenicity in domestic animals |
| title_full_unstemmed | Development and validation of animal variant classification guidelines to objectively evaluate genetic variant pathogenicity in domestic animals |
| title_short | Development and validation of animal variant classification guidelines to objectively evaluate genetic variant pathogenicity in domestic animals |
| title_sort | development and validation of animal variant classification guidelines to objectively evaluate genetic variant pathogenicity in domestic animals |
| topic | (clinical) genetic testing genetic variant datasets interpretation reproducibility in silico variant effect predictor tools across-species classification |
| url | https://www.frontiersin.org/articles/10.3389/fvets.2024.1497817/full |
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