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Commercial genetic testing for type 2 polysaccharide storage myopathy and myofibrillar myopathy does not correspond to a histopathological diagnosis.
Abstract: Commercial genetic tests for type 2 polysaccharide storage myopathy (PSSM2) and myofibrillar myopathy (MFM) have not been validated by peer-review, and formal regulation of veterinary genetic testing is lacking. Objective: To compare genotype and allele frequencies of commercial test variants (P variants) in MYOT (P2; rs1138656462), FLNC (P3a; rs1139799323), FLNC (P3b; rs1142918816) and MYOZ3 (P4; rs1142544043) between Warmblood (WB) and Arabian (AR) horses diagnosed with PSSM2/MFM by muscle histopathology, and phenotyped breed-matched controls. To quantify variant frequency in public repositories of ancient and modern horse breeds. Methods: Cross sectional using archived clinical material and publicly available data. Methods: We studied 54 control-WB, 68 PSSM2/MFM-WB, 30 control-AR, 30 PSSM2/MFM-AR and 205 public genotypes. Variants were genotyped by pyrosequencing archived DNA. Genotype and allele frequency, and number of variant alleles or loci were compared within breed between controls, PSSM2/MFM combined and MFM or PSSM2 horses considered separately using additive/genotypic and dominant models (Fisher's exact tests). Variant frequencies in modern, early domestic and Przewalski horses were determined from a public data repository. Results: There was no significant association between any P locus and a histopathological diagnosis of PSSM2/MFM, and no difference between control and myopathic horses in total loci with alternative alleles, or total alternate alleles when PSSM2/MFM was considered combined or separately as PSSM2 or MFM. For all tests, sensitivity was <0.33. Allele frequencies in WB (controls/cases) were: 8%/15% (P2), 5%/6% (P3a/b) and 9%/13% (P4); in AR, frequencies were: 12%/17% (P2), 2%/2% (P3a/b) and 7%/12% (P4). All P variants were present in early domestic (400- to 5500-year-old) horses and P2 present in the Przewalski. Conclusions: Because of the lack of significant association between a histopathological diagnosis of PSSM2 or MFM and the commercial genetic test variants P2, P3 and P4 in WB and AR, we cannot recommend the use of these variant genotypes for selection and breeding, prepurchase examination or diagnosis of a myopathy.
© 2020 The Authors. Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.
Publication Date: 2020-10-29 PubMed ID: 32896939PubMed Central: PMC7937766DOI: 10.1111/evj.13345Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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The research examines the efficacy of commercial genetic tests for diagnosing type 2 polysaccharide storage myopathy (PSSM2) and myofibrillar myopathy (MFM), diseases occurring in Arabian and Warmblood horses. The evaluation revealed a lack of significant association between histopathological diagnosis of these conditions and genetic variants tested, suggesting the tests’ limited usefulness for diagnosis or breeding decisions.
Research Objectives
- The primary goal of the study included comparing the genotype (genetic makeup) and allele (different forms of the gene) frequencies of commercial test variants in MYOT, FLNC, and MYOZ3 genes between Warmblood (WB) and Arabian (AR) horses.
- These horses either had a histopathologically confirmed diagnosis of PSSM2/MFM, or they were healthy controls from the same breeds.
- The researchers also wanted to calculate how frequently these variants occur across a broad sample of horse breeds, both in modern and ancient times.
Research Methods
- This cross-sectional study used past clinical material and publicly available data.
- A total of 387 horses were studied, which included control and PSSM2/MFM diagnosed from both the Warmblood and Arabian breeds, and a large public-genotype group.
- Archived DNA was used to genotype the variant, and different statistical models were employed to compare genotypes and allele frequencies within breeds between the controls and the PSSM2/MFM diagnosed horses.
- Also, variant frequencies in modern, early domestic and Przewalski horses were determined from a public data repository.
Research Findings
- The main finding of the study was that there was no significant correlation between any of the commercial test variants (P2, P3, and P4) and a histopathologically confirmed diagnosis of PSSM2/MFM.
- In addition, there was no difference between the control and myopathic horses concerning the total loci (gene locations) with alternative alleles or total alternate alleles when considering PSSM2/MFM as combined or separately as PSSM2 or MFM.
- It was also found that all the variants were present in early domestic horses (400- to 5500-year-old) and P2 present in the Przewalski breed, a wild horse.
Conclusions
- This study concludes that due to the absence of a significant relationship between histopathological diagnosis of PSSM2 or MFM and the commercial genetic variants, these commercial genetic tests are not recommended for selection and breeding or pre-purchase examination or diagnosis of these myopathies in Warmblood and Arabian horses.
Cite This Article
APA
Valberg SJ, Finno CJ, Henry ML, Schott M, Velez-Irizarry D, Peng S, McKenzie EC, Petersen JL.
(2020).
Commercial genetic testing for type 2 polysaccharide storage myopathy and myofibrillar myopathy does not correspond to a histopathological diagnosis.
Equine Vet J, 53(4), 690-700.
https://doi.org/10.1111/evj.13345 Publication
Researcher Affiliations
- Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA, USA.
- Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA.
- Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA.
- Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA, USA.
- Department of Clinical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA.
- Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE, USA.
MeSH Terms
- Animals
- Cross-Sectional Studies
- Genetic Testing / veterinary
- Horse Diseases / diagnosis
- Horse Diseases / genetics
- Horses
- Muscle, Skeletal
- Myopathies, Structural, Congenital
- Polysaccharides
Grant Funding
- L40 TR001136 / NCATS NIH HHS
- L40TR001136 / Foundation for the National Institutes of Health
- Mary Anne McPhail Endowment at Michigan State University
Conflict of Interest Statement
S.J. Valberg runs the Neuromuscular Diagnostic Laboratory at Michigan State University that processes muscle biopsies through the Michigan State Veterinary Diagnostic Laboratory. She has no personal financial interest in muscle biopsy submissions. S.J. Valberg and other colleagues license commercial laboratories to perform type 1 PSSM testing and personally receive royalties; this test was not part of the analysis in the current proposal. Other authors report no competing interests.
References
This article includes 40 references
Citations
This article has been cited 4 times.- Valberg SJ, Henry ML, Herrick KL, Velez-Irizarry D, Finno CJ, Petersen JL. Absence of myofibrillar myopathy in Quarter Horses with a histopathological diagnosis of type 2 polysaccharide storage myopathy and lack of association with commercial genetic tests. Equine Vet J 2023 Mar;55(2):230-238.
- Williams ZJ, Velez-Irizarry D, Gardner K, Valberg SJ. Integrated proteomic and transcriptomic profiling identifies aberrant gene and protein expression in the sarcomere, mitochondrial complex I, and the extracellular matrix in Warmblood horses with myofibrillar myopathy. BMC Genomics 2021 Jun 11;22(1):438.
- Lindsay-McGee V, Massey C, Li YT, Clark EL, Psifidi A, Piercy RJ. Characterisation of phenotypic patterns in equine exercise-associated myopathies. Equine Vet J 2025 Mar;57(2):347-361.
- Durward-Akhurst SA, Marlowe JL, Schaefer RJ, Springer K, Grantham B, Carey WK, Bellone RR, Mickelson JR, McCue ME. Predicted genetic burden and frequency of phenotype-associated variants in the horse. Sci Rep 2024 Apr 10;14(1):8396.
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