Muscle disease test validation study
With the increasing recognition of the importance of genetic disease in horses and other livestock, and the development of new technologies such as whole genome sequencing (WGS) and whole exome sequencing (WES), there is an increased commercial interest in the rapid development and marketing of genetic tests for horses. WGS, specifically, is capable of identifying many dozens of alleles with predicted effects on protein structure or function that may or may not contribute to disease 1,2,3. However, it is critical that researchers conclusively demonstrate that tests based on alleles identified only by WGS are disease-causing 1,2,4.
The development and marketing of genetic tests based only on predicted effects of the allele on a protein, with incomplete assessment or acquisition of other genetic, informatic and experimental evidence, has important implications and consequences. False assignment of alleles as disease-causing and commercialization of genetic tests that are incompletely validated can have severe consequences for horses, horse owners and veterinarians and can result in incorrect diagnosis and prognosis, inappropriate treatment and management of affected individuals, poor breeding decisions, and a loss of public confidence in genetic testing and genetic research 1.
We feel it is extremely important that the equine genome research community works to generate data that will either uphold or invalidate claims of accurate and clinically useful diagnostic tests for which there is no publicly available data. Rising concern about commercialization of genetic tests for horses without documented scientific evidence has led a world-wide group of equine genetic researchers to draft a “Consensus Statement on the Translation and Application of Genomics in the Equine Industries.”
It is also important for researchers, owners, breeders, veterinarians and commercial companies to recognize that diseases that were once assumed to be simple Mendelian traits are often more complicated than previously thought. For example, type 1 polysaccharide storage myopathy (PSSM1) caused by a mutation in the GYS1 gene, is modified by factors including diet and exercise, the presence of a RYR1 mutation, and the individual’s genetic background, including breed 5–7. Only by considering the possible impact of all potential risk and disease modifying alleles, environmental factors, as well as likely clinical outcomes based on genetic background, can appropriate decisions be made by owners, veterinarians and breeders.
In this study we aim to use our long-term expertise in genetic muscle disease in horses combined with our large network of muscle disease cases and the development of valid genetic tests to determine if the alleles currently marketed for genetic testing of type 2 polysaccharide storage myopathy (PSSM2), myofibrillar myopathy (MFM), and recurrent exertional rhabdomyolysis (RER) are indeed associated with muscle disease. In addition to looking for the impact of these alleles singly or in combination with one another, we will also determine if these alleles modify clinical muscle disease in horses with one of the four published disease mutations (HYPP, IMM, MH, PSSM1), and determine if diet or exercise impact disease expression.
For more detailed explanations on how we examine genetic muscle disease in horses, please visit:
- Is this disease genetic?
- Mendelian Inheritance
- Simple v. complex genetic diseases
- Clinical Signs of Muscle Disease
How can you contribute?
We are requesting the help of horse owners to assist in this study by doing the following:
- Provide information in our Muscle Disease in Horses survey for a horse on your property with suspected or diagnosed muscle disease.
- Provide the same information in the same survey for another horse of similar age and breed on your property without suspected or diagnosed muscle disease.
- Upload photos, videos, bloodwork results (if available), muscle biopsy results (if available), and genetic testing results (if available) for each horse to our secure folder on Dropbox
- Submit hair root or blood samples from each horse for genetic analysis as well as hay, grain, and supplement samples.
New Participants - please find all details for participating in this study in the links below:
- Participation requirements
- Participant instructions
- Frequently Asked Questions (FAQs)
- Owner Checklist
- Copy of Owner's Informed Consent - Muscle Disease in Horses
Quick Access Links for Returning Participants:
- Muscle Disease in Horses Survey
- Dropbox link
- Owner Checklist
- Participant instructions
- Sample submission form – affected horses
- Sample submission form – unaffected Horses
Do you have more specific questions not answered on our website? Please email email@example.com.
- Macarthur DG, Manolio TA, Dimmock DP, et al. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014;508. doi:10.1038/nature13127.
- Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. 2015. doi:10.1038/gim.2015.30.
- Bell CJ, Dinwiddie DL, Miller NA, et al. Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing. Sci Transl Med. 2011;3(65):65ra4-65ra4. doi:10.1126/scitranslmed.3001756.
- Goldstein DB, Allen A, Keebler J, et al. Sequencing studies in human genetics: design and interpretation. Nat Rev Genet. 2013;14(7):460-470. doi:10.1038/nrg3455.
- McCue ME, Valberg SJ, Miller MB, et al. Glycogen synthase (GYS1) mutation causes a novel skeletal muscle glycogenosis. Genomics. 2008;91(5). doi:10.1016/j.ygeno.2008.01.011.
- McCue ME, Valberg SJ, Lucio M, Mickelson JR. Glycogen synthase 1 (GYS1) mutation in diverse breeds with polysaccharide storage myopathy. J Vet Intern Med. 2008;22(5). doi:10.1111/j.1939-1676.2008.0167.x.
- McCue ME, Valberg SJ, Jackson M, Borgia L, Lucio M, Mickelson JR. Polysaccharide storage myopathy phenotype in quarter horse-related breeds is modified by the presence of an RYR1 mutation. NeuromusculDisord. 2009;19(1):37-43. http://www.ncbi.nlm.nih.gov/pubmed/19056269.