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Owing to poor response to therapy and progression of symptoms, the puppies were euthanised. Post\u2010mortem histology revealed perineuronal incrustations in the spinal cord, suggestive of ischemia or neuronal necrosis. Clinical symptoms, combined with necropsy and histopathology findings, led to a suspicion of startle disease, prompting a referral to a specialised clinical genetics centre. Whole exome sequencing (WES) of the nuclear family identified a homozygous truncating variant in the <jats:italic>SLC6A5<\/jats:italic> gene in affected individuals, with both unaffected parents being heterozygous. Additional population screening found three phenotypically unaffected carriers, indicating that the variant segregates within the Old English Sheepdog breed. This raises concerns about the management of carriers and their breeding contributions if not properly guided by DNA testing. This study addresses a frameshift variant <jats:italic>SLC6A5:c.1322del<\/jats:italic> found in Old English Sheepdogs. Next to this, the value of genetic counselling and clinical genetics services in breeding programmes is highlighted to identify carriers and guide informed breeding decisions. Finally, the findings demonstrate the utility of WES in veterinary diagnostics and provide practical insights for breeders, veterinarians and geneticists to improve the health and welfare of Old English Sheepdogs.<\/jats:p>","DOI":"10.1111\/age.70003","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T22:52:54Z","timestamp":1741733574000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A frameshift variant in the <i>SLC6A5<\/i> gene is associated with startle disease in a family of Old English Sheepdogs"],"prefix":"10.1111","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5717-5544","authenticated-orcid":false,"given":"Fr\u00e9derique","family":"Boeykens","sequence":"first","affiliation":[{"name":"Laboratory of Animal Genetics, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine Ghent University  Merelbeke Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Hermans","sequence":"additional","affiliation":[{"name":"Nesto Veterinary Referral Center Orion  Herentals Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Adant","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Genetics, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine Ghent University  Merelbeke Belgium"},{"name":"Centre for Clinical Genetics of Companion Animals, Faculty of Veterinary Medicine Ghent University  Merelbeke Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert","family":"De Jonge","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine Ghent University  Merelbeke Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"Chiers","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine Ghent University  Merelbeke Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenny","family":"Bossens","sequence":"additional","affiliation":[{"name":"Nesto Veterinary Referral Center Orion  Herentals Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart J. 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