Genetic Panel Screening of Nearly 100 Mutations Reveals New Insights into the Breed Distribution of Risk Variants for Canine Hereditary Disorders

BackgroundThe growing number of identified genetic disease risk variants across dog breeds challenges the current state-of-the-art of population screening, veterinary molecular diagnostics, and genetic counseling. Multiplex screening of such variants is now technologically feasible, but its practical potential as a supportive tool for canine breeding, disease diagnostics, pet care, and genetics research is still unexplored.ResultsTo demonstrate the utility of comprehensive genetic panel screening, we tested nearly 7000 dogs representing around 230 breeds for 93 disease-associated variants using a custom-designed genotyping microarray (the MyDogDNA® panel test). In addition to known breed disease-associated mutations, we discovered 15 risk variants in a total of 34 breeds in which their presence was previously undocumented. We followed up on seven of these genetic findings to demonstrate their clinical relevance. We report additional breeds harboring variants causing factor VII deficiency, hyperuricosuria, lens luxation, von Willebrand’s disease, multifocal retinopathy, multidrug resistance, and rod-cone dysplasia. Moreover, we provide plausible molecular explanations for chondrodysplasia in the Chinook, cerebellar ataxia in the Norrbottenspitz, and familiar nephropathy in the Welsh Springer Spaniel.ConclusionsThese practical examples illustrate how genetic panel screening represents a comprehensive, efficient and powerful diagnostic and research discovery tool with a range of applications in veterinary care, disease research, and breeding. We conclude that several known disease alleles are more widespread across different breeds than previously recognized. However, careful follow up studies of any unexpected discoveries are essential to establish genotype-phenotype correlations, as is readiness to provide genetic counseling on their implications for the dog and its breed.

背景：随着犬种中识别出的遗传疾病风险变异种类的日益增多，对人群筛查、兽医分子诊断和遗传咨询领域的当前技术水平提出了挑战。此类变异的多重筛查在技术上已可行，但其作为犬类育种、疾病诊断、宠物护理和遗传研究辅助工具的实践潜力仍待探索。结果：为了展示全面遗传检测面板的实用性，我们使用定制设计的基因分型微阵列（MyDogDNA®面板测试）对约230个品种的近7000只犬进行了93种疾病相关变异的检测。除了已知的品种疾病相关突变外，我们在34个品种中发现了15个之前未被记录的风险变异。我们对其中七个遗传发现进行了后续研究，以证明其临床相关性。我们报告了携带导致因子VII缺乏、高尿酸尿症、晶状体脱位、冯·维勒布兰德病、多灶性视网膜病变、多药耐药性和视杆细胞-视锥细胞发育不良变异的其他品种。此外，我们为奇努克犬的软骨发育不良、诺尔博腾斯皮茨犬的共济失调以及威尔士 Springer Spaniel犬的家族性肾病提供了合理的分子解释。结论：这些实际案例展示了遗传检测面板作为一种全面、高效且强大的诊断和研究发现工具，在兽医护理、疾病研究和育种等领域具有广泛的应用。我们得出结论，一些已知的疾病等位基因在不同品种中的分布比之前认识的更为广泛。然而，对任何意外发现的仔细后续研究对于建立基因型-表型关联至关重要，同样重要的是准备就其对犬及其品种的影响提供遗传咨询服务。