Post-Doctoral Scholar & Veterinary Student North Carolina State University College of Veterinary Medicine Raleigh, NC, United States
Background – Hypertrophic cardiomyopathy (HCM) is a naturally-occurring disease characterized by left ventricular (LV) thickening that commonly affects humans and cats, but rarely dogs. 1,500 and three genetic mutations explain HCM in humans and cats, respectively. To date, no variants have been described in dogs. HCM in a Golden Retriever (GR) family was identified following sudden cardiac death of three puppies. Hypothesis/Objectives – An underlying deleterious sarcomeric variant that changes protein structure and/or function explains HCM in this GR family. Animals – A Whole-Genome Association Study (WGAS) population of three HCM-affected puppies and 11 echocardiographically-confirmed normal nuclear members (n=14). 2,771 previously sequenced unphenotyped dogs. A validation cohort of 45 HCM-unaffected GRs. Additional LV tissues from five control dogs. Methods – A WGAS assuming an autosomal-recessive mode of inheritance (PAllelic-value < 0.024). Allele frequencies of variants were calculated in the unphenotyped cohort of previously WGSed samples and subsequently interrogated in the phenotyped GR population via PCR. LV tissue immunofluorescence of candidate protein(s) was performed for the HCM-affected and -unaffected groups. Results – WGAS identified a single segregating missense mutation in Cardiac Troponin-I (TNNI3). This variant was not observed in the unphenotyped cohort and only one carrier was identified in the validation population GRs. Immunofluorescent staining of LV tissues did not reveal obvious aberrant protein localization and/or expression at the sarcomeric-level. Conclusions and Clinical Importance – This variant represents the first-ever reported pathogenic HCM variant in any canine species; its identification holds promise for establishing translational models, genetic screening, and early disease prevention.
