A Genomic Study of Myxomatous Mitral Valve Disease in Cavalier King Charles Spaniels

SIMPLE SUMMARY: Myxomatous mitral valve disease is the most common acquired cardiopathy in dogs. The earliest onset and the highest incidence of the disease is found in cavalier King Charles spaniels. Previous studies have suggested a polygenic inheritance of the disease in this breed. Here, we aim to expand the knowledge of the genetic basis of early-onset myxomatous mitral valve disease in cavalier King Charles spaniels. The selection of cases and controls is a crucial point of the study and is based on clinical, echocardiographic, and genealogical examinations. We perform three complementary genomic analyses that have never been used for investigating this pathology to identify 10 genes differentiating the genomes of the two groups. After examining these genes, we conclude that HEPACAM2, CDK6, and FAH (which are also related to transforming growth factor β (TGF-β) pathway, probably associated with the development of the disease) are the ones that are most likely involved in the pathogenesis of myxomatous mitral valve disease. ABSTRACT: Cavalier King Charles spaniels (CKCSs) show the earliest onset and the highest incidence of myxomatous mitral valve disease (MMVD). Previous studies have suggested a polygenic inheritance of the disease in this breed and revealed an association with regions on canine chromosomes 13 and 14. Following clinical and echocardiographic examinations, 33 not-directly-related CKCSs were selected and classified as cases (n = 16) if MMVD was present before 5 years of age or as controls (n = 17) if no or very mild MMVD was present after 5 years of age. DNA was extracted from whole blood and genotyped with a Canine 230K SNP BeadChip instrument. Cases and controls were compared with three complementary genomic analyses (Wright’s fixation index—F(ST), cross-population extended haplotype homozygosity—XP-EHH, and runs of homozygosity—ROH) to identify differences in terms of heterozygosity and regions of homozygosity. The top 1% single-nucleotide polymorphisms (SNPs) were selected and mapped, and the genes were thoroughly investigated. Ten consensus genes were found localized on chromosomes 3-11-14-19, partially confirming previous studies. The HEPACAM2, CDK6, and FAH genes, related to the transforming growth factor β (TGF-β) pathway and heart development, also emerged in the ROH analysis. In conclusion, this work expands the knowledge of the genetic basis of MMVD by identifying genes involved in the early onset of MMVD in CKCSs.