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.

中文翻译：

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骑士国王查尔斯猎犬狗二尖瓣粘液瘤的基因组研究

骑士查尔斯国王猎犬（CKCSs）发生最早，也是粘液性二尖瓣疾病（MMVD）的最高发病率。先前的研究表明该犬种具有该病的多基因遗传性，并揭示了与犬13号和14号染色体区域的相关性。在临床和超声心动图检查后，选择了33个非直接相关的CKCS并归类为病例（n = 16）。如果5岁之前存在MMVD或作为对照（n = 17），如果5岁以后不存在或非常轻微的MMVD。从全血中提取DNA并用Canine 230K SNP BeadChip仪器进行基因分型。将病例和对照与三个互补的基因组分析进行比较（赖特固定指数-F _ST，跨群体扩展单倍型纯合子（XP-EHH）和纯合子运行（ROH），以鉴定杂合子和纯合子区域方面的差异。选择并绘制了最高的1％单核苷酸多态性（SNP），并对基因进行了彻底的研究。发现10个共有基因位于3-11-14-19号染色体上，部分证实了先前的研究。该HEPACAM2，CDK6，和FAH基因，与转化生长因子β（TGF-β）途径和心脏的发展，也出现了ROH分析。总之，这项工作通过鉴定与CKCS中MMVD早期发作有关的基因，扩展了MMVD遗传基础的知识。