Key result
Dual risk-allele homozygosity in LMOD2 and lncRNA linked to ~50-fold higher MMVD risk.
Why the study?
Previous genome-wide association studies identified canine chromosomes 13 and 14 associated with early onset MMVD in Cavalier King Charles Spaniels, prompting whole genome sequencing to pinpoint specific variants.
Does concomitant homozygosity for risk alleles in LMOD2 and a lncRNA increase the risk of myxomatous mitral valve disease in Cavalier King Charles Spaniels?
Case-Control (n=250)
Yes
Does concomitant homozygosity for risk alleles in LMOD2 and a lncRNA increase the risk of myxomatous mitral valve disease in Cavalier King Charles Spaniels?
Identified a combination of genetic variants in LMOD2 and a lncRNA strongly associated with early-onset myxomatous mitral valve disease in Cavalier King Charles Spaniels, enabling potential targeted breeding programs.
May support selective breeding to curb early MMVD in Cavaliers; leaves open causality and human relevance.
A previous genome-wide association study identified regions on canine chromosome (cfa) 13 and 14 associated with early onset myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCS). In the present study, whole genome sequencing (WGS) of 9 CKCS cases (mitral regurgitation (MR) before 4.5 years or congestive heart failure (CHF) at any age due to MMVD) and 10 CKCS controls (no or mild MR after 8 years of age) identified > 2000 genetic variants in the MMVD associated cfa13 and cfa14 regions. Ensembl Variant Effect Predictor (VEP) identified a possible functional impact of 18 variants. These were genotyped in 250 CKCS; 117 cases and 133 controls. The most significantly associated variants were a splice-site variant in a long noncoding RNA (lncRNA) on cfa13, a nonsynonymous variant in HYAL4, a 39 base-pair insertion in LMOD2 and a synonymous variant in ENSCAFG00000024436 (p-values from 2.03E-08 to 4.20E-06). Concomitant homozygosity for risk alleles in LMOD2 and the lncRNA gave an odds-ratio for MMVD of 52.5 compared to homozygosity for the nonrisk alleles (p = 0.00034, 95% CI: 8.8-1023.8). Upon validation of our results in an independent cohort, this gene variant combination in CKCS is expected to enable targeted breeding programs to reduce MMVD prevalence in CKCS.
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Olsen et al. (2026) conducted a case-control in Myxomatous mitral valve disease (MMVD) (n=250). Concomitant homozygosity for risk alleles in LMOD2 and a lncRNA vs. Homozygosity for nonrisk alleles was evaluated on Myxomatous mitral valve disease (MMVD) (OR 52.54, 95% CI 8.75-1023.85, p=0.0003). Concomitant homozygosity for risk alleles in LMOD2 and a lncRNA was strongly associated with myxomatous mitral valve disease, with an OR of 52.54 compared to homozygosity for nonrisk alleles.
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