Ontiveros ES, Ueda Y, 99 Lives Consortium, et al. Precision medicine validation: identifying the MYBPC3 A31P variant with whole-genome sequencing in two Maine Coon cats with hypertrophic cardiomyopathy. J Feline Med Surg. 2018 Dec 18:1098612X18816460. doi: 10.1177/1098612X18816460. [Epub ahead of print]
One of the most common forms of heart disease in cats is hypertrophic cardiomyopathy (HCM). Winn Feline Foundation has long been supportive of research about HCM in cats (the Ricky Fund) and a previous Winn-funded study of a colony of Maine Coon (MC) cats with HCM ultimately led to the identification of the MYBPC3 A31P variant in Maine coon cats by the candidate gene approach. Another Winn-funded study further identified the R820W MYBPC3 HCM variant in the Ragdoll breed of cats also through the candidate gene approach.
Because of limitations to the candidate gene approach, whole-genome sequencing (WGS) has emerged as a powerful tool to determine variants associated with inherited diseases. Current next-generation sequencing (NGS) technology has led to a decrease in WGS cost and, therefore, higher integration of its use for precision medicine. Researchers now find conducting NGS studies in cats beneficial for the detection of novel disease-causing genetic variants, such as single nucleoside polymorphism (SNP) and/or insertion/deletions (indels). Winn has long been supportive of the 99 Lives Cat Genome Sequencing Initiative that offers a large control group of cats that have been whole genome sequenced. This work has already led to significant advances in the healthcare of cats.
In this proof-of-concept study, the authors’ goal was to demonstrate the efficacy of WGS by identifying the MYBPC3 A31P variant in two cats affected by HCM, one MC and one MC/domestic shorthair cross (MCX) that were distantly related when compared with 79 controls of various breeds. This would be an important step in validating using this methodology for future genetic studies that look to identify other novel HCM variants in cats. In addition, previous studies have published results showing that the MC/MCX cat MYBPC3 A31P variant may not be the sole HCM-associated variant in this breed. Additional genetic studies are needed to determine the presence or absence of other relevant variants associated with HCM in MC/MCX cats.
After strict filtering, four variants were identified in the two MC/MCX cats with HCM when compared to the 79 controls. Three of the four variants identified in genes did not segregate with disease in a separate group of seven HCM-affected and five control MC/MCX cats. The last and fourth variant, MYBPC3, segregated with disease status. This gene was found to be previously associated with heart disease and encodes for a protein with sarcomeric (heart muscle) function. One candidate variant was noted in the gene SLITRK5. Because this gene has been previously associated with heart disease though not with a HCM-associated gene and also did not segregate with HCM status, the authors comment that such variants warrant future consideration in feline HCM, potentially in the role of a compound variant and modifier gene.
To the authors’ knowledge, this was the first WGS study that used two distantly related HCM cases to identify a disease-causing variant. One limitation of the study is that a pedigree analysis to determine the pattern of inheritance was not performed. The authors also state that the efficient variant filtering and successful identification of the known MYBPC3 A31P variant demonstrates the huge potential of this technology and the worth of the 99 Lives Cat Genome Sequencing Initiative. This methodology can be used to discover variants associated with HCM in a small sample cat group when compared with a large control population. Determining these novel variants can lead to a genetic test to reduce the prevalence of this disease in cats. (VT)
Kittleson MD, Meurs KM, Harris SP. The genetic basis of hypertrophic cardiomyopathy in cats and humans. J Vet Cardiol. 2015 Dec; 17 Suppl 1:S53-73.
Granstrom S, Godliksen ME, et al. Genotype-phenotype correlation between the cardiac myosin binding protein C mutation A31P and hypertrophic cardiomyopathy in a cohort of Maine Coon cats: a longitudinal study. J Vet Cardiol. 2015 Dec; 17 Suppl 1:S266-81.