A feline orthologue of the human MYH7 c.5647G>A (p.(Glu1883Lys)) variant causes hypertrophic cardiomyopathy in a Domestic Shorthair cat

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited human heart disease. The same disease has a high prevalence in cats, where it is also suspected to be inherited. More than 1500 variants in MYBPC3, MYH7 and other sarcomeric genes are associated with human HCM, while in cats, only two causative variants in MYBPC3 are currently known. Here, we describe an adult Domestic Shorthair cat with arterial thromboembolism and heart failure that was diagnosed with HCM on necropsy. Sequencing of the coding regions of MYBPC3 and MYH7 revealed 21 variants, of which the MYH7 c.5647G>A (p.(Glu1883Lys)) variant was further analysed, because its orthologous variant had already been reported in a human patient with HCM, but with limited causal evidence. This variant affects the highly conserved assembly competence domain, is predicted in silico to be damaging and was found only once in population databases. Recently, functional studies have confirmed its predicted damaging effect and a paralogous variant in MYH6 has been associated with cardiac disease in humans as well. This report of an orthologous variant in a cat with HCM and its absence in 200 additional cats provides further evidence for its disease-causing nature. As the first report of feline HCM caused by a variant in MYH7, this study also emphasises this gene as a candidate gene for future studies in cats and highlights the similarity between human and feline HCM.

Fig. 1

Position and evolutionary conservation of the ACD. a Tail-to-tail dimerisation of the coiled coils formed by myosin heavy chains. The ACD regions are shaded light-grey. b The amino acid sequence and charge pattern of the ACD in myosin-7 (myosin heavy chain for Drosophila) orthologues across species (1) and skeletal and cardiac muscle myosin heavy chain paralogues in humans (2). Accession numbers are given in parentheses and identical amino acids are depicted as “.”. The variants cause the substitution of a conserved, negatively charged glutamic acid residue by a positively charged lysine residue. c Chromatograms of a homozygous wild-type cat (1) and the heterozygous case (2). The variant changes codon 1883 from GAG to AAG. d Agarose gel electrophoresis of an uncleaved amplicon (1), 376 bp long, the cleaved amplicons of a homozygous wild-type cat (2) and the heterozygote case (3) and a negative control (4). The amplicon is always cleaved at an internal cleavage site in a large fragment of 335 bp and a small fragment of 41 bp. The wild-type large fragment contains a second recognition site and is cleaved in fragments of 187 and 148 bp, while the variant large fragment does not contain a recognition site and remains intact. Two percent agarose gel with HyperLadder V