In other species: woolly monkeys , Rhesus monkey , dog , pig , Arabian camel , taurine cattle

Categories: Cardiovascular system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 615396 (trait) , 115197 (trait) , 600958 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2005

Cross-species summary: Increase in volume of the muscle tissue of the heart, due to an increase in the size of muscle cells, primarily in the left ventricle and ventricular septum.

Species-specific name: Feline familial HCM

Species-specific symbol: HCM

Species-specific description: Feline hypertrophic cardiomyopathy (HCM), characterized by left ventricular hypertrophy, is the most common heart disease in domestic cats. Causative mutations in MYBPC3 have been identified in Maine Coon cats and Ragdolls. Affected cats can appear clinically normal, or they can present with signs of arterial thromboembolism or congestive heart failure. A test is available for Maine Coon and Ragdoll cats. Edited by Meg Sleeper, VMD and Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT Other forms of inherited hypertrophic cardiomyopathy have been reported - for examples see 'OMIA:002212-9685 Cardiomyopathy, hypertrophic, MYH7-related', 'OMIA:002316-9685 Cardiomyopathy, hypertrophic, ALMS1-related' and 'OMIA:002304-9685 Cardiomyopathy, hypertrophic, TNNT2-related'.

Inheritance: The mode of inheritance is autosomal dominant with 100% penetrance in Main Coon cats (Kittleson et al., 1999) and reported as possibly incomplete dominant in Ragdoll cats (Borgeat et al., 2014).

Molecular basis: HCM is genetically heterogeneous in the overall cat population. By sequencing a very likely comparative candidate gene (based on the homologous human disorder), Meurs et al. (2005) identified the causative mutation in Maine Coon cats as a G to C substitution in exon 3, codon 31 of MYBPC3. This changes a conserved amino acid (alanine to proline; A31P), which most likely changes protein conformation. The exact role of this myosin binding protein C, cardiac is still unknown, though it may bind myosin or actin, or interact with other cardiac proteins that form sarcomeres (Meurs et al., 2005). Affected Maine Coon cats were found to be either heterozygous or homozygous for the A31P mutation. Meurs et al. (2007) identified the causative mutation in Ragdoll cats as a C to T substitution in the same gene (MYBPC3), which changes the amino acid from arginine to tryptophan (R820W). As a result, the secondary structure of the myosin binding protein is changed, affecting sarcomere function. Wess et al. (2010) proposed that a third mutation A74T is causative in Maine Coons, but the explanations by Kittleson et al. (2010) and the extensive data of Longeri et al. (2013) have, in essence, disproved this claim.

Clinical features: About half or more of cats with HCM can appear clinically normal, but left ventricular hypertrophy can be identified by ultrasonography, and abnormal auscultation can be detected, such as systolic heart murmurs, gallop, and arrhythmia (Payne et al., 2010; Trehiou-Sechi et al., 2012). First clinical signs appear in young adults or adults, although Ragdoll cats may have an earlier onset than other breeds. Clinical presentation of HCM can be attributed to cardiac failure and affected cats can present with signs of congestive heart failure (increased respiratory effort, lethargy and exercise intolerance) and associated pulmonary edema, pleural effusion and ascites (Trehiou-Sechi et al., 2012). Other clinical signs can be caused by arterial thromboembolism (Trehiou-Sechi et al., 2012), such as bilaterally painful, contracted hindlimb muscles, bilateral hindlimb ischemia, and pulseless rear limbs with blanched pads. Clinical severity may be correlated to genotype (heterozygous vs. homozygous for the causative mutation, Meurs et al., 2005). For cats with moderate to severe HCM, increased levels of cardiac biomarkers, such as N-terminal pro B-type natriuretic peptide and troponin-I, may be seen but are less useful as a screening tool for breeding of Maine Coon and Ragdoll cats (Häggström, Luis Fuentes, & Wess, 2015). [IT thanks DVM students Jane Ang and Dongyue Du for contributions to this entry in April 2022]. Stern et al. (2023) report results from investigations of a "research colony of purpose-bred cats carrying the A31P mutation in MYBPC3 ... . Cardiac function in four generations was assessed by periodic echocardiography and measurement of blood biomarkers. Results showed that HCM penetrance was age-dependent, and that penetrance occurred earlier and was more severe in successive generations, especially in homozygotes. Homozygosity was also associated with progression from preclinical to clinical disease. A31P homozygous cats represent a heritable model of HCM with early disease penetrance and a severe phenotype ... ."

Pathology: For cats with mild to moderate HCM, left ventricular (LV) wall thickening can be identified on echocardiography (Häggström, Fuentes & Wess, 2015). The thickened wall results in LV diastolic dysfunction, an increase in LV diastolic pressure and ultimately an increase in left atrial (LA) pressure (Kittleson & Côté, 2021). In severe cases, features will further include LA enlargement, enlarged pulmonary vein and pulmonary oedema (Kittleson & Côté, 2021). Right heart disease may be present, but it is unlikely to progress to right-side CHF because the degree of pulmonary hypertension is usually mild (Kittleson & Côté, 2021). Histologically, the cardiac muscle shows myofibrillar or myocyte disarray (Kittleson et al., 1999). The MYBPC3 mutations do not eliminate the protein, but reduce the amount present in cardiac muscle. [IT thanks DVM student Dongyue Du for contributions to this entry in April 2022].

Prevalence: Hypertrophic cardiomyopathy is the most common cardiac disease in domestic cats. Longeri et al. (2013) reported the results of an extensive survey of the three reported mutations (see Molecular Basis section) in 1855 cats of 28 breeds, with echocardiograph data available of 446 of these cats: "The MYBPC3 A31P and R820W were restricted to MCO [Maine Coon] and RD Ragdoll] respectively. Both purebred and random bred cats had HCM and the incidence increased with age. The A74T polymorphism was not associated with any phenotype. HCM was most prevalent in MCO homozygote for the A31P mutation and the penetrance increased with age. The penetrance of the heterozygote genotype was lower (0.08) compared to the P/P genotype (0.58) in MCO. . . . A31P mutation occurs frequently in MCO cats. The high incidence of HCM in homozygotes for the mutation supports the causal nature of the A31P mutation. Penetrance is incomplete for heterozygotes at A31P locus, at least at a young age. The A74T variant does not appear to be correlated with HCM." O'Donnell et al. (2021) evaluated "the presence of the known MYBPC3 and MYH7 variants in a population of cats with HCM. DNA was isolated from samples collected from non-Ragdoll and non-Maine Coon domestic cats diagnosed with HCM through the North Carolina State University College of Veterinary Medicine and genotyped for the three variants. One-hundred and three DNA samples from cats with HCM were evaluated from domestic shorthair, domestic longhair and purebred cats. All samples were wt for the MYBPC3 and MYH7 variants. Although this study was limited by its inclusion of cats from one tertiary hospital, the lack of these MYBPC3 and MYH7 variants in this feline HCM population indicates that the clinical utility of genetic testing for these variants may be isolated to the two cat breeds in which these variants have been identified." Akiyama et al. (2023) investigate “the ubiquitous occurrence of HCM-associated genetic variants [Myosin binding protein C3: MYBPC3 p.A31P, p.A74T, p.R820W; Myosin heavy chain 7: MYH7 p.E1883K; Alstrom syndrome protein 1: ALMS1 p.G3376R] among cat breeds, using 57 HCM-affected, 19 HCM-unaffected, and 227 non-examined cats from the Japanese population. Genotyping of the five variants revealed the presence of MYBPC3 p.A31P and ALMS1 p.G3376R in two (Munchkin and Scottish Fold) and five non-specific breeds (American Shorthair, Exotic Shorthair, Minuet, Munchkin and Scottish Fold), respectively, in which the variants had not been identified previously. … . Overall, our results suggest that these two specific variants may still be found in other cat breeds and should be examined in detail in a population-driven manner.”

Control: A test is available for MYBPC3 mutations in Maine Coon and Ragdoll cats. Breeding of affected cats is not recommended. The MYBPC3 p.A31P has been identified in other breeds Akiyama et al. (2023). In a proof-of-concept project aimed at validating the use of precision medicine, Ontiveros et al. (2019) showed that the likely causal variants of two affected Maine Coon cats could be identified by whole-genome sequencing of those cats, followed by sequence comparison with 79 control cats of various breeds. In the case of these two affected cats, this strategy identified the A31P variant first described by Meurs et al. (2005). Likely causal variants in other genes have been reported to cause HCM in other breeds - for examples see 'OMIA002212-9685 Cardiomyopathy, hypertrophic, MYH7-related', 'OMIA002316-9685 Cardiomyopathy, hypertrophic, ALMS1-related' and 'OMIA002304-9685 Cardiomyopathy, hypertrophic, TNNT2-related'.

Genetic testing: Tests for MYBPC3 variants are available for the Maine Coon and Ragdoll breeds. The MYBPC3 p.A31P has been identified in other breeds Akiyama et al. (2023). However, clinically affected cats may not have the MYBPC3 variants listed here, and variants in other genes have been identified and should be considered for testing.

Breeds: American Bobtail (Cat) (VBO_0100003), American Bobtail Shorthair (Cat) (VBO_0100005), American Shorthair (Cat) (VBO_0100018), Highlander (Cat) (VBO_0100114), Maine Coon (Cat) (VBO_0100154), Maine Coon Polydactyl (Cat) (VBO_0100155), Munchkin (Cat) (VBO_0100169), Norwegian Forest Cat (Cat) (VBO_0100178), Persian (Cat) (VBO_0100188), Pixiebob Longhair (Cat) (VBO_0100192), Ragamuffin (Cat) (VBO_0100195), Ragdoll (Cat) (VBO_0100196), Scottish Fold (Cat) (VBO_0100209), Siberian (Cat) (VBO_0100223), Sphynx (Cat) (VBO_0100230).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: