A Novel Homozygous Intronic Variant in TNNT2 Associates With Feline Cardiomyopathy

McNamara, James W.; Schuckman, Maggie; Becker, Richard C.; Sadayappan, Sakthivel

doi:10.3389/fphys.2020.608473

Cited by 11 publications

(12 citation statements)

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“…This is currently not yet the case for a recently reported intronic variant in the cardiac troponin T2 ( TNNT2 ) gene. This variant, TNNT2 :c.95‐108G>A, was deemed to be the cause of cardiomyopathy in a homozygous Maine Coon, based on a one case–parent trio and in silico predictions of aberrant splicing (McNamara et al, 2020).…”

Section: G/g G/a A/amentioning

confidence: 99%

“…The complete disruption of gene function by a null variant is considered the strongest evidence for pathogenicity. The predicted splice site would cause the loss of over 80% of the protein's amino acids (McNamara et al, 2020), and truncating variants in TNNT2 can cause HCM in humans (Walsh et al, 2017). To meet this criterion for splice site variants, functional mRNA or protein evidence is required (Richards et al, 2015), but this was not presented in the report by McNamara et al (2020).…”

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confidence: 99%

“…The predicted splice site would cause the loss of over 80% of the protein's amino acids (McNamara et al, 2020), and truncating variants in TNNT2 can cause HCM in humans (Walsh et al, 2017). To meet this criterion for splice site variants, functional mRNA or protein evidence is required (Richards et al, 2015), but this was not presented in the report by McNamara et al (2020). The cDNA sequencing in this study did not show the predicted incorporation of an intronic sequence, so this criterion is not met.…”

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confidence: 99%

“…The control group, although generally older than the affected group, included some young animals, which may develop HCM at a later age. However, all controls were older than the proband described by McNamara et al (2020) at the age of diagnosis, and removing the 23 youngest control cats did not substantially change the odds ratio or its p-value. If this proband showed a typical manifestation of the cardiomyopathy caused by homozygosity of the TNNT2:c.95-108G>A variant, expectations are that the older homozygotes in this study would be affected.…”

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The TNNT2:c.95‐108G>A variant is common in Maine Coons and shows no association with hypertrophic cardiomyopathy

et al. 2022

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Hypertrophic cardiomyopathy (HCM) is a common and potentially fatal heart disease in many cat breeds. An intronic variant in TNNT2, c.95-108G>A, was recently reported as the cause of HCM in the Maine Coon. The aim of this study was to determine this variant's allele frequency in different populations and its possible association with HCM. Based on 160 Maine Coon samples collected in Belgium, Italy, Sweden and the USA, the variant's allele frequency was estimated to be 0.32. Analysis of the 99 Lives feline whole genome sequencing database showed that the TNNT2 variant also occurs in other breeds, as well as mixed-breed cats. Comparison of 31 affected and 58 healthy cats did not reveal significantly increased odds for HCM in homozygotes. Based on the combined evidence and in agreement with the standards and guidelines for the interpretation of sequence variants, this variant is currently classified as a variant of unknown significance and should not be used for breeding decisions regarding HCM.

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Section: G/g G/a A/amentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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The TNNT2:c.95‐108G>A variant is common in Maine Coons and shows no association with hypertrophic cardiomyopathy

et al. 2022

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“…Recently, a second mutation in cardiac troponin T was identified in one Maine Coon cat with HCM. 45 The natural history and pathophysiology of the R820W (c.2460C >T; p.R820W) myosin binding protein C mutation in Ragdoll cats has not been as well studied but the pattern appears to be similar to that seen in Maine Coon cats. 40 The same R820W mutation seen in Ragdoll cats causes both HCM and LVNC in humans.…”

Section: Etiologymentioning

confidence: 99%

The Feline Cardiomyopathies: 2. Hypertrophic cardiomyopathy

Kittleson

Côté

2021

Journal of Feline Medicine and Surgery

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Practical relevance: Hypertrophic cardiomyopathy (HCM) is the most common form of feline cardiomyopathy observed clinically and may affect up to approximately 15% of the domestic cat population, primarily as a subclinical disease. Fortunately, severe HCM, leading to heart failure or arterial thromboembolism (ATE), only occurs in a small proportion of these cats. Patient group: Domestic cats of any age from 3 months upward, of either sex and of any breed, can be affected. A higher prevalence in male and domestic shorthair cats has been reported. Diagnostics: Subclinical feline HCM may or may not produce a heart murmur or gallop sound. Substantial left atrial enlargement can often be identified radiographically in cats with severe HCM. Biomarkers should not be relied on solely to diagnose the disease. While severe feline HCM can usually be diagnosed via echocardiography alone, feline HCM with mild to moderate left ventricular (LV) wall thickening is a diagnosis of exclusion, which means there is no definitive test for HCM in these cats and so other disorders that can cause mild to moderate LV wall thickening (eg, hyperthyroidism, systemic hypertension, acromegaly, dehydration) need to be ruled out. Key findings: While a genetic cause of HCM has been identified in two breeds and is suspected in another, for most cats the cause is unknown. Systolic anterior motion of the mitral valve (SAM) is the most common cause of dynamic left ventricular outflow tract obstruction (DLVOTO) and, in turn, the most common cause of a heart murmur with feline HCM. While severe DLVOTO is probably clinically significant and so should be treated, lesser degrees probably are not. Furthermore, since SAM can likely be induced in most cats with HCM, the distinction between HCM without obstruction and HCM with obstruction (HOCM) is of limited importance in cats. Diastolic dysfunction, and its consequences of abnormally increased atrial pressure leading to signs of heart failure, and sluggish atrial blood flow leading to ATE, is the primary abnormality that causes clinical signs and death in affected cats. Treatment (eg, loop diuretics) is aimed at controlling heart failure. Preventive treatment (eg, antithrombotic drugs) is aimed at reducing the risk of complications (eg, ATE). Conclusions: Most cats with HCM show no overt clinical signs and live a normal or near-normal life despite this disease. However, a substantial minority of cats develop overt clinical signs referable to heart failure or ATE that require treatment. For most cats with clinical signs caused by HCM, the long-term prognosis is poor to grave despite therapy. Areas of uncertainty: Genetic mutations (variants) that cause HCM have been identified in a few breeds, but, despite valiant efforts, the cause of HCM in the vast majority of cats remains unknown. No treatment currently exists that reverses or even slows the cardiomyopathic process in HCM, again despite valiant efforts. The search goes on.

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Genetics of Feline Diseases and Traits

Lyons

2025

The Cat

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A Novel Homozygous Intronic Variant in TNNT2 Associates With Feline Cardiomyopathy

Cited by 11 publications

References 33 publications

The TNNT2:c.95‐108G>A variant is common in Maine Coons and shows no association with hypertrophic cardiomyopathy

The TNNT2:c.95‐108G>A variant is common in Maine Coons and shows no association with hypertrophic cardiomyopathy

The Feline Cardiomyopathies: 2. Hypertrophic cardiomyopathy

Genetics of Feline Diseases and Traits

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