Categories: Cardiovascular system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 191045 (gene) , 601494 (trait) , 612422 (trait) , 115195 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Probably autosomal recessive

Considered a defect: yes

Key variant known: no

Key variant is published: no

History: McNamara et al. (2020) report the association between a predicted splice mutation affecting the TNNT2 gene and hypertrophic cardiomyopathy in a single affected Main Coon cat that "was born from consanguineous breeding". Mutations in the TNNT2 gene are associated with 'Cardiomyopathy, dilated' in turkeys (OMIA 000162-9103) and various inherited human cardiomyopathies.

Molecular basis: McNamara et al. (2020) “identified a novel, homozygous intronic variant in cardiac troponin T (TNNT2)” in a “Maine Coon [cat] with cardiomyopathy that tested negative for the MYBPC3 A31P variant” [OMIA000515-9685]. “In silico analysis of the variant suggested that it may affect normal splicing of exon 3 of TNNT2. Both parents tested heterozygous for the mutation, but were unaffected by the disease.” Schipper et al. (2022) provided convincing evidence against the TNNT2 variant being actually causal: "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." Because HCM due to mutations in TNNT2 has been reported in humans, the OMIA curators have decided to retain the phene name.

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: McNamara et al. (2020): “The proband was a privately-owned male pure-bred Maine Coon. At 8 months of age, he presented with left ventricular, right atrial, and borderline left atrial dilatation and borderline septal hypertrophy, with preserved-to-elevated systolic function …, when compared to reference echocardiography values for the Maine Coon (Drourr et al., 2005). Diastolic function could not be quantified as a result of fusion of E and A waves. Progressive enlargement of all four chambers of the heart was noted at 14 months of age, while borderline septal hypertrophy and preserved systolic function was still noted. This was diagnosed as a primary unclassified cardiomyopathy with possible early congestive heart failure.”

Breed: Maine Coon (Cat) (VBO_0100154).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below