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

Abstract

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.

Classification of feline hypertrophic cardiomyopathy-associated gene variants according to the American College of Medical Genetics and Genomics guidelines

“…The TNNT2:c.95-108G > A was found in all five breeds, with allelic frequencies ranging between 2 and 27%. In addition to the breeds studied here, the variant has also been found previously in Persian, Siamese, Tennessee Rex, and Thai breeds, as well as domestic shorthair cats and allelic frequencies were very similar to this study, ranging between 1 and 25% (33). Hence, this is a widespread variant, occurring at high allelic frequencies.…”

“…For TNNT2:c.95-108G > A, no OR was reported in the original publication, but based on the data, an allelic OR of 5 was found (22). In a subsequent study, the allelic OR and genotypic OR (based on an autosomal recessive mode of inheritance) were 1.2 and 2.43, which is similar to our results of 1.84 and 2.17, respectively (33). For MYH7:c.5647G > A [E1883K], no ORs were calculated as the variant was never observed, which is also according to expectations as it was postulated to be an extremely rare variant (21).…”

“…While the allelic frequency in the literature also tended to be higher, ranging between 14 and 23% (36,46), a more recent study showed an allele frequency of 3% in Ragdolls (26). Recently, this variant was also found in the American Bobtail (with an allele frequency of 11.4% in the S6), a trend similar to that for MYBPC3:c.91G > C [A31P] is observed, which might be a consequence of breeder selection (33,36,(46)(47)(48). The TNNT2:c.95-108G > A was found in all five breeds, with allelic frequencies ranging between 2 and 27%.…”

“…Compared to phenotypic testing, genetic tests have several advantages, but only when the association these tests are based on is valid. As several variants for HCM were only recently discovered, and as there is a history of spurious associations [i.e., for MYBPC3:c.220G > A [A74T] and TNNT2:c.95-108G > A, the initial associations have not been replicated in subsequent studies (33,36)], our goal was to classify all six currently published variants based on the ACMG guidelines.…”

“…The classification of the variants into five categories (pathogenic, likely pathogenic, variant of unknown significance, likely benign, and benign) was done in two stages. In the first stage, the ACMG guidelines were used except for the criteria related to allele frequency, in agreement with what has been done in earlier studies (21,32,33). In the second stage, the additional effect of using these allelic frequency criteria for classification was evaluated.…”