Cerebellar Abiotrophy (NCCD)

@article{pmid38371598,

title = {Classification of feline hypertrophic cardiomyopathy-associated gene variants according to the American College of Medical Genetics and Genomics guidelines},

author = {Fréderique Boeykens and Marie Abitbol and Heidi Anderson and Tanushri Dargar and Paolo Ferrari and Philip R Fox and Jessica J Hayward and Jens Häggström and Stephen Davison and Mark D Kittleson and Frank van Steenbeek and Ingrid Ljungvall and Leslie A Lyons and Maria Longeri and Åsa Ohlsson and Luc Peelman and Caroline Dufaure de Citres and Pascale Smets and Maria Elena Turba and Bart J G Broeckx},

doi = {10.3389/fvets.2024.1327081},

issn = {2297-1769},

year  = {2024},

date = {2024-01-01},

urldate = {2024-01-01},

journal = {Front Vet Sci},

volume = {11},

pages = {1327081},

abstract = {INTRODUCTION: The correct labeling of a genetic variant as pathogenic is important as breeding decisions based on incorrect DNA tests can lead to the unwarranted exclusion of animals, potentially compromising the long-term health of a population. In human medicine, the American college of Medical Genetics (ACMG) guidelines provide a framework for variant classification. This study aims to apply these guidelines to six genetic variants associated with hypertrophic cardiomyopathy (HCM) in certain cat breeds and to propose a modified criterion for variant classification.nnMETHODS: Genetic samples were sourced from five cat breeds: Maine Coon, Sphynx, Ragdoll, Devon Rex, and British Short- and Longhair. Allele frequencies were determined, and in the subset with phenotypes available, odds ratios to determine the association with HCM were calculated.  evaluation followed with joint evidence and data from other publications assisting in the classification of each variant.nnRESULTS: Two variants, MYBPC3:c.91G > C [A31P] and MYBPC3:c.2453C > T [R818W], were designated as pathogenic. One variant, MYH7:c.5647G > A [E1883K], was found likely pathogenic, while the remaining three were labeled as variants of unknown significance.nnDISCUSSION: Routine genetic testing is advised solely for the MYBPC3:c.91G > C [A31P] in the Maine Coon and MYBPC3:c.2453C > T [R818W] in the Ragdoll breed. The human ACMG guidelines serve as a suitable foundational tool to ascertain which variants to include; however, refining them for application in veterinary medicine might be beneficial.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Meurs2021,

title = {A deleterious mutation in the ALMS1 gene in a naturally occurring model of hypertrophic cardiomyopathy in the Sphynx cat},

author = {Kathryn M. Meurs and Brian G. Williams and Dylan DeProspero and Steven G. Friedenberg and David E. Malarkey and J. Ashley Ezzell and Bruce W. Keene and Darcy B. Adin and Teresa C. DeFrancesco and Sandra Tou},

doi = {10.1186/s13023-021-01740-5},

issn = {1750-1172},

year  = {2021},

date = {2021-02-27},

urldate = {2021-02-27},

journal = {Orphanet J Rare Dis},

volume = {16},

number = {1},

publisher = {Springer Science and Business Media LLC},

abstract = {Background

Familial hypertrophic cardiomyopathy is a common inherited cardiovascular disorder in people. Many causal mutations have been identified, but about 40% of cases do not have a known causative mutation. Mutations in the ALMS1 gene are associated with the development of Alstrom syndrome, a multisystem familial disease that can include cardiomyopathy (dilated, restrictive). Hypertrophic cardiomyopathy has not been described. The ALMS1 gene is a large gene that encodes for a ubiquitously expressed protein. The function of the protein is not well understood although it is believed to be associated with energy metabolism and homeostasis, cell differentiation and cell cycle control. The ALMS1 protein has also been shown to be involved in the regulation of cell cycle proliferation in perinatal cardiomyocytes. Although cardiomyocyte cell division and replication in mammals generally declines soon after birth, inhibition of ALMS1 expression in mice lead to increased cardiomyocyte proliferation, and deficiency of Alstrom protein has been suggested to impair post-natal cardiomyocyte cell cycle arrest. Here we describe the association of familial hypertrophic cardiomyopathy in Sphynx cats with a novel ALMS1 mutation.



Results

A G/C variant was identified in exon 12 (human exon 13) of the ALMS1 gene in affected cats and was positively associated with the presence of hypertrophic cardiomyopathy in the feline population (p < 0.0001). The variant was predicted to change a highly conserved nonpolar Glycine to a positively charged Arginine. This was predicted to be a deleterious change by three in silico programs. Protein prediction programs indicated that the variant changed the protein structure in this region from a coil to a helix. Light microscopy findings included myofiber disarray with interstitial fibrosis with significantly more nuclear proliferative activity in the affected cats than controls ( p < 0.0001).



Conclusion

This study demonstrates a novel form of cardiomyopathy associated with ALMS1 in the cat. Familial hypertrophic cardiomyopathy is a disease of genetic heterogeneity; many of the known causative genes encoding for sarcomeric proteins. Our findings suggest that variants in genes involved with cardiac development and cell regulation, like the ALMS1 gene, may deserve further consideration for association with familial hypertrophic cardiomyopathy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}