Categories: Cardiovascular system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 606844 (gene) , 203800 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Probably autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2021

Molecular basis: Meurs et al. (2021) "DNA from 14 affected Sphynx cats and the 13 control cats was submitted for ... whole genome sequencing ... . The most promising variants were selected for further evaluation by Sanger Sequencing of DNA from 68 affected Sphynx diagnosed as previously described and the 214 cats with no known history of cardiac disease (controls). ... A G/C variant was identified in exon 12 (human exon 13) of the ALMS1 gene in affected cats ... . The variant was positively associated with the presence of feline hypertrophic cardiomyopathy in the cat population with a p value of < 0.0001 and was identified in 62 (27 heterozygotes, 35 homozygotes) of 71 affected Sphynx. ... 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." Turba et al. (2023): "Genetic screening of the variant [A3: g.92439157G>C] ... was offered to Sphynx cat owners and breeders in Italy. ... In one case where the samples of a trio were available, inconsistency in the vertical transmission of the variant suggested an allele dropout (ADO) of the wt allele. A new external primer pair was designed as an alternative to the original. The larger PCR product obtained was Sanger sequenced, and five novel single nucleotide variants (SNVs) ... were detected. Three of these SNVs were within the original primer-binding regions and were assumed to have caused ADO. ... To accurately genotype ALMS1 g.92439157G>C in the samples, we set up a real-time TaqMan MGB assay while avoiding all surrounding SNVs. At g.92439157G>C, for 136 Sphynx cats, g.92439157 C variant was highly widespread (freq. >0.50). The present study reports five new variants surrounding ALMS1 g.92439157G>C that must be considered when designing the test. The study also indicates the need to verify the correspondence between the g.92439157 C variant frequency and the prevalence of HCM ... ."

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

Pathology: Meurs et al. (2021): "Light microscopy findings included myofiber disarray with interstitial fibrosis with significantly more nuclear proliferative activity in the affected cats than controls (p < 0.0001)."

Prevalence: The association between an ALMS1 variant and hypertrophic cardiomyopathy was first reported in Sphynx cats (Meurs et al., 2021). 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.”

Breeds: American Shorthair (Cat) (VBO_0100018), Exotic Shorthair (Cat) (VBO_0100096), Munchkin (Cat) (VBO_0100169), Scottish Fold (Cat) (VBO_0100209), Sphynx (Cat) (VBO_0100230).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: