In other species: African ostrich , golden eagle , Rose-ringed parakeet , blue-fronted amazon , bald eagle , jackass penguin

Categories: Cardiovascular system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 157700 (trait) , 607829 (trait) , 610840 (trait)

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Disease-related: yes

Key variant known: no

Cross-species summary: Renamed from 'Mitral valve disease' [28/06/2023]. Disease due to mitral valve (also called bicuspid valve or left atrioventricular valve) or tricuspid valve (also called right atrioventricular valve) or aortic valve degeneration. More than one valve may be may be involved in individual patients. The pathophysiology is unclear, but genetic predispositions have been reported in some species.

Species-specific name: Myxomatous mitral valve disease

Species-specific symbol: MMVD

Mapping: By conducting a GWAS on 139 affected and 102 normal Cavalier King Charles Spaniels, each genotyped with the Canine HD Bead Chip (yielding 84,693 SNPs for analysis), Madsen et al. (2011) "identified a 1.58 Mb region on CFA13 (P(genome) = 4.0× 10(-5)) and a 1.68 Mb region on CFA14 (P(genome) = 7.9× 10(-4)) associated with development of MMVD". By conducting a GWAS on 36 Cavalier King Charles Spaniel, each genotyped with the Illumina HD SNP chip (yielding more than 170,000 SNPs for analysis), French et al. (2012) were not able to identify any chromosomal regions of interest. Williams et al. (2021) "evaluated DNA from 50 affected dogs from five different dog breeds in a whole genome sequencing approach to identify shared variants across and within breeds that could be associated with MMVD. .... Only one of these could be associated with the cardiac valve (Chr12:36801705, COL12A1; CKCS [Cavalier King Charles Spaniel]) but when evaluated in an additional 100 affected CKCS the variant was only identified in 84/100 affected dogs, perhaps indicating genetic heterogeneity in this disease." Axelsson et al. (2021) "analysed eight dog breeds and identified an increased mutational load in the cKCs breed [Cavalier King Charles Spaniels], which is highly bottlenecked. This breed has a high frequency of MMVD. Looking for derived alleles of high frequency specifically in this breed, we identified four highly conserved variants in protein coding genes that may relate to MMVD as well as several candidate regulatory variants near the NEBL gene. We find that some of these NEBL variants are associated with MMVD in dachshund and may be affecting gene expression in multiple relevant heart cell types and thus probably affect heart function. These results merit further validation in separate cohorts." Mead et al. (2022): "Previous research has suggested that selected candidate risk alleles for MMVD are fixed in CKCSs [Cavalier King Charles Spaniels], including six locations within the Nebulette (NEBL) gene on CFA2. The current study analysed genotypes of 180 Australian CKCSs at the identified risk loci. Of these, 178 were phenotyped for severity of disease by echocardiographic measurements of left atrium to aortic root ratio (LA:Ao) and weight normalised left ventricular end diastolic diameter (LVIDdN). Genotyping array markers correctly predicted the genotype at the risk-variant loci in the CKCS population, and the NEBL1, NEBL2 and NEBL3 variants were observed to be in perfect linkage disequilibrium in this cohort. The CKCS cohort included 6/178 dogs being heterozygous for the protective/wild-type alleles at the NEBL locus. The mean LA:Ao and LVIDdN scores of these dogs heterozygous at NEBL1-3 variants were significantly smaller, and with significantly lower variance compared to age-matched CKCSs that were homozygous for risk alleles. The lower cardiac measurements in the heterozygous dogs indicate a significantly reduced risk of severe MMVD disease. Our analysis suggests that despite relative fixation of the NEBL risk alleles, healthy reference alleles at NEBL1-3 exist in low frequency in the CKCS breed and can be used to reduce MMVD severity and mortality."

Breeds: Borzoi (Dog) (VBO_0200197), Cavalier King Charles Spaniel (Dog) (VBO_0200309), Dachshund (Dog) (VBO_0200406), Miniature Schnauzer (Dog) (VBO_0200896), Poodle, Miniature (Dog) (VBO_0201051), Yorkshire Terrier (Dog) (VBO_0201448).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).