Categories: Digestive / alimentary phene

Possibly relevant human trait(s) and/or gene(s) (MIM number): 160720 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2022

Cross-species summary: Palatoschisis

History: Vaiman et al. (2022): "A new form of non-syndromic cleft palate arose recently in Limousine cattle, with animals referred to the French National Observatory of Bovine Abnormalities since 2012. Since the number of affected animals has increased steadily ..." Jacinto et al. (2023) report a Swiss Limousine cow with cleft palate with the same likely causal variants in MYH3.

Inheritance: Vaiman et al. (2022): "Based on pedigree analysis, occurrence of cleft palate in Limousine cattle was concordant with an autosomal recessive mode of inheritance."

Mapping: Vaiman et al. (2022): "Genotyping of 16 affected animals and homozygosity mapping led to the identification of a single disease-associated haplotype on Bos taurus chromosome (BTA)19."

Molecular basis: Vaiman et al. (2022): "The genome of two affected animals was sequenced ... . ... two fully linked mutations in exon 24 of the MYH3 (myosin heavy chain) gene were detected: a 1-bp non-synonymous substitution (BTA19:g.29609623A>G) and a 11-bp frameshift deletion (BTA19:g.29609605-29609615del). These two mutations were specific to the Limousine breed, with an estimated allele frequency of 2.4% and are predicted to be deleterious. ... mRNA and protein analyses in muscles from wild-type and affected animals revealed a decrease in MYH3 expression in affected animals ... . MYH3 is mostly expressed in muscles, including craniofacial muscles, during embryogenesis, and its absence may impair palate formation." Jacinto et al. (2023) identified the same homozygous variants identified by Vaiman et al. (2022) (chr19:29609604TGTCAGCTCAAG>T; NP_001095305.1:p.Leu958_Leu962delinsThrGlyGlnGlyTer and chr19:29609623A>G, c.2864T>C; NP_001095305.1:p.Ile955Thr) in an affected Swiss Limousine heifer. The authors conclude that whether "the MYH3 missense or the loss-of-function variant, or both, is actually causal remains open."

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

Clinical features: Vaiman et al. (2022): "Twenty-six Limousine calves presenting with CP [cleft palate] ... . Bilateral nasal discharge after suckling was observed in the calves shortly after birth ... . Life expectancy was generally short; most animals were euthanized in the first 2 weeks of life due to their difficulty to feed. However, five calves reached 1 month of age or more. In these five affected animals, chronic lower airway infection was often reported, due to dysphagia. CP was classified as Veau II, as it always affected both the soft and hard palates ... . CP was non-syndromic for approximately two thirds of the cases. In the remaining one third, other clinical signs were associated with CP, such as a stunted growth (6/26), bent/twisted neck (3/26 ...), vertebral column deformations, for example kyphosis or scoliosis (3/26), macroglossia (2/26 ...), or joint deformations (1/26)."

Prevalence: Jacinto et al. (2023) estimated the prevalence of MYH3 carriers within the Swiss Limousine population: "The frequency of the variant allele in 1167 genotyped cattle was 1.5%, with only 34 heterozygous carriers detected."

Genetic testing: Vaiman et al. (2022): "The mutations were included on the Illumina EuroG10k v8 and EuroGMD v1 SNP chips ..."

Breed: Limousin (Cattle) (VBO_0000274).
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: