Categories: Growth / size / body region phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 602274 (gene) , 618885 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2021

Species-specific name: Small Calf Syndrome

Mapping: Reynolds et al. (2021) “report one of the largest sequence-resolution screens of cattle to date, targeting discovery and validation of non-additive effects in 130,725 animals. We highlight six novel recessive loci with impacts [on body weight, stature or body condition score] generally exceeding the largest-effect variants identified from additive genome-wide association studies … [and] detail six novel putative causative mutations with effects ranging from mild (3.5% reduction in body weight) to severe (>25% reduction in body weight and increased early-life mortality). … The most significant bodyweight and stature effects identified from GWAS highlighted loci on chromosome 28 at 0.7Mbp and 1.3Mbp respectively.”

Molecular basis: Reynolds et al. (2021): “The top-associated SNP in these analyses presented a highly correlated … c.1561-1G>A splice acceptor mutation in GALNT2 as potentially responsible for these effects … .” The authors “had provisionally mapped the variant as a candidate stature mutation (unpublished), and subsequently as a variant for which homozygotes were depleted … (Charlier et al., 2016).”

Clinical features: Homozygous animals are characterised by significantly reduced growth parameters. Neurological and behavioural traits were not assessed by Reynolds et al. (2021), but significant reduction in circulating triglycerides (though high-density lipoproteins were not significantly different), creatinine and serum albumin were reported. Differential expression analysis of liver biopsy samples of affected and control animals revealed a total of 14 genes significantly over-expressed, and 15 genes significantly under-expressed in animals homozygous for the GALNT2 c.1561-1G>A variant (Reynolds et al., 2021). Embryonic lethality was reported: only 16% GALNT2 c.1561-1G>A homozygotes were identified in heterozygous matings (Reynolds et al., 2021).

Prevalence: The alternative allele frequency in New Zealand dairy cattle was reported as 0.055 in Holstein Friesian cattle, 0.001 in Jersey cattle and 0.033 in the 32,224 dairy cattle genotyped (Reynolds et al., 2021). Krull and Brenig (2022) reported that the c.1561-1G>A variant (OMIA variant 1327) was absent from 5005 German Holsteins. In 6191 cattle of a range of breeds from the 1000Bull Genomes Project, Krull and Brenig (2022) reported four heterozygotes, three of which came from New Zealand and the other of unknown origin. They concluded that "we currently do not have any indication that the deleterious variant has been introduced into the Holstein cattle population outside NZ. This is probably due to the fact that the syndrome results in poor production performance and therefore carriers (and also the disease allele) have never been emitted from NZ."

Breeds: Holstein Friesian (Cattle) (VBO_0000239), Jersey (Cattle) (VBO_0000250).
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).

Associated gene: