Possibly relevant human trait(s) and/or gene(s) (MIM number): 200610

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2014

Species-specific name: Holstein bull-dog dwarfism

History: As reported by Agerholm et al. (2001), calves with a bull-dog-like phenotype have been reported in the Holstein breed by Berger and Innes (1948), Gotink et al. (1955), Greene et al. (1974), Jones et al. (1978) and Jayo et al. (1987).

Mapping: On 14 February 2000, in a post to the Angenmap discussion group (http://www.animalgenome.org/community/angenmap/mail/view.php?f=db/1824), Eggen and Boichard reported that this disorder had been mapped (to an undisclosed site) and hence a DNA test (based on linked microsatellites) was available.

Molecular basis: In a remarkable indication of the power of whole-genome sequence analysis, Daetwyler et al. (2014) identified a causal mutation for this disorder as a missense mutation (g.32475732G>A [UMD3.1 reference sequence]; p.Gly960Arg) in the COL2A1 gene (which encodes the alpha-1 chain of type II collagen), by comparing the sequence of only two affected calves with sequence from bulls in the 1000-bull-genome project. Noting that the disorder is most likely dominant, the authors "filtered for heterozygous polymorphisms in the two affected calves that were (i) absent in the 1000 bull genomes project database (except for Igale [the sire of the two affected calves]), as none of the other bulls sequenced had been reported to carry the syndrome and most had been extensively progeny tested, and (ii) predicted modified the amino acid sequence of a protein". This analysis yielded just two candidate mutations, only one of which was in a functional candidate gene, namely COL2A1. The authors then confirmed the causality of this mutation: "Genotyping by PCR and RFLP of the g.32475742G>A mutation in ten additional affected calves showed perfect association between this mutation and the syndrome and suggested mosaicism in the Igale [a Holstein bull] germ line, given the small proportion of affected calves and the fact that affected calves were heterozygous at this position. Finally, Sanger sequencing of the products from conventional PCR and nested PCR performed after PCR and RFLP definitively confirmed mosaicism for Igale at the locus".

Agerholm et al. (2016) reported a different likely COL2A1 causal mutation in Danish Holstein cattle: g.32473300 G>A; c.2463 + 1G>A: "This private sequence variant was predicted to affect splicing as it altered the conserved splice donor sequence GT at the 5’-end of COL2A1 intron 36, which was changed to AT. All five available cases carried the mutant allele in heterozygous state and all five dams were homozygous wild type. The sire VH Cadiz Captivo was shown to be a gonadal and somatic mosaic as assessed by the presence of the mutant allele at levels of about 5 % in peripheral blood and 15 % in semen".

Bourneuf et al. (2017) reported three de novo likely causal missense variants for this disorder: g.32469820G>A (c.1791G>A; p.G600D) in the offspring of a Charolais (sire) x Salers cross; g.32476082G>A (c.2986G>A; p.G996S) in a Holstein pedigree; and g.32471813G>A (c.2158G>A; p.G720S) in another Holstein pedigree.

Reinartz et al. (2017) reported the above g.32476082G>A (c.2986G>A; p.G996S) variant as being causal in the offspring of another Holstein bull named Energy P.

Clinical features: Agerholm et al. (2001) provided a detailed clinical description of this lethal phenotype, which they classified as ‘‘Dexter bulldog type", i.e. having similar clinical features to Dwarfism, aggrecan type (OMIA 001271-9913), namely "disproportionate growth retardation characterized by fascial dysplasia and shortening of the vertebral column and the abaxial skeleton. Endochondral osteogenesis was disturbed with disorganization of epiphyseal plate chondrocytes, a lesion consistent with generalized chondrodysplasia".

The combination of these clinical signs with a causal mutation in COL2A1 (as described above) led Daetwyler et al. (2014) to conclude that this disorder is homologous to Achondrogenesis, type II in humans (see OMIM link above).

Breeds: Charolais, Holstein.

Associated gene: