Lethal chondrodysplasia in a family of Holstein cattle is due to a de novo mutation in the COL2A1 gene

Lethal chondrodysplasia is a well-known congenital syndrome in cattle and occurs sporadically in many breeds. A genetic aetiology has been suspected in many cases, but causal mutations have not been identified until recently. However, chondrodysplasia still remains a puzzle, e.g. cases have occurred among the offspring of a French Holstein sire without significant inbreeding. Genomic analysis of those cases revealed that the mosaic sire transmitted a dominant acting missense COL2A1 mutation. In 2015, the Danish Holstein sire VH Cadiz Captivo produced several cases of chondrodysplastic calves. Here we report the investigation of these cases.The lesions were consistent with chondrodysplasia. Genomic analyses identified a causative spontaneous dominant acting mutation in COL2A1, which must have occurred during the early foetal development of the sire. Germline mosaicism is a relatively frequent mechanism in the origin of genetic disorders and explains the prevalence of a certain fraction of affected offspring. Paternal dominant de novo mutations are a risk in cattle breeding, especially because the ratio of defective offspring may be very high and be associated with significant animal welfare problems.