A large deletion in the COL2A1 gene expands the spectrum of pathogenic variants causing bulldog calf syndrome in cattle

Abstract

Background Congenital bovine chondrodysplasia, also known as bulldog calf syndrome, is characterized by disproportionate growth of bones resulting in a shortened and compressed body, mainly due to reduced length of the spine and the long bones of the limbs. In addition, severe facial dysmorphisms including palatoschisis and shortening of the viscerocranium are present. Abnormalities in the gene collagen type II alpha 1 chain (COL2A1) have been associated with some cases of the bulldog calf syndrome. Until now, six pathogenic single-nucleotide variants have been found in COL2A1. Here we present a novel variant in COL2A1 of a Holstein calf and provide an overview of the phenotypic and allelic heterogeneity of the COL2A1-related bulldog calf syndrome in cattle. Case presentation The calf was aborted at gestation day 264 and showed generalized disproportionate dwarfism, with a shortened compressed body and limbs, and dysplasia of the viscerocranium; a phenotype resembling bulldog calf syndrome due to an abnormality in COL2A1. Whole-genome sequence (WGS) data was obtained and revealed a heterozygous 3513 base pair deletion encompassing 10 of the 54 coding exons of COL2A1. Polymerase chain reaction analysis and Sanger sequencing confirmed the breakpoints of the deletion and its absence in the genomes of both parents. Conclusions The pathological and genetic findings were consistent with a case of “bulldog calf syndrome”. The identified variant causing the syndrome was the result of a de novo mutation event that either occurred post-zygotically in the developing embryo or was inherited because of low-level mosaicism in one of the parents. The identified loss-of-function variant is pathogenic due to COL2A1 haploinsufficiency and represents the first structural variant causing bulldog calf syndrome in cattle. Furthermore, this case report highlights the utility of WGS-based precise diagnostics for understanding congenital disorders in cattle and the need for continued surveillance for genetic disorders in cattle.

A 6.7 kb deletion in the COL2A1 gene in a Holstein calf with achondrogenesis type II and perosomus elumbis

“…This has been speculated recently as a cause for a BD case showing a heterozygous 3.5 kb deletion encompassing 10 exons of COL2A1. 8 On the other hand, the variant detected herein is deleting 1413 bp of the coding sequence representing an in-frame deletion that affects 438 residues of the triple helical region of the COL2A1 protein. Owing to the lack of suitable material, it remains unclear whether this shortened transcript encoding a significantly truncated protein is expressed or not.…”

“…This variant has been deposited to the European Variant Archive under study PRJEB41991. This novel variant was predicted to be deleterious by several prediction programs (SNPs&GO score 0.898, MutPred2 score: 0.914, and Provean score: À9.600) [6][7][8] and has been named 'b h '. The brown husky sire was b h /b s , one brown husky dam was b s /b s , one brown husky-mix dam was b s /b c , and one non-brown husky dam was B/b s .…”

“…Recessively inherited variants in the ACAN gene are associated with the so‐called lethal Dexter BD type 2 (OMIA 001271‐9913), whereas dominant inherited COL2A1 variants are related to forms of bovine achondrogenesis type II or BD (OMIA 001926‐9913). The latter may be inherited from mosaic parents 3–6 or due post‐zygotic de novo muations 5,7,8 . So far, a total of seven pathogenic variants in the COL2A1 have been reported 3–8 …”

“…The latter may be inherited from mosaic parents [3][4][5][6] or due post-zygotic de novo muations. 5,7,8 So far, a total of seven pathogenic variants in the COL2A1 have been reported. [3][4][5][6][7][8] Own analysis A stillborn purebred Holstein male calf was delivered after dystocia.…”

“…5,7,8 So far, a total of seven pathogenic variants in the COL2A1 have been reported. [3][4][5][6][7][8] Own analysis A stillborn purebred Holstein male calf was delivered after dystocia. Gross pathology findings revealed a phenotype resembling the bovine chondrodysplasia type II with the additional presence of perosomus elumbis (Fig.…”