TY - JOUR

T1 - A large deletion in the COL2A1gene expands the spectrum of pathogenic variants causing bulldog calf syndrome in cattle

AU - Jacinto, Joana Goncalves Pontes

AU - Hafliger, Irene Monika

AU - Letko, Anna

AU - Drogemuller, Cord

AU - Agerholm, Jorgen Steen

PY - 2020

Y1 - 2020

N2 - 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 genecollagen 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 inCOL2A1. Here we present a novel variant inCOL2A1of a Holstein calf and provide an overview of the phenotypic and allelic heterogeneity of theCOL2A1-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 inCOL2A1. Whole-genome sequence (WGS) data was obtained and revealed a heterozygous 3513 base pair deletion encompassing 10 of the 54 coding exons ofCOL2A1. 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 toCOL2A1haploinsufficiency 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.

AB - 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 genecollagen 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 inCOL2A1. Here we present a novel variant inCOL2A1of a Holstein calf and provide an overview of the phenotypic and allelic heterogeneity of theCOL2A1-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 inCOL2A1. Whole-genome sequence (WGS) data was obtained and revealed a heterozygous 3513 base pair deletion encompassing 10 of the 54 coding exons ofCOL2A1. 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 toCOL2A1haploinsufficiency 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.

KW - Chondrodysplasia

KW - Congenital

KW - Malformation

KW - Precision medicine

KW - Rare disease

KW - Type II collagenopathy

KW - Whole-genome sequencing

KW - DWARFISM

KW - GENOME

U2 - 10.1186/s13028-020-00548-w

DO - 10.1186/s13028-020-00548-w

M3 - Journal article

C2 - 32894162

VL - 62

JO - Acta Veterinaria Scandinavica

JF - Acta Veterinaria Scandinavica

SN - 0044-605X

M1 - 49

ER -