Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital

A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Orbital cysticercosis

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Posterior uveal melanoma incidence and survival by AJCC tumour size in a 70-year nationwide cohort

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Jørgen S Agerholm
  • Fintan J McEvoy
  • Steffen Heegaard
  • Carole Charlier
  • Vidhya Jagannathan
  • Cord Drögemüller
View graph of relations

BACKGROUND: Surveillance for bovine genetic diseases in Denmark identified a hitherto unreported congenital syndrome occurring among progeny of a Holstein sire used for artificial breeding. A genetic aetiology due to a dominant inheritance with incomplete penetrance or a mosaic germline mutation was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause.

RESULTS: Seven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial dysplasia and complete prolapse of the eyes. Consequently the syndrome was named facial dysplasia syndrome (FDS). Furthermore, extensive brain malformations, including microencephaly, hydrocephalus, lobation of the cerebral hemispheres and compression of the brain were present. Subsequent data analysis of progeny of the sire revealed that around 0.5% of his offspring suffered from FDS. High density single nucleotide polymorphism (SNP) genotyping data of the seven cases and their parents were used to map the defect in the bovine genome. Significant genetic linkage was obtained for three regions, including chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events in the germline of the sire.

CONCLUSIONS: FDS is a novel genetic disorder of Holstein cattle. Mutations in the human FGFR2 gene are associated with various dominant inherited craniofacial dysostosis syndromes. Given the phenotypic similarities in FDS affected calves, the genetic mapping and absence of further high impact variants in the critical genome regions, it is highly likely that the missense mutation in the FGFR2 gene caused the FDS phenotype in a dominant mode of inheritance.

Original languageEnglish
JournalBMC Genetics
Issue number1
Pages (from-to)1-9
Publication statusPublished - 2 Aug 2017

    Research areas

  • Amino Acid Sequence, Animals, Cattle, Cattle Diseases, Ectodermal Dysplasia, Female, Genes, Dominant, Male, Mutation, Missense, Pedigree, Phenotype, Receptor, Fibroblast Growth Factor, Type 2, Sequence Homology, Syndrome, Journal Article, Research Support, Non-U.S. Gov't

ID: 52766548