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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.    Electronic supplementary material  The online version of this article (doi:10.1186/s12863-017-0541-3) contains supplementary material, which is available to authorized users.

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