A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle
Abstract 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 muta...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2017-08-01
|
| Series: | BMC Genetics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12863-017-0541-3 |
| _version_ | 1818539890066849792 |
|---|---|
| author | Jørgen S. Agerholm Fintan J. McEvoy Steffen Heegaard Carole Charlier Vidhya Jagannathan Cord Drögemüller |
| author_facet | Jørgen S. Agerholm Fintan J. McEvoy Steffen Heegaard Carole Charlier Vidhya Jagannathan Cord Drögemüller |
| author_sort | Jørgen S. Agerholm |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-11T21:48:05Z |
| format | Article |
| id | doaj.art-91807075d42c44db9e0c8d542f99db98 |
| institution | Directory Open Access Journal |
| issn | 1471-2156 |
| language | English |
| last_indexed | 2024-12-11T21:48:05Z |
| publishDate | 2017-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genetics |
| spelling | doaj.art-91807075d42c44db9e0c8d542f99db982022-12-22T00:49:33ZengBMCBMC Genetics1471-21562017-08-011811910.1186/s12863-017-0541-3A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattleJørgen S. Agerholm0Fintan J. McEvoy1Steffen Heegaard2Carole Charlier3Vidhya Jagannathan4Cord Drögemüller5Department of Clinical Veterinary Sciences, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Clinical Veterinary Sciences, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Pathology, Rigshospitalet, University of CopenhagenUnit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of LiègeInstitute of Genetics, Vetsuisse Faculty, University of BernInstitute of Genetics, Vetsuisse Faculty, University of BernAbstract 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.http://link.springer.com/article/10.1186/s12863-017-0541-3BovineCongenitalMalformationRare diseaseHereditaryFibroblast growth factor receptor 2 |
| spellingShingle | Jørgen S. Agerholm Fintan J. McEvoy Steffen Heegaard Carole Charlier Vidhya Jagannathan Cord Drögemüller A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle BMC Genetics Bovine Congenital Malformation Rare disease Hereditary Fibroblast growth factor receptor 2 |
| title | A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle |
| title_full | A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle |
| title_fullStr | A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle |
| title_full_unstemmed | A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle |
| title_short | A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle |
| title_sort | de novo missense mutation of fgfr2 causes facial dysplasia syndrome in holstein cattle |
| topic | Bovine Congenital Malformation Rare disease Hereditary Fibroblast growth factor receptor 2 |
| url | http://link.springer.com/article/10.1186/s12863-017-0541-3 |
| work_keys_str_mv | AT jørgensagerholm adenovomissensemutationoffgfr2causesfacialdysplasiasyndromeinholsteincattle AT fintanjmcevoy adenovomissensemutationoffgfr2causesfacialdysplasiasyndromeinholsteincattle AT steffenheegaard adenovomissensemutationoffgfr2causesfacialdysplasiasyndromeinholsteincattle AT carolecharlier adenovomissensemutationoffgfr2causesfacialdysplasiasyndromeinholsteincattle AT vidhyajagannathan adenovomissensemutationoffgfr2causesfacialdysplasiasyndromeinholsteincattle AT corddrogemuller adenovomissensemutationoffgfr2causesfacialdysplasiasyndromeinholsteincattle AT jørgensagerholm denovomissensemutationoffgfr2causesfacialdysplasiasyndromeinholsteincattle AT fintanjmcevoy denovomissensemutationoffgfr2causesfacialdysplasiasyndromeinholsteincattle AT steffenheegaard denovomissensemutationoffgfr2causesfacialdysplasiasyndromeinholsteincattle AT carolecharlier denovomissensemutationoffgfr2causesfacialdysplasiasyndromeinholsteincattle AT vidhyajagannathan denovomissensemutationoffgfr2causesfacialdysplasiasyndromeinholsteincattle AT corddrogemuller denovomissensemutationoffgfr2causesfacialdysplasiasyndromeinholsteincattle |