OMIA 001551-9615 : Brachycephaly in Canis lupus familiaris

In other species: domestic cat

Possibly relevant human trait(s) and/or gene(s) (MIM number): 613456

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2012

Mapping: By conducting an across-breed GWAS on 25 affected and 31 control dogs from a range of breeds, each genotyped with the Affymetrix Version 2 Custom Canine SNP (comprising 49,663 SNPs), Bannasch et al. (2010) highlighted a region on chromosome CFA1. Fine-mapping reduced the region to 31Kb containing just one gene, THBS2. Sequencing this gene and a neighbouring gene, SMOC-2, failed to reveal a causal mutation.

Building on the results of previous mapping studies (e.g. Haworth et al., 2001; Bannasch e al., 2010), Schoenebeck et al. (2012) genotyped 576 dogs from 62 breeds recognised by the American Kennel Club each with a canine SNP chip (61,270 SNPs) and used GWAS analysis based on brachycephaly-dolichocephaly classification to identify five QTL, on CFA1, CFA5, CFA24, CFA32 and CFAX.

Marchant et al. (2017) conducted a GWAS, using the 170,000 SNP Illumina CanineHD Whole-Genome Genotyping BeadChip, on "morphometrics of skull isosurfaces derived from 374 pedigree and mixed-breed dogs to dissect the genetics of skull form. Through deconvolution of facial forms, we identified quantitative trait loci that are responsible for canine facial shapes and sizes . . . [, namely] "a highly significant QTL associated with canine brachycephaly on CFA1, as well as numerous other suggestive associations. Focusing on the CFA1 QTL, we defined a 187.7-kb critical interval common to 30 of 37 brachycephalic dogs".

Molecular basis: Extensive whole-genome resequencing of the main QTL on CFA32 (see mapping section above) enabled Schoenebeck et al. (2012) to identify a quantitative trait nucleotide (QTN) for brachycephaly: "a SNP at 8,196,098 that encodes a missense mutation [C/A transversion] in BMP3, changing a phenylalanine to a leucine (BMP3F452L or F452L)".

Concentrating on their CFA1 candidate region (see Mapping section), Marchant et al. (2017) "resequenced 28 brachycephalic dogs to approximately 30-fold depth and filtered polymorphisms within the critical interval against variants called in 319 other resequenced canid genomes. Among five variants that were retained, we detected a long interspersed nuclear element (LINE-1) within the SPARC-related modular calcium binding (SMOC2) gene. Transcript analyses revealed alternative splice isoforms that occur in the presence of the LINE-1, causing the incorporation of a premature stop codon after the eighth exon of SMOC2’s canonical 13-exon transcript. SMOC2 mRNA levels are downregulated in a dose-dependent manner with the LINE-1 element". Marchant et al. (2017) report that "SMOC2 disruption affects the facial skeleton in a dose-dependent manner. The size effects of the associated SMOC2 haplotype are profound, accounting for 36% of facial length variation in the dogs we tested." They conclude that "Our data suggest that SMOC2 dysfunction is responsible for canine brachycephaly."

Associated genes:

Symbol Description Species Chr Location OMIA gene details page Other Links
SMOC2 SPARC related modular calcium binding 2 Canis lupus familiaris 1 NC_006583.3 (55826354..55986053) SMOC2 Homologene, Ensembl, NCBI gene
BMP3 bone morphogenetic protein 3 Canis lupus familiaris 32 NC_006614.2 (8172037..8196170) BMP3 Homologene, Ensembl, NCBI gene


By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Brachycephaly BMP3 missense CanFam3.1 32 g.5231894C>A c.1344C>A p. F448L 2012 22876193 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool
Brachycephaly SMOC2 insertion, gross (>20) "a long interspersed nuclear element (LINE-1) within the SPARC-related modular calcium binding (SMOC2) gene" 2017 28552356


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2020 Sophocleous, R.A., Sluyter, V., Curtis, B.L., Curtis, S.J., Jurak, L.M., Faulks, M., Spildrejorde, M., Gates, S., Proctor, E.J., Seavers, A., Watson, D., Kuit, T., Dowton, M., Stokes, L., Sluyter, R. :
Association of a P2RX7 gene missense variant with brachycephalic dog breeds. Anim Genet 51:127-131, 2020. Pubmed reference: 31774195. DOI: 10.1111/age.12884.
2019 Ravn-Mølby, E.M., Sindahl, L., Nielsen, S.S., Bruun, C.S., Sandøe, P., Fredholm, M. :
Breeding French bulldogs so that they breathe well-A long way to go. PLoS One 14:e0226280, 2019. Pubmed reference: 31841527. DOI: 10.1371/journal.pone.0226280.
2018 Fawcett, A., Barrs, V., Awad, M., Child, G., Brunel, L., Mooney, E., Martinez-Taboada, F., McDonald, B., McGreevy, P. :
Consequences and Management of Canine Brachycephaly in Veterinary Practice: Perspectives from Australian Veterinarians and Veterinary Specialists. Animals (Basel) 9:, 2018. Pubmed reference: 30577619. DOI: 10.3390/ani9010003.
2017 Marchant, T.W., Johnson, E.J., McTeir, L., Johnson, C.I., Gow, A., Liuti, T., Kuehn, D., Svenson, K., Bermingham, M.L., Drögemüller, M., Nussbaumer, M., Davey, M.G., Argyle, D.J., Powell, R.M., Guilherme, S., Lang, J., Ter Haar, G., Leeb, T., Schwarz, T., Mellanby, R.J., Clements, D.N., Schoenebeck, J.J. :
Canine Brachycephaly Is Associated with a Retrotransposon-Mediated Missplicing of SMOC2. Curr Biol 27:1573-1584.e6, 2017. Pubmed reference: 28552356. DOI: 10.1016/j.cub.2017.04.057.
2016 Anon. :
Brachycephaly: an issue for cats as well as dogs. Vet Rec 179:371, 2016. Pubmed reference: 27738208. DOI: 10.1136/vr.i5507.
2013 Arnold, T.S., Wittenburg, L.A., Powell, C.C. :
Effect of topical naltrexone 0.3% on corneal sensitivity and tear parameters in normal brachycephalic dogs. Vet Ophthalmol :, 2013. Pubmed reference: 23802568. DOI: 10.1111/vop.12079.
Knight, S.M., Radlinsky, M.G., Cornell, K.K., Schmiedt, C.W. :
Postoperative Complications Associated with Caudectomy in Brachycephalic Dogs with Ingrown Tails. J Am Anim Hosp Assoc :, 2013. Pubmed reference: 23690492. DOI: 10.5326/JAAHA-MS-5858.
Roedler, F.S., Pohl, S., Oechtering, G.U. :
How does severe brachycephaly affect dog's lives? Results of a structured preoperative owner questionnaire. Vet J :, 2013. Pubmed reference: 24176279. DOI: 10.1016/j.tvjl.2013.09.009.
2012 Schoenebeck, J.J., Hutchinson, S.A., Byers, A., Beale, H.C., Carrington, B., Faden, D.L., Rimbault, M., Decker, B., Kidd, J.M., Sood, R., Boyko, A.R., Fondon, J.W., Wayne, R.K., Bustamante, C.D., Ciruna, B., Ostrander, E.A. :
Variation of BMP3 contributes to dog breed skull diversity. PLoS Genet 8:e1002849, 2012. Pubmed reference: 22876193. DOI: 10.1371/journal.pgen.1002849.
2011 Quilez, J., Short, A.D., Martínez, V., Kennedy, L.J., Ollier, W., Sanchez, A., Altet, L., Francino, O. :
A selective sweep of >8 Mb on chromosome 26 in the Boxer genome. BMC Genomics 12:339, 2011. Pubmed reference: 21722374. DOI: 10.1186/1471-2164-12-339.
2010 Bannasch, D., Young, A., Myers, J., Truvé, K., Dickinson, P., Gregg, J., Davis, R., Bongcam-Rudloff, E., Webster, M.T., Lindblad-Toh, K., Pedersen, N. :
Localization of canine brachycephaly using an across breed mapping approach. PLoS One 5:e9632, 2010. Pubmed reference: 20224736. DOI: 10.1371/journal.pone.0009632.
Boyko, A.R., Quignon, P., Li, L., Schoenebeck, J.J., Degenhardt, J.D., Lohmueller, K.E., Zhao, K., Brisbin, A., Parker, H.G., vonHoldt, B.M., Cargill, M., Auton, A., Reynolds, A., Elkahloun, A.G., Castelhano, M., Mosher, D.S., Sutter, N.B., Johnson, G.S., Novembre, J., Hubisz, M.J., Siepel, A., Wayne, R.K., Bustamante, C.D., Ostrander, E.A. :
A simple genetic architecture underlies morphological variation in dogs. PLoS Biol 8:e1000451, 2010. Pubmed reference: 20711490. DOI: 10.1371/journal.pbio.1000451.
Oechtering, G.U., Schlüter, C., Lippert, J.P. :
[Brachycephaly in dog and cat: a "human induced" obstruction of the upper airways]. Pneumologie 64:450-2, 2010. Pubmed reference: 20632241. DOI: 10.1055/s-0030-1255513.
2009 Hünemeier, T., Salzano, F.M., Bortolini, M.C. :
TCOF1 T/Ser variant and brachycephaly in dogs. Anim Genet 40:357-8, 2009. Pubmed reference: 19220226. DOI: 10.1111/j.1365-2052.2008.01838.x.
2001 Haworth, KE., Islam, I., Breen, M., Putt, W., Makrinou, E., Binns, M., Hopkinson, D., Edwards, Y. :
Canine TCOF1; cloning, chromosome assignment and genetic analysis in dogs with different head types. Mamm Genome 12:622-9, 2001. Pubmed reference: 11471057.

Edit History

  • Created by Frank Nicholas on 28 Feb 2011
  • Changed by Frank Nicholas on 19 Dec 2012
  • Changed by Frank Nicholas on 21 May 2013
  • Changed by Frank Nicholas on 05 Jul 2017