Categories: Skeleton phene (incl. short stature & teeth)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 184840 (trait) , 215150 (trait) , 120290 (gene) , 614524 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2013

Cross-species summary: A mild form of disproportionate dwarfism, characterized by short limbs

Species-specific name: Skeletal dysplasia 2

Species-specific symbol: SD2

Species-specific description: Skeletal dysplasia 2 (SD2) is a mild form of disproportionate dwarfism in Labrador Retrievers. Affected dogs have short legs and their shoulder height is reduced by ~6 cm compared to non-affected dogs.

History: Skeletal dysplasia 2 was characterized by Frischknecht et al. (2013). Other genetically distinct forms of inherited skeletal dysplasias in Labrador Retrievers have been described by Goldstein et al. (2010; Mamm Genome 21:398-408) [OMIA 001522-9615; OMIA 001523-9615] and Smit et al. (2011; Vet J 187:269-71) [OMIA 001790-9615].

Inheritance: SD2 is inherited as a monogenic autosomal recessive trait. However, as this mild form of disproportionate dwarfism is superimposed on the normal variation in height, it is sometimes very difficult to unambiguously determine the phenotype.

Mapping: SD2 was mapped to CFA 12 in a genome-wide association study (GWAS) using 23 cases and 37 controls. The best raw p-value in this analysis was 4.4E-16. The critical interval defined by homozygosity mapping spanned 4.44 Mb. This analysis revealed that 22 out of the 23 initially considered cases were homozygous for a shared haplotype in the critical interval. The 23rd case did not carry this haplotype and was assumed to represent a phenocopy (Frischknecht et al. 2013).

Molecular basis: By whole-genome resequencing one of the affected dogs at 30X coverage, Frischknecht et al. (2013) identified 92 non-synonymous variants in the 4.44 Mb region mentioned in the Mapping section above. Two non-synonymous variants in the critical interval were perfectly associated with SD2 in larger cohorts of dogs. Of the two that were perfectly associated with the trait the most likely causative variant is COL11A2:c.143G>C, which is predicted to result in p.R48P on the protein level. This amino acid exchange is at an evolutionary conserved position at the N-terminus of the collagen molecule, before the beginning of the triple-helical domain. It is assumed to have only a minor impact on COL11A2 function as Col11a2 knock out mice and human patients with other COL11A2 mutations show more severe phenotypes.

Clinical features: The SD2 phenotype is characterized by short legs with normal body length and width. In most cases the forelegs are slightly more affected than the hind legs. The international breed standard calls for shoulder heights of 56 cm–57 cm in male and 54 cm–56 cm in female Labrador Retrievers, respectively. The shoulder height in affected animals is reduced by ~6 cm on average. However, it must be noted that shoulder height is only an imperfect proxy for the SD2 phenotype as shoulder height is a complex trait with significant variance due to genetic and environmental factors. According to breeders' reports SD2-affected dogs are not particurlarly prone to secondary joint degeneration or any other health problems apart from the disproportionate dwarfism.

Prevalence: SD2 occurs predominantly in so called working lines of Labrador Retrievers. Frischknecht et al (2013) reported a carrier frequency of 12% in the European Labrador Retriever population at the time of mutation discovery.

Genetic testing: There is a test available to detect the causative mutation. Affected dogs are not reliably identified by their body proportions alone and genetic heterogeneity exists. Therefore, the genetic test can help to confirm a diagnosis. Breeding animals should be tested to avoid the non-intended production of affected puppies.

Breed: Labrador Retriever (Dog) (VBO_0200800).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: