Bernd Tellhelm

A COL11A2 Mutation in Labrador Retrievers with Mild Disproportionate Dwarfism

We describe a mild form of disproportionate dwarfism in Labrador Retrievers, which is not associated with any obvious health problems such as secondary arthrosis. We designate this phenotype as skeletal dysplasia 2 (SD2). It is inherited as a monogenic autosomal recessive trait with incomplete penetrance primarily in working lines of the Labrador Retriever breed. Using 23 cases and 37 controls we mapped the causative mutation by genome-wide association and homozygosity mapping to a 4.44 Mb interval on chromosome 12. We re-sequenced the genome of one affected dog at 30x coverage and detected 92 non-synonymous variants in the critical interval. Only two of these variants, located in the lymphotoxin A (LTA) and collagen alpha-2(XI) chain gene (COL11A2), respectively, were perfectly associated with the trait. Previously described COL11A2 variants in humans or mice lead to skeletal dysplasias and/or deafness. The dog variant associated with disproportionate dwarfism, COL11A2:c.143G>C or p.R48P, probably has only a minor effect on collagen XI function, which might explain the comparatively mild phenotype seen in our study. The identification of this candidate causative mutation thus widens the known phenotypic spectrum of COL11A2 mutations. We speculate that non-pathogenic COL11A2 variants might even contribute to the heritable variation in height.

Genetic analyses of elbow and hip dysplasia in the German shepherd dog

Results from radiographic screening for canine hip dysplasia (CHD) and elbow dysplasia (CED) of 48 367 German shepherd dogs born in 2001-07 were used for the population genetic analyses. Available information included CHD scores for 47 730 dogs, CED scores for 28 011 dogs and detailed veterinary diagnoses of primary ED lesions for a subsample of 18 899 dogs. Quasi-continuous traits were CHD, CED and cases of CED without radiographically visible primary lesion (CED-ARTH). Binary coding was used for fragmented medial coronoid process of the ulna (FCP), borderline findings and mild to severe signs of dysplasia in hip and elbow joints. Genetic parameters were estimated in univariate threshold and multivariate linear and mixed linear-threshold models using Gibbs sampling. Correlations between univariately predicted breeding values (BV) indicated genetic differences between borderline and affected disease status for both CHD (r(BV) = 0.5) and CED (r(BV) = 0.3). Multivariate genetic analyses with separate consideration of borderline findings revealed moderate heritabilities of 0.2-0.3 for the quasi-continuous traits with positive additive genetic correlation of 0.3 between CHD and both CED and CED-ARTH. For FCP, heritability of 0.6 and additive genetic correlations of +0.1 to CHD and -0.1 to CED-ARTH were estimated. Results supported the relevant genetic determination of CHD and CED, argued for both diseases against interpretation of borderline findings as healthy and implied genetic heterogeneity of CED. Accordingly, future breeding strategies to reduce the prevalences of CHD and CED in the German shepherd dog should be most efficient when based on BV from multivariate genetic evaluation for CHD, CED-ARTH and FCP with use of the whole scale of categories for classification of CHD and CED.

MR‐IMAGING OF LUMBOSACRAL INTERVERTEBRAL DISC DEGENERATION IN CLINICALLY SOUND GERMAN SHEPHERD DOGS COMPARED TO OTHER BREEDS

German shepherd dogs are overrepresented in the group of dogs with cauda equina compression syndrome due to degenerative lumbosacral stenosis. A congenital predisposition for early degeneration of the lumbosacral intervertebral disc has been suspected. Our aims were to assess the morphologic appearance of the lumbosacral intervertebral disc and the lumbosacral junction in healthy German shepherd dogs compared to other breeds and to evaluate for an early onset of degenerative changes. The lumbosacral spine of 110 clinically sound German shepherd dogs and 47 healthy dogs of other large breeds was examined using magnetic resonance (MR) imaging. The degeneration of every intervertebral disc was graded using an established classification system. Signal intensity of the entire lumbosacral disc and the nucleus pulposus was determined independently. Lumbosacral malalignment was assessed according to a previously described method. The findings for the German shepherd dogs were compared to those of the other breeds. Although most dogs were younger than 18 months at the date of examination, significantly higher grades of degeneration were detected for the lumbosacral intervertebral disc of German shepherd dogs (P < 0.003). Degeneration of the lumbosacral intervertebral disc was independent from findings in the other lumbar discs. We conclude that the German shepherd dog has a predisposition for degenerative changes in the lumbosacral intervertebral disc.

Skeletal morphology and morphometry of the lumbosacral junction in German shepherd dogs and an evaluation of the possible genetic basis for radiographic findings

The aim of this study was to identify skeletal variations in the lumbosacral junction (LSJ) of the German shepherd dog (GSD) compared with other large breeds. The radiographic traits of the LSJ were investigated in a group of 733 GSDs and a control group of 334 dogs of other breeds that were matched in terms of size. Nine morphological and 17 morphometric traits were recorded and analysed. Furthermore, the possibility of a genetic basis for these radiographic features was evaluated by calculation of genetic variance components. Five of the morphological and 14 of the morphometric traits varied significantly between the GSD group and the control group (P<0.05). Osteochondrosis of the sacral endplate (SOC) had a higher prevalence in the GSDs (10.1%) compared with controls (5.7%). The majority of LSJ degenerative changes recorded from the radiographs occurred in the GSDs. The extent and relative proportion of lumbosacral step formations were greater in the GSD group compared with controls (P<0.001). The lumbosacral vertebral canal height was reduced in the GSD compared with the control dogs (P<0.001) suggesting a primary stenosis. This was accentuated by an abrupt tapering of the vertebral canal at the level of the LSJ indicated by a lumbosacral ratio of 1.51 in the GSD. The skeletal morphology and morphometry of the LSJ in the GSD seem to be different from that found in other large dogs. For multiple traits frequently observed in GSD such as SOC, step formations, and LSJ stenosis, moderate to high non-zero heritabilities were noted. As these features are also assumed to promote lumbosacral disease, selection against these traits is suggested.

Static and dynamic ultrasonography for the early diagnosis of canine hip dysplasia

OBJECTIVE To determine the feasibility of sonographical examination of hip joints in non-sedated puppies and to assess the value of static and dynamic ultrasonography for the early diagnosis of canine hip dysplasia (CHD). METHODS Prospective study was carried out. Five hundred and sixty-six puppies between the ages of 16 and 49 days underwent sonographical determination of the α-angle, joint laxity and distraction value (DV). Sonographical parameters were correlated to conventional radiographic CHD classification in the adult dogs. RESULTS α-Angles between 74° and 89° (X±sd=82·8°±2·31°) were measured. Despite the feasibility of sonographical hip assessment in puppies, no statistically significant correlation was found between sonographical determinations of the α-angle, joint laxity, DV and conventional radiographic hip joint classification at the age of 12 to 24 months. CLINICAL SIGNIFICANCE Results of our study suggest that static and dynamic ultrasonography of hip joints in puppies between 16 and 49 days of age is technically feasible but cannot be recommended for detecting puppies that will develop CHD between the ages of 12 and 24 months.

Prospective evaluation of a patented DNA test for canine hip dysplasia (CHD)

Genetic testing has been propagated as a suitable means to specify individual risks for canine hip dysplasia (CHD). However, the current lack of validation of most genetic CHD tests has left dog owners and breeders in the dark about their practical utility. Therefore, the Society for German Shepherd Dogs (Verein für Deutsche Schäferhunde, SV) initiated a prospective study of 935 animals to assess independently the value of a genetic CHD test (European Patent Specification EP 2 123 777 B1) that was developed by Distl et al. (2009) on the basis of the SV animal stock. Dogs were followed-up for 3 years after birth, classified regarding their CHD phenotype using the scheme of the Fédération Cynologique Internationale, and genotyped for the 17 single nucleotide polymorphisms (SNPs) constituting the CHD test in question. Individual SNP genotypes were combined into animal-specific genomic breeding values (GBVs), calculated as the weighted sum of SNP-wise scores as laid down in the patent specification. Logistic regression analysis revealed that, unexpectedly, the odds ratio for CHD decreased, rather than increased, by a factor of 0.98 per unit increase of the GBV. Nevertheless, since this effect was not statistically significant (95% CI: 0.93–1.03), and the area-under-curve of the test was only 0.523, it must be concluded that the genetic test patented by Distl et al. (2009) is unsuitable for individual CHD risk assessment.