Genetic disorders occur from time to time in all companion animal breeds. It is not uncommon for breeders to identify new disorders that are largely unknown in the literature. For these new (or simply rare) disorders, the first response is usually to attribute the loss of the animal to environmental causes - and this might be a fair thing to do. However, the second time the disorder is observed in a particular family of animals, a red flag is raised that there may be a genetic component to the observation.

This talk will focus on two stories such as this that came through our laboratory in recent years. In response to the challenge presented to the breeders of observing problems that had no obvious environmental cause but which were possibly genetic - two individual breeders approached us for help. Using new genetic and genomic technologies efficiently, and with the help of a ready supply of student labor, we were able to develop genetic tests for these two conditions and provide the breeders with a means of avoiding the disorders in the future.

To do this, we employed a combination of gene mapping using the wonderful genetic marker resources available for the dog (the Illumina Canine High Density genotyping array that assesses 170,000 genetic markers across the dog genome), the canine reference genome, and some next-generation DNA sequencing from members of the affected families.

These stories reveal how by working together, breeders and geneticists can solve some tricky problems and prevent the breeding of affected offspring in the future.

Comma Defect in the Miniature Schnauzer

Comma defect is a congenital problem that has been observed in multiple litters of Miniature Schnauzers in Australia. Pups with this condition are born alive but die either immediately or within a few days of birth. The pups may look relatively normal; however, they are usually around 1/3 shorter than the usual length with the hindquarters being relatively reduced in size compared with the forequarter.

While from the outside the pups appear fairly normal, this is definitely not the case. The affected pups (shown on the right below) have an incompletely developed spine and ribs compared with a normal pup of the same age (shown on the left). The pups die because they are unable to breathe normally.

Figure 1. Normal and affected pups

The inheritance of this disorder is recessive and, as with all recessive disorders, the disorder gene is able to hide away for long periods of time and may be rarely observed. Also, because the pups die near birth and look fairly normal from the outside, it is very possible that breeders may see the disorder but might mistake it for a stillborn pup, one that has died during birth, or a fading pup. We sought the support of Schnauzer owners to allow us to take a DNA sample from their dog, so that we could understand whether this disorder was of concern to Schnauzer breeders.

As a result of this collaboration, we successfully developed a DNA test for the mutation creating this disorder. The mutation was found to occur in a gene called HES-7 (Hairy Enhancer of Split - 7). This gene was known to produce similar problems in other species when the gene was disabled.

Atypical Progressive Retinal Atrophy in the Hungarian Puli

In 2012, a Sydney Puli breeder approached us requesting help because some dogs in his kennel were losing their vision. The breeder had taken the affected dogs to a vet for an eye examination, and the dogs were observed to have abnormalities in their eyes including hyperreflectivity, that is usually a sign of degraded retina, shrinking of blood vessels, and atrophy in the optic nerve head.

All are signs of progressive retinal atrophy or PRA, and this was the clinical diagnosis. This was a surprise to owner because commercial testing for PRA had been carried out (for several forms of the defect) and all tests came back as negative/normal.

Figure 2. The Puli pedigree

Using genomic strategies, we identified a defect in a gene called BBS4 (Bardet-Biedl Syndrome 4). In other species, changes in this gene affect not only vision but also obesity and fertility. We went back to the owner of the affected dogs and discovered that these also had higher than normal body weight, and the male was infertile.

As a result of this study, we have identified a gene that causes Bardet-Biedl syndrome in the dog, and have developed a mutation-based test for use in the Hungarian Puli breed.