1. Keeshond Club Genetic Counselling Scheme December 4, 2009 Stephen J.G. Hall University of Lincoln

2. Background The idea of a genetic tendency to epilepsy was first published in 1964. EEG investigations (1970s) proved fruitless. In late 1980s the late Dr. Margaret Wallace carried out pedigree analysis of 15 animals diagnosed by vets as epileptic and of 34 litters that didn’t show the condition. The simplest hypothesis – a single non-sex-linked recessive gene – was tested by assuming both parents of an affected pup were carriers. For 26 litters of which both parents were thought to be carriers, numbers of normal and affected progeny were known (91 and 29 respectively). This is the same, statistically, as a 3:1 ratio which is what would be expected from the hypothesis proposed. All the fitters were found to be inbred to either a dog born in 1971, or to his great grandsire.

3. Operation of the scheme In 1989 following a lecture by Dr. Wallace the Keeshond Club decided to start a genetic counselling scheme and when Dr. Wallace retired, I continued with it. Veterinary practice and genetic counselling have been completely separate; I play no part in diagnosis and will only enter an animal on the list of carriers if it is a parent of an epileptic and if this is communicated to me by the Club’s scheme co-ordinator.

4. Uptake of the scheme Breeders who anticipate using specific animals for breeding, provide pedigree details to the co-ordinator who forwards them to SJGH. Numbers of these notifications, and of requests for advice, fluctuate from year to year (next slide, where trend lines are also given).

5. Numbers of advices requested and of animals notified to the scheme

6. Criteria for approval of matings Advice on matings is based purely on a calculation of the probability that a resulting pup will be a carrier. Other factors, such as inbreeding, are not taken into account. A threshold was set at the start of the scheme; a calculated probability of greater than 0.26 (26%) would disqualify the mating. The rationale behind this threshold was explained in a scientific publication (Hall & Wallace, 1996*). Generally, a high proportion of matings are approved (next slide, with trend line). *Vet. Rec. (1996) 138, 358

7. Percentages of proposed matings that were approved

8. Trends in calculated carrier probabilities The next slide shows a possible downward trend in the carrier probabilities of proposed matings. However, this is not strong evidence of a reduction in the frequency of the recessive gene. Perhaps breeders are making their own calculations or estimates and are no longer submitting matings for advice that are likely to be very near the threshold.

9. Average carrier probabilities of proposed matings

10. Is the scheme working (1)? In addition to the trend implied in the previous slide, there is a downward tendency in the carrier probabilities of animals being notified to the scheme This would suggest the frequency of the recessive gene is declining, at least in the segment of the breed that uses the scheme

11. Average carrier probabilities of all animals notified to scheme Year of birth of dog

12. Is the scheme working (2)? There is more powerful evidence for a beneficial effect. This was found in a project funded by the Canine Supporters’ Charity. KC records were examined in 2004. It was found that many of the matings had not been referred to the scheme. Carrier probabilities were calculated for all registered litters. Evidently (next slide), over the breed as a whole carrier probability is declining, i.e. the frequency of the recessive gene is declining.

13. Average carrier probabilities of all KC registered Keeshond litters

14. Next steps Ideally, there would be a direct DNA test by which carrier animals would be identified. However, this would require a sample of at least 12 epileptic animals and also of non-epileptics. Repeated efforts have been made to contact the worker at Cambridge University reported to be particularly interested in a direct DNA test, with a view to coordinating the scheme with proposed research work, but these attempts have been rebuffed. However, if a DNA test does appear, it will be much easier to put it into effect if the frequency of the recessive gene has already been reduced. Accordingly, it is suggested that the current scheme continues to offer real benefits to the breed and should continue to be supported. SJGH 4 December 2009