In early 2008 we were contacted by a southern Poll Merino breeder who reported a problem of 'freak lambs' in her flock over the previous five years She described 2 lambs born in a flock of 400 ewes and that lambs were of small size with fine bones and did not survive long. Numbers were increasing over successive years (2, 2, 8,12 sequentially) and she admitted 'they have been pushing the lines hard'.
Three neonatal lambs, one male and two female, were submitted for necrospy. All 3 lambs had a remarkably similar phenotype, weighing 1.4kg, with crown rump lengths of 35cm. They had failed to walk, breath or feed and the most striking external macroscopic findings were the small body size, prominent abdominal distension and pronounced inferior brachygnathia causing a 2cm malocclusion of the unerupted lower incisors and the upper dental pad. The cranium appeared shortened which appeared to have caused mild caudal compressed the brain and broadening of the orbits, resulting in prominent bilateral exopthalmia.
On opening the body cavities, the thoracic cavity appeared smaller than expected as a result of small thin ribs (there were 13) and brachysternum. It contained an enlarged rounded heart, the cardiomegally occurring from right sided ventricular hypertrophy in particular. The heart and lungs occupied the majority of the thoracic space. The abdominal cavity was characterized by an enlarged dark congested liver with rounded edges and small kidneys. The remaining viscera appeared normal. Histopathology of the liver showed marked congestion with hepatocellular atrophy and biliary retention. Kidneys were markedly hypoplastic with tubular necrosis. Other organs were micoscopically normal.
Morphological diagnosis. Multiple congenital defects including dwarfism, brachygnathia, brachysternum, exopthalmia, cardiomegally and renal hypoplasia Provisional aetiological diagnosis. Likely genetic defect, previously unreported in the veterinary literature.
Subsequent breeding data was studied by segregation analysis and suggested the defect was a fully penetrant lethal recessive inherited defect. The frequency of affected lambs in annual lambing dropping from 2.5% of lambs affected in 2004 to 0.5% 2009 due to elimination of putative carriers from the breeding cohort. All of the affected lambs were from a common family with no parental animals affected.
DNA samples from affected animals, parents and unrelated normal animals were genotyped with the new Ovine SNP chip (developed by the International Sheep Genomics Consortium) that enables 50,000 genetic markers to be tested at once. A single genomic region associated with the defect was identified. Further studies to identify the causative mutation are proposed that may lead to a genetic test for use in Merino populations for carriers of the defect but more importantly, add to our understanding of developmental biology of this genomic region in all mammals.
Bovine genetic defects have been commonly described in Australian cattle (Jolly and Windsor, 2010) and are likely to also be common in Australian sheep. However with the exception of holoprosencephaly in Border Leicester lambs (Roth et al, 1987), spider syndrome in Suffolk lambs (Philips et al, 1992) and neurovisceral ceriod lipofuscinosis (NCL) in Merino sheep which is analogous to CLN6 in humans (Tammen et al, 2006), inherited defects of sheep in Australia have been rarely studied in sufficient detail to identify the mode of inheritance, let alone identify the causative mutation.
As congenital cardiac malformations are one of the most important of clinical defects in humans with an estimated prevalence of 4 to 50 per 1000 live births (Pierpont et al. 2007), studies of this novel ovine defect causing congenital heart disease is considered potentially important. To further this work, we would be pleased to hear from anyone who has this or similar defects in this or other breeds.
The cooperation of the owners is essential to this work and is the staff in the team from the Faculty of Veterinary Science involved in this study, including Mohammad Shariflou, Claire Wade, Frank Nicholas and Imke Tammen.