A large deletion on CFA28 omitting ACSL5 is associated with lipid malabsorption in Australian Kelpies

Inborn errors of metabolism are rare genetic conditions characterised by a disruption of intermediary metabolic pathways, causing defective absorption and metabolism of dietary nutrients. In a Kelpie breeding population, 14 puppies presented with lipid malabsorption. Juvenile dogs exhibited stunted postnatal growth, steatorrhea, abdominal bloating and a wiry coat. Pancreatic enzyme supplementation improved growth and reduced juvenile mortality rates, though adult dogs remain smaller in stature and continue to suffer intolerance to dietary fat. Using genome-wide association analysis, an associated locus on CFA28 (Praw= 2.87E-06) was discovered and validated in a closely related population (Praw = 1.75E-45). A 103.7 kb deletion containing genes Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5) and Zinc Finger DHHC-Type Containing 6 (ZDHHC6), was characterised using whole transcriptomic data. Comparative analysis revealed no expression of ACSL5 and disrupted splicing of ZDHHC6 in jejunal tissue of affected Kelpies. ACSL5 plays a key role in long chain fatty acid absorption while ZDHHC6 has not been previously implicated in metabolic disorders. A PCR-based diagnostic test was developed and confirmed fully penetrant Mendelian recessive mode of inheritance. We conclude the structural variant causing a deletion of the ACSL5 gene is the most likely cause for lipid malabsorption in the Australian Kelpie.