LMF1 frameshift deletion in Franches-Montagnes horses with hypertriglyceridemia-induced pancreatitis

Hypertriglyceridemia (HTG) may be inherited and caused by variants in genes encoding enzymes of lipid metabolism. This study was prompted by the observation of eight Franches-Montagnes (FM) foals showing elevated plasma triglyceride levels and episodes of fatal acute pancreatitis. We termed this phenotype hypertriglyceridemia-induced pancreatitis (HIP). The affected foals were distantly related and inbred to a prominent stallion suggesting autosomal recessive inheritance. Whole genome sequencing of an affected foal identified a homozygous loss of function variant in LMF1 encoding lipase maturation factor 1. The variant, XM_023616679.1:c.369_373delinsTCT, leads to an early frameshift and is predicted to alter or truncate 78% of the LMF1 coding sequence. We genotyped the variant in a cohort of 2122 FM horses and identified 11 homozygous mutant animals including all eight foals that had initially been identified based on their clinical presentation. The three additional homozygous mutant animals had a comparable phenotype and were inbred to the same stallion. We concluded that all 11 had been affected by the same disease. Thus, we found perfect genotype-phenotype association in the tested cohort. The carrier frequency in the 2111 unaffected FM horses was 15.0%. Our findings enable genetic testing to prevent the unintentional breeding of further HIP-affected foals.