Prevalence of the RAPGEF5 c.2624C>A and PLOD1 c.2032G>A variants associated with equine familial isolated hypoparathyroidism and fragile foal syndrome in the US Thoroughbred population (1988-2019)

Background Equine familial isolated hypoparathyroidism (EFIH) and fragile foal syndrome (FFS) are both fatal recessive conditions reported in Thoroughbred foals. The causal variants for EFIH (RAPGEF5 c.2624C>A; EquCab3.0. chr4: g.54108297G>T) and FFS (PLOD1 c.2032G>A; EquCab3.0, chr2: g.39927817) were recently reported. Prevalence assessment for these variants in a large cohort of samples is needed to provide evidence-based recommendations for genetic testing. Objectives To estimate the frequency of the EFIH and FFS variant alleles in the United States Thoroughbred population between 1988 and 2019, and determine whether these are recent mutations or are increasing in frequency due to current breeding practices. Study design Population allele frequency study. Methods Genomic DNA from hair and serum samples were genotyped for the EFIH and FFS. Allele frequencies between cohorts, based on year of birth (1988-2000, n = 728) and (2001-2019, n = 1059), as well as across the seven geographical regions of the United States were compared by Fisher's Exact tests. Results EFIH and FFS allele frequencies were not significantly different between the two time points studied (0.008 and 0.004, respectively, in the older cohorts and 0.008 and 0.009 in most recent years). No EFIH or FFS homozygotes were detected. A sample from 1992 was identified as a carrier for EFIH and one from 1993 a carrier for FFS. Non-significant changes in geographical distribution of carriers for both traits were observed. Main limitations The earliest samples available for study were from foals born in 1988. Conclusions The EFIH and FFS variants are present at low frequency in the United States Thoroughbred population but are not recent mutations. There is no evidence to support changes in allele frequency over time. However, given the closed studbook and breeding practices, continued monitoring of breed allele frequencies and genetic testing is recommended to avoid the mating of carriers and production of affected foals.