Autosomal dominant primary hyperparathyroidism in the Keeshond dog breed is strongly associated with a missense...

Primary hyperparathyroidism (PHPT) is an inherited disorder that leads to inappropriate secretion of parathyroid hormone by neoplastic parathyroid cells. Dogs of the Keeshond breed are predisposed to adenomas or hyperplasia of the parathyroid that lead to PHPT. The disorder is inherited in a dominant Mendelian fashion with a high age-related penetrance. The age of onset in PHPT-affected Keeshonden is typically later than 8 years. Genome-wide association studies with 27 affected and 42 unaffected Keeshonden genotyped with 30 896 markers identified a region of strong association with the PHPT phenotype on canine chromosome 20. The most significant array marker was NC_049241.1.g.55977819 C>G. The strength of association of this region with the case phenotype was unique in the genome and concordant with the hypothesis of dominant inheritance (i.e. all case animals in the genome-wide association studies were heterozygous for the most associated variant). Fine-scale variant analysis in the region of association revealed a mutation that creates both a missense and a possible splice-site variant within exon 2 of the gene SIRT6 (NC_049241.1g.55817330A>G; XM_038567756.1.c.193A>G; XP_038423684.1.p.65R>G). The variant appears uniquely within affected dogs when compared with 1987 other genotyped samples in the public domain. Strong concordance was observed between genotypes for the variant in SIRT6 and a promoter variant in eukaryotic elongation factor 2 (NC_049241.1.g. 55973578_55973593dupinsN[180]) used for disorder testing in the USA since 2008. Based on the absence of the SIRT6 variant in any healthy dog and modelled functional behaviour of the variant we conclude that the SIRT6 variant is probably pathogenic for PHPT.