Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs

Abstract

Hundreds of genetic variants implicated in Mendelian disease have been characterized in dogs and commercial screening is being offered for most of them worldwide. There is typically limited information available regarding the broader population frequency of variants and uncertainty regarding their functional and clinical impact in ancestry backgrounds beyond the discovery breed. Genetic panel screening of disease-associated variants, commercially offered directly to the consumer or via a veterinary clinician, provides an opportunity to establish large-scale cohorts with phenotype data available to address open questions related to variant prevalence and relevance. We screened the largest canine cohort examined in a single study to date (1,054,293 representative dogs from our existing cohort of 3.5 million; a total of 811,628 mixed breed dogs and 242,665 purebreds from more than 150 countries) to examine the prevalence and distribution of a total of 250 genetic disease-associated variants in the general population. Electronic medical records from veterinary clinics were available for 43.5% of the genotyped dogs, enabling the clinical impact of variants to be investigated. We provide detailed frequencies for all tested variants across breeds and find that 57% of dogs carry at least one copy of a studied Mendelian disease-associated variant. Focusing on a subset of variants, we provide evidence of full penetrance for 10 variants, and plausible evidence for clinical significance of 22 variants, on diverse breed backgrounds. Specifically, we report that inherited hypocatalasia is a notable oral health condition, confirm that factor VII deficiency presents as subclinical bleeding propensity and verify two genetic causes of reduced leg length. We further assess genome-wide heterozygosity levels in over 100 breeds, and show that a reduction in genome-wide heterozygosity is associated with an increased Mendelian disease variant load. The accumulated knowledge represents a resource to guide discussions on genetic test relevance by breed.

Fig 1

A) Presence of 250 Mendelian disease-associated variants and B) distribution of 242 Mendelian disease-associated variants in a cohort of 811,628 mixed breed and 242,665 purebred dogs.

Fig 2. Genome-wide heterozygosity in mixed breed dogs and 104 breeds (N ≥100 dogs tested) ranked from most to least diverse.

The figure shows medians and interquartile range boxes representing the middle 50% of the data, with whiskers representing the ranges for the bottom and top 25% of the data values excluding outliers (data points >1.5x the interquartile range from the boxes; shown as asterisks). The red vertical reference lines represent the median heterozygosity in the combined purebred dog group (35.98%) and mixed breed dogs (44.87%).

Fig 3

The relationship between genome-wide genetic heterozygosity and autosomal disease-associated variants present in A) heterozygous state and B) homozygous state; based on 178 recessive and 13 semi-dominant or dominant variants tested in 1,054,293 dogs. Medians and interquartile range boxes representing the middle 50% and whiskers representing the bottom and top 25% of the data excluding outliers (data points >1.5x the interquartile range from the boxes; asterisks) are shown.

Fig 4. Disproportionate dwarfism phenotypes in mixed breed dogs.

A) Skeletal dysplasia 2 (SD2) manifests as a mild phenotype in which the front legs are typically shorter than the hind legs and the body and head are of normal size. B-C) ITGA10 gene-related disproportionate short-limbed chondrodysplasia manifests as shortened, typically crooked legs with a normal sized head and body and in some cases like D) also as abnormally short outer digits.