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.

Genotypic and allelic frequencies of progressive rod‐cone degeneration and other main variants associated with progressive retinal atrophy in Italian dogs

“…The allelic frequency for PRCD in Australian shepherd dogs was 0.38% (tested for 2293 dogs), while our study identified a lower incidence of that risk allele (0.02%) although the population size in our study was only 120 dogs (Table S2). The allelic frequency in 94 toy poodles was estimated to be 2.1%, 38 compared with 11.7% in our sample of 175 dogs from the Italian population. In other breeds, when the number of animals tested was higher, as in the case of the standard poodle, the frequency of the risk allele was more comparable.…”

“…The PRCD was 0.5% in 4197 standard poodles, 38 compared with 5.8% in 52 dogs from the Italian population. The frequency of the PRCD allele in the English cocker spaniel was estimated to be 9.5% based on 579 dogs, 38 compared with our result of 14.3% for 77 dogs in the Italian cohort.…”

“…In other breeds, when the number of animals tested was higher, as in the case of the standard poodle, the frequency of the risk allele was more comparable. The PRCD was 0.5% in 4197 standard poodles, 38 compared with 5.8% in 52 dogs from the Italian population. The frequency of the PRCD allele in the English cocker spaniel was estimated to be 9.5% based on 579 dogs, 38 compared with our result of 14.3% for 77 dogs in the Italian cohort.…”

“…In recent years, there have been few published studies on the genotypic and allelic frequencies of canine PRA in other countries. [34][35][36][37] One genetic study, 38 with sample sizes consisting of millions of dogs from 150 countries, reported results on 250 genetic disease-associated variants in the general dog population. It included PRA-related statistics that varied between purebred and mixed breed dogs.…”

Association of the FGF4L2 retrogene with fibrocartilaginous embolic myelopathy in dogs

“…Independence of FCE and FGF4L2 and FGF4L1 genotype status was determined using all study cases where genotyping was successful. FCE retrogene allele frequency was compared to the predicted frequency of the FGF4L1 and FGF4L2 alleles in the UC Davis veterinary hospital general population over the duration of the collected samples based on general population reported allele frequencies (15.215% and 11.951% respectively) in 1 054 293 mixed and pure‐bred dogs from more than 150 countries 47,48 …”