Phenotype of the inherited disproportionate dwarfism.
(A) Photograph of a female affected Labrador Retriever. Notice the relatively long body in relation to the length of the legs. (B) Affected mother (left) with her non-affected daughter (right). The affected dog has shorter forelegs. (C) Photograph of three littermates. The affected male has short legs and different proportions compared to his non-affected sister. (D) Radiograph of the left front limb of a male control Labrador Retriever and (E) his affected full brother at 12 months of age. In the affected dog ulna and radius are 2.7 cm and 1.9 cm shorter and slightly more bent than in the control, respectively. The diameter of the diaphysis of the long bones is not affected (Table S1).

Phenotype of the inherited disproportionate dwarfism. (A) Photograph of a female affected Labrador Retriever. Notice the relatively long body in relation to the length of the legs. (B) Affected mother (left) with her non-affected daughter (right). The affected dog has shorter forelegs. (C) Photograph of three littermates. The affected male has short legs and different proportions compared to his non-affected sister. (D) Radiograph of the left front limb of a male control Labrador Retriever and (E) his affected full brother at 12 months of age. In the affected dog ulna and radius are 2.7 cm and 1.9 cm shorter and slightly more bent than in the control, respectively. The diameter of the diaphysis of the long bones is not affected (Table S1).

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We describe a mild form of disproportionate dwarfism in Labrador Retrievers, which is not associated with any obvious health problems such as secondary arthrosis. We designate this phenotype as skeletal dysplasia 2 (SD2). It is inherited as a monogenic autosomal recessive trait with incomplete penetrance primarily in working lines of the Labrador R...

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... In the Dogo Argentino breed, a PRKG2 splice site variant represents a candidate causal variant for disproportionate dwarfism characterized by forelimb deformations and a disproportionally large head [11]. A missense variant in COL11A2 was reported in Labrador Retrievers with a mild form of disproportionate dwarfism, designated as skeletal dysplasia 2 (SD2) [12]. In Norwegian Elkhounds, a nonsense variant in ITGA10 was described, and proposed to cause chondrodysplasia in nine affected dogs [13]. ...
... This assumption is supported by the observation that its phenotype showed some deviation from the other cases, notably a shortened lower jaw ( Figure S2). Heterogeneity in skeletal dysplasias is well documented in humans and dogs [2,4,12]. ...
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Disproportionate dwarfism phenotypes represent a heterogeneous subset of skeletal dysplasias and have been described in many species including humans and dogs. In this study, we investigated Vizsla dogs that were affected by disproportionate dwarfism that we propose to designate as skeletal dysplasia 3 (SD3). The most striking skeletal changes comprised a marked shortening and deformation of the humerus and femur. An extended pedigree with six affected dogs suggested autosomal recessive inheritance. Combined linkage and homozygosity mapping localized a potential genetic defect to a ~4 Mb interval on chromosome 33. We sequenced the genome of an affected dog, and comparison with 926 control genomes revealed a single, private protein-changing variant in the critical interval, PCYT1A:XM_038583131.1:c.673T>C, predicted to cause an exchange of a highly conserved amino acid, XP_038439059.1:p.(Y225H). We observed perfect co-segregation of the genotypes with the phenotype in the studied family. When genotyping additional Vizslas, we encountered a single dog with disproportionate dwarfism that did not carry the mutant PCYT1A allele, which we hypothesize was due to heterogeneity. In the remaining 130 dogs, we observed perfect genotype–phenotype association, and none of the unaffected dogs were homozygous for the mutant PCYT1A allele. PCYT1A loss-of-function variants cause spondylometaphyseal dysplasia with cone–rod dystrophy (SMD-CRD) in humans. The skeletal changes in Vizslas were comparable to human patients. So far, no ocular phenotype has been recognized in dwarf Vizslas. We propose the PCYT1A missense variant as a candidate causative variant for SD3. Our data facilitate genetic testing of Vizslas to prevent the unintentional breeding of further affected puppies.
... Several other studies evaluated the effects of height-related alleles segregating within breeds. In the Labrador retriever, a COL11A2 missense variant conferred a 10% reduction in height at the shoulders [14]. A variant in ADAMTS17 confers a risk of glaucoma in Petit Basset Griffon Vendéen (PBGV) and Shar Pei but was also demonstrated to have an effect on height. ...
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Two FGF4 retrogenes (FGF4L1 on chromosome 18 and FGF4L2 on chromosome 12) have been identified to cause dwarfism across many dog breeds. Some breeds are nearly homozygous for both retrogenes (e.g., Dachshunds) and others are homozygous for just one (e.g., Beagles and Scottish Terriers). Since most breeds do not segregate both of these retrogenes, it is challenging to evaluate their individual effects on long bone length and body size. We identified two dog breeds selected for hunting ability, the Alpine Dachsbracke and the Schweizer Niederlaufhund, that segregate both of these retrogenes. Using individual measurements of height at the shoulder, back length, head width, thorax depth and width, and thoracic limb measurements, we evaluated the combined effects of FGF4 retrogenes within these breeds. We applied multivariable linear regression analysis to determine the effects of retrogene copy numbers on the measurements. Copy numbers of both retrogenes had significant effects reducing height at the shoulders and antebrachial length, with FGF4L1 having a much greater effect than FGF4L2. FGF4L1 alone influenced the degree of carpal valgus and FGF4L2 alone increased head width. Neither retrogene had an effect on thorax width or depth. Selectively breeding dogs with FGF4L1 and without FGF4L2 would likely lead to a reduction in the FGF4L2-related risk of intervertebral disc herniation while maintaining the reduction in leg length resulting from FGF4L1.
... A rare form of chondrodysplasia is caused by a nonsense variant in the ITGA10 gene present in Karelian bear dogs and Norwegian Elkhounds [13] (OMIA 001886-9615). Skeletal dysplasia 2 (SD2) is a mild form of disproportionate dwarfism in Labrador Retrievers, and the underlying causative variant is a missense variant in COL11A2 [14] (OMIA 001772-9615). Osteochondrodysplasia is produced by a 130 kb deletion in the SLC13A1 gene in Miniature Poodles [15] (OMIA 001315-9615). ...
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Dwarfism phenotypes occur in many species and may be caused by genetic or environmental factors. In this study, we investigated a family of nine Dogo Argentino dogs, in which two dogs were affected by disproportionate dwarfism. Radiographs of an affected dog revealed a decreased level of endochondral ossification in its growth plates, and a premature closure of the distal ulnar physes. The pedigree of the dogs presented evidence of monogenic autosomal recessive inheritance; combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 34 genome segments, totaling 125 Mb. The genome of an affected dog was sequenced and compared to 795 control genomes. The prioritization of private variants revealed a clear top candidate variant for the observed dwarfism. This variant, PRKG2:XM_022413533.1:c.1634 + 1G>T, affects the splice donor site and is therefore predicted to disrupt the function of the PKRG2 gene encoding protein, kinase cGMP-dependent type 2, a known regulator of chondrocyte differentiation. The genotypes of the PRKG2 variant were perfectly associated with the phenotype in the studied family of dogs. PRKG2 loss-of-function variants were previously reported to cause disproportionate dwarfism in humans, cattle, mice, and rats. Together with the comparative data from other species, our data strongly suggest PRKG2:c.1634+1G>T to be a candidate causative variant for the observed dwarfism phenotype in Dogo Argentino dogs.
... In addition to analyzing variants in candidate genes as indicated by VarElect, we also focused on homozygous autosomal recessive variants predicted to alter a protein, of which there were 4. A missense variant in the gene CAST also was observed in 2/616 DBVDC genomes (1 homozygous and 1 heterozygous Labrador Retriever, 1 of these was of German ancestry, was submitted for research at the age of 14 months with skeletal dysplasia type 2 (SD2) and was 1 of the cases previously reported. 35 There was no report of sensory neuropa- (Table S1). This variant also was not found in 360 dogs of 120 breeds, (Table S2). ...
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Background Hereditary sensory and autonomic neuropathies (HSANs) are a group of genetic disorders affecting the peripheral nervous system. Two different associated variants have been identified in dogs: 1 in Border Collies and 1 in Spaniels and Pointers. Objectives Clinically and genetically characterize HSAN in a family of mixed breed dogs. Animals Five 7-month-old mixed breed dogs from 2 related litters were presented for evaluation of a 2-month history of acral mutilation and progressive pelvic limb gait abnormalities. Methods Complete physical, neurological, electrodiagnostic, and histopathological evaluations were performed. Whole genome sequencing of 2 affected dogs (1 from each litter) was used to identify variants that were homozygous or heterozygous in both cases, but wild type in 217 control genomes of 100 breeds. Immunohistochemistry was used to assess protein expression. Results Complete physical, neurological, electrodiagnostic, and histopathological evaluations confirmed a disorder affecting sensory and autonomic nerves. Whole genome sequencing identified a missense variant in the RETREG1 (reticulophagy regulator 1) gene (c.656C > T, p.P219L). All affected dogs were homozygous for the variant, which was not detected in 1193 dogs from different breeds. Immunohistochemistry showed no expression of RETREG1 in the cerebellum of affected dogs. One of the affected dogs lived for 5 years and showed gradual progression of the clinical signs. Conclusions and Clinical Importance We confirmed the diagnosis of HSAN in a family of mixed breed dogs and identified a novel and possibly pathogenic RETREG1 variant. Affected dogs experienced gradual deterioration over several years.
... www.nature.com/scientificreports/ years, reports on a growing number of inherited diseases have challenged this "healthy" image of the breed [16][17][18][19][20][21][22][23][24][25][26] . Researchers at University of California Davis Veterinary Genetics Laboratory (UCD VGL) report that, while genetic diversity in Labrador Retrievers in the US is reasonable in comparison to other breeds, some bloodlines are more inbred than others, and they used this background to explain why Labrador Retrievers are predisposed to several disorders 14 . ...
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The Labrador Retriever is one of the most popular dog breeds worldwide, therefore it is important to have reliable evidence on the general health issues of the breed. Using anonymised veterinary clinical data from the VetCompass Programme, this study aimed to explore the relative risk to common disorders in the Labrador Retriever. The clinical records of a random sample of dogs were reviewed to extract the most definitive diagnoses for all disorders recorded during 2016. A list of disorders was generated, including the 30 most common disorders in Labrador Retrievers and the 30 most common disorders in non-Labrador Retrievers. Multivariable logistic regression was used to report the odds of each of these disorders in 1462 (6.6%) Labrador Retrievers compared with 20,786 (93.4%) non-Labrador Retrievers. At a specific-level of diagnostic precision, after accounting for confounding, Labrador Retrievers had significantly increased odds of 12/35 (34.3%) disorders compared to non-Labrador Retrievers; osteoarthritis (OR 2.83) had the highest odds. Conversely, Labrador Retrievers had reduced odds of 7/35 (20.0%) disorders; patellar luxation (OR 0.18) had the lowest odds. This study provides useful information about breed-specific disorder predispositions and protections, which future research could evaluate further to produce definitive guidance for Labrador Retriever breeders and owners.
... Several forms of hereditary disproportional dwarfism have been described in dogs [4][5][6][7][8][9][10]. A recessive mode of inheritance is reported in many breeds [4][5][6][7][8][9][10] and associated genes or possible causative mutations are known in some of them. ...
... Several forms of hereditary disproportional dwarfism have been described in dogs [4][5][6][7][8][9][10]. A recessive mode of inheritance is reported in many breeds [4][5][6][7][8][9][10] and associated genes or possible causative mutations are known in some of them. A nonsense-mutation in the ITGA10gene cause chondrodysplasia in Norwegian elkhounds and Karelian bear dogs [4]. ...
... A nonsense-mutation in the ITGA10gene cause chondrodysplasia in Norwegian elkhounds and Karelian bear dogs [4]. In Labrador retrievers, a mild form of chondrodysplasia is associated with a mutation in the COL11A2-gene [6]. A deletion in the SLC13A1gene has been associated with chondrodysplasia in miniature poodles [5]. ...
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Background Cases of foreleg deformities, characterized by varying degrees of shortened and bowed forelegs, have been reported in the Havanese breed. Because the health and welfare implications are severe in some of the affected dogs, further efforts should be made to investigate the genetic background of the trait. A FGF4-retrogene on CFA18 is known to cause chondrodystrophy in dogs. In most breeds, either the wild type allele or the mutant allele is fixed. However, the large degree of genetic diversity reported in Havanese, could entail that both the wild type and the mutant allele segregate in this breed. We hypothesize that the shortened and bowed forelegs seen in some Havanese could be a consequence of FGF4RG-associated chondrodystrophy. Here we study the population prevalence of the wild type and mutant allele, as well as effect on phenotype. We also investigate how the prevalence of the allele associated with chondrodystrophy have changed over time. We hypothesize that recent selection, may have led to a gradual decline in the population frequency of the lower-risk, wild type allele. Results We studied the FGF4-retrogene on CFA18 in 355 Havanese and found variation in the presence/absence of the retrogene. The prevalence of the non-chondrodystrophic wild type is low, with allele frequencies of 0.025 and 0.975 for the wild type and mutant allele, respectively (linked marker). We found that carriers of the beneficial wild type allele were significantly taller at the shoulder than mutant allele homozygotes, with average heights of 31.3 cm and 26.4 cm, respectively. We further found that wild type carriers were born on average 4.7 years earlier than mutant allele homozygotes and that there has been a gradual decline in the population frequency of the wild type allele during the past two decades. Conclusions Our results indicate that FGF4RG-associated chondrodystrophy may contribute to the shortened forelegs found in some Havanese and that both the wild type and mutant allele segregate in the breed. The population frequency of the wild type allele is low and appear to be decreasing. Efforts should be made to preserve the healthier wild type in the population, increase the prevalence of a more moderate phenotype and possibly reduce the risk of foreleg pathology.
... The molecular genetic underpinnings of limb length variability in dog breeds are becoming more completely understood although many unexplained types of skeletal dysplasia remain. Several skeletal dysplasias in specific dog breeds have been associated with mutations in members of the collagen gene family or its binding proteins (8)(9)(10), fibrilin related protein (11), as well as an altered sulfate transporter protein (12). However, overexpression of FGF4 associated with insertion of FGF4 retrogenes on CFA12 and CFA18 appear to have broader influences on limb length across many breeds and are the only genes to have been implicated in body size in across-breed association studies (3,(13)(14)(15)(16). ...
... However, overexpression of FGF4 associated with insertion of FGF4 retrogenes on CFA12 and CFA18 appear to have broader influences on limb length across many breeds and are the only genes to have been implicated in body size in across-breed association studies (3,(13)(14)(15)(16). While many breed specific mutations are considered undesirable (8)(9)(10)12) some of these genes have been under positive selection in specific breeds due to their effects on height, despite associated pathologies including glaucoma and IVDD (11,13). ...
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Premature degeneration of the intervertebral disc and its association with specific chondrodystrophic dog breeds has been recognized for over a century. Several lines of evidence including disease breed predisposition, studies suggesting heritability of premature intervertebral disc degeneration (IVDD) and association of a dog chromosome 12 (CFA 12) locus with intervertebral disc calcification have strongly supported a genetic component in IVDD in dogs. Recent studies documenting association of IVDD with an overexpressing FGF4 retrogene on CFA 12 have opened up new areas of investigation to further define the pathophysiology of premature IVDD. While preliminary data from studies investigating FGF4 retrogenes in IVDD implicate FGF4 overexpression as a major disease factor, they have also highlighted knowledge gaps in our understanding of intervertebral disc herniation which is a complex and multifactorial disease process.
... WGS and WES involve the resequencing of a genome or exome, respectively, which was made possible for canines once the first reference genome was published in 2005 [51]. In 2013, the first WGS [52][53][54] and WES [55] studies identified mutations associated with inherited canine disorders. Since that time, despite improvements to canine exome designs [56], the use of WES lagged behind. ...
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Background Although, in general, cancer is considered a multifactorial disease, clustering of particular cancers in pedigrees suggests a genetic predisposition and could explain why some dog breeds appear to have an increased risk of certain cancers. To our knowledge, there have been no published reports of whole genome sequencing to investigate inherited canine mammary tumor (CMT) risk, and with little known about CMT genetic susceptibility, we carried out whole genome sequencing on 14 purebred dogs diagnosed with mammary tumors from four breed-specific pedigrees. Following sequencing, each dog’s data was processed through a bioinformatics pipeline. This initial report highlights variants in orthologs of human breast cancer susceptibility genes. Results The overall whole genome and exome coverage averages were 26.0X and 25.6X, respectively, with 96.1% of the genome and 96.7% of the exome covered at least 10X. Of the average 7.9 million variants per dog, initial analyses involved surveying variants in orthologs of human breast cancer susceptibility genes, BRCA1, BRCA2, CDH1, PTEN, STK11, and TP53, and identified 19 unique coding variants that were validated through PCR and Sanger sequencing. Statistical analyses identified variants in BRCA2 and STK11 that appear to be associated with CMT, and breed-specific analyses revealed the breeds at the highest risk. Several additional BRCA2 variants showed trends toward significance, but have conflicting interpretations of pathogenicity, and correspond to variants of unknown significance in humans, which require further investigation. Variants in other genes were noted but did not appear to be associated with disease. Conclusions Whole genome sequencing proves to be an effective method to elucidate risk of CMT. Risk variants in orthologs of human breast cancer susceptibility genes have been identified. Ultimately, these whole genome sequencing efforts have provided a plethora of data that can also be assessed for novel discovery and have the potential to lead to breakthroughs in canine and human research through comparative analyses.
... 6 Although this type of research may not seem particularly impactful for general practice, it provides important information regarding specific breeds that could potentially increase our understanding of diseases that correspond to human conditions. [7][8][9] These studies also yield important insight regarding the evolution of dogs and humans and reveal key information about the canine genome. 10,11 Most of the diseases in dogs studied using GWAS have been rare diseases that appear within a single breed or small subset of breeds as a result of intense artificial selection. ...
Article
Dog owners are increasingly interested in using commercially available testing panels to learn about the genetics of their pets, both to identify breed ancestry and to screen for specific genetic diseases. Helping owners interpret and understand results from genetic screening panels is becoming an important issue facing veterinarians. The objective of this review article is to introduce basic concepts behind genetic studies and current genetic screening tests while highlighting their value in veterinary medicine. The potential uses and limitations of commercially available genetic testing panels as screening tests are discussed, including appropriate cautions regarding the interpretation of results. Future directions, particularly with regard to the study of common complex genetic diseases, are also described.
... Additional variants in canine homologs for Cartilage specific integrin alpha 10 (ITGA10) 40 , collagen alpha-2(XI) chain (COL11A1) 41 , and two collagen type IX genes (COL9A2 and COL9A3) 42 genes were annotated within the critical region for feline dwarfism. Unfortunately, no coding or splice variants were identified within these genes in the region. ...
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Despite the contribution of a few major genes for disproportionate dwarfism in humans, many dwarf patients are yet genetically undiagnosed. In domestic cats, disproportionate dwarfism has led to the development of a defined breed, the Munchkin or Minuet. This study examined the genetic aspects of feline dwarfism to consider cats as a new biomedical model. DNA from dwarf cats was genetically analyzed using parentage, linkage, and genome-wide association studies as well as whole genome sequencing. Each genetic approach localized the dwarfism phenotype to a region on cat chromosome B1. No coding variants suspected as causal for the feline dwarfism were identified but a critical region of ~5.7 Mb from B1:170,278,183-175,975,857 was defined, which implicates a novel gene controlling disproportionate dwarfism. A yet unidentified but novel gene variant, likely structural or regulatory, produces disproportionate dwarfism in cats, which may define undiagnosed human patients.