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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.
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Relevância Clínica , Testes Genéticos , Cães , Humanos , Animais , Prevalência , Frequência do Gene , FenótipoRESUMO
In the largest DNA-based study of domestic cats to date, 11,036 individuals (10,419 pedigreed cats and 617 non-pedigreed cats) were genotyped via commercial panel testing elucidating the distribution and frequency of known disease, blood type, and physical trait associated genetic variants across cat breeds. This study provides allele frequencies for many disease-associated variants for the first time and provides updates on previously reported information with evidence suggesting that DNA testing has been effectively used to reduce disease associated variants within certain pedigreed cat populations over time. We identified 13 disease-associated variants in 47 breeds or breed types in which the variant had not previously been documented, highlighting the relevance of comprehensive genetic screening across breeds. Three disease-associated variants were discovered in non-pedigreed cats only. To investigate the causality of nine disease-associated variants in cats of different breed backgrounds our veterinarians conducted owner interviews, reviewed clinical records, and invited cats to have follow-up clinical examinations. Additionally, genetic variants determining blood types A, B and AB, which are relevant clinically and in cat breeding, were genotyped. Appearance-associated genetic variation in all cats is also discussed. Lastly, genome-wide SNP heterozygosity levels were calculated to obtain a comparable measure of the genetic diversity in different cat breeds. This study represents the first comprehensive exploration of informative Mendelian variants in felines by screening over 10,000 pedigreed cats. The results qualitatively contribute to the understanding of feline variant heritage and genetic diversity and demonstrate the clinical utility and importance of such information in supporting breeding programs and the research community. The work also highlights the crucial commitment of pedigreed cat breeders and registries in supporting the establishment of large genomic databases, that when combined with phenotype information can advance scientific understanding and provide insights that can be applied to improve the health and welfare of cats.
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Variação Genética , Genoma , Animais , Gatos/genética , Frequência do Gene , Genoma/genética , Epidemiologia Molecular , FenótipoRESUMO
The coat color phenotype 'sable' occurs in the English Cocker Spaniel dog breed. It closely resembles other canine color patterns known as domino/grizzle/pied (eA allele) and grizzle/domino (eG allele) determined by variants in the melanocortin 1 receptor gene (MC1R; 'extension' or E locus), a key multi-allele regulator of coat color. We examined genetic variation in MC1R, and found one new non-synonymous variant, c.250G>A (p.(Asp84Asn)), consistently associated with the English Cocker Spaniel 'sable' phenotype. We propose calling this newly identified allele eH and further show that the eA , eH and eG (previously known as EG ) alleles associate with similar phenotypes in dogs impacting genotypes regulated by beta-defensin 103 gene (CBD103; K locus) and agouti signaling protein gene (ASIP; A locus) in the absence of the EM and E alleles. This suggests that all three alleles are putative reduced-function variants of the MC1R gene. We propose the revised and updated E locus dominance hierarchy to be EM > E > eA /eH /eG > e1-3 .
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Cor de Cabelo , Receptor Tipo 1 de Melanocortina , Cães , Animais , Cor de Cabelo/genética , Receptor Tipo 1 de Melanocortina/genética , Genótipo , Fenótipo , AlelosRESUMO
Cats with a distinctive white hair pattern of unknown molecular cause have been discovered in the Finnish domestic cat population. Based on the unique appearance of these cats, we have named this phenotype salmiak ("salty licorice"). The use of a commercially available panel test to genotype four salmiak-colored cats revealed the absence of all known variants associated with white-haired phenotypic loci: full White (W), Spotting (Ws) and the Birman white Gloves associated (wg) allele of the KIT proto-oncogene (KIT) gene. Whole-genome sequencing on two salmiak-colored cats was conducted to search for candidate causal variants in the KIT gene. Despite a lack of coding variants, visual inspection of the short read alignments revealed a large ~95 kb deletion located ~65 kb downstream of the KIT gene in the salmiak cats. Additional PCR genotyping of 180 domestic cats and three salmiak-colored cats confirmed the homozygous derived variant genotype fully concordant with the salmiak phenotype. We suggest the newly identified variant be designated as wsal for "w salmiak".
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Cor de Cabelo , Proteínas Proto-Oncogênicas c-kit , Animais , Gatos/genética , Cor de Cabelo/genética , Proteínas Proto-Oncogênicas c-kit/genética , Fenótipo , Deleção de Sequência , Finlândia , Genótipo , Sequenciamento Completo do Genoma/veterináriaRESUMO
INTRODUCTION: Implementing a health system-based hypertension programme may lower blood pressure (BP). METHODS: We performed a randomized, controlled pilot study to assess feasibility, acceptability, and safety of a home-based virtual hypertension programme integrating evidence-based strategies to overcome current barriers to BP control. Trained clinical pharmacists staffed the virtual collaborative care clinic (vCCC) to remotely manage hypertension using a BP dashboard and phone "visits" to monitor BP, adherence, side effects of medications, and prescribe anti-hypertensives. Patients with uncontrolled hypertension were identified via electronic health records. Enrolled patients were randomized to either vCCC or usual care for 3 months. We assessed patients' home BP monitoring behaviour, and patients', physicians', and pharmacists' perspectives on feasibility and acceptability of individual programme components. RESULTS: Thirty-one patients (vCCC = 17, usual care = 14) from six physician clinics completed the pilot study. After 3 months, average BP decreased in the vCCC arm (P = 0.01), but not in the control arm (P = 0.45). The vCCC participants measured BP more (9.9 vs. 1.2 per week, P < 0.001). There were no intervention-related adverse events. Participating physicians (n = 6), pharmacists (n = 5), and patients (n = 31) rated all programme components with average scores of >4.0, a pre-specified benchmark. Nine adaptations in vCCC design and delivery were made based on potential barriers to implementing the programme and suggestions. CONCLUSION: A home-based virtual hypertension programme using team-based care, technology, and a logical integration of evidence-based strategies is safe, acceptable, and feasible to intended users. These pilot data support studies to assess the effectiveness of this programme at a larger scale.
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Hipertensão , Humanos , Projetos Piloto , Estudos de Viabilidade , Hipertensão/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Pressão SanguíneaRESUMO
Understanding how ecological communities are organized and how they change through time is critical to predicting the effects of climate change. Recent work documenting the co-occurrence structure of modern communities found that most significant species pairs co-occur less frequently than would be expected by chance. However, little is known about how co-occurrence structure changes through time. Here we evaluate changes in plant and animal community organization over geological time by quantifying the co-occurrence structure of 359,896 unique taxon pairs in 80 assemblages spanning the past 300 million years. Co-occurrences of most taxon pairs were statistically random, but a significant fraction were spatially aggregated or segregated. Aggregated pairs dominated from the Carboniferous period (307 million years ago) to the early Holocene epoch (11,700 years before present), when there was a pronounced shift to more segregated pairs, a trend that continues in modern assemblages. The shift began during the Holocene and coincided with increasing human population size and the spread of agriculture in North America. Before the shift, an average of 64% of significant pairs were aggregated; after the shift, the average dropped to 37%. The organization of modern and late Holocene plant and animal assemblages differs fundamentally from that of assemblages over the past 300 million years that predate the large-scale impacts of humans. Our results suggest that the rules governing the assembly of communities have recently been changed by human activity.
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Agricultura/história , Ecossistema , Atividades Humanas/história , Fenômenos Fisiológicos Vegetais , Animais , História Antiga , Humanos , América do Norte , Dinâmica Populacional , Fatores de TempoRESUMO
[This corrects the article DOI: 10.1371/journal.pgen.1007361.].
RESUMO
Knowledge on the genetic epidemiology of disorders in the dog population has implications for both veterinary medicine and sustainable breeding. Limited data on frequencies of genetic disease variants across breeds exists, and the disease heritage of mixed breed dogs remains poorly explored to date. Advances in genetic screening technologies now enable comprehensive investigations of the canine disease heritage, and generate health-related big data that can be turned into action. We pursued population screening of genetic variants implicated in Mendelian disorders in the largest canine study sample examined to date by examining over 83,000 mixed breed and 18,000 purebred dogs representing 330 breeds for 152 known variants using a custom-designed beadchip microarray. We further announce the creation of MyBreedData (www.mybreeddata.com), an online updated inherited disorder prevalence resource with its foundation in the generated data. We identified the most prevalent, and rare, disease susceptibility variants across the general dog population while providing the first extensive snapshot of the mixed breed disease heritage. Approximately two in five dogs carried at least one copy of a tested disease variant. Most disease variants are shared by both mixed breeds and purebreds, while breed- or line-specificity of others is strongly suggested. Mixed breed dogs were more likely to carry a common recessive disease, whereas purebreds were more likely to be genetically affected with one, providing DNA-based evidence for hybrid vigor. We discovered genetic presence of 22 disease variants in at least one additional breed in which they were previously undescribed. Some mutations likely manifest similarly independently of breed background; however, we emphasize the need for follow up investigations in each case and provide a suggested validation protocol for broader consideration. In conclusion, our study provides unique insight into genetic epidemiology of canine disease risk variants, and their relevance for veterinary medicine, breeding programs and animal welfare.
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Doenças do Cão/genética , Cães/genética , Animais , Cruzamento , Bases de Dados Genéticas , Doenças do Cão/epidemiologia , Feminino , Frequência do Gene , Genes Recessivos , Predisposição Genética para Doença , Testes Genéticos/veterinária , Variação Genética , Vigor Híbrido , Masculino , Epidemiologia Molecular , Análise de Sequência com Séries de Oligonucleotídeos/veterinária , Prevalência , Especificidade da EspécieRESUMO
Leishmaniasis is a vector-borne parasitic disease caused by protozoa of the genus Leishmania. Twenty different species are known to cause disease in humans with varying degrees of pathology. These diseases are transmitted throughout the geographic range of phlebotomine sandflies, found between the latitudes 50°N and 40°S. This study explores antibody dependent enhancement (ADE) as the cause of disease exacerbation in heterologous exposure of L. major primed mice to L. infantum challenge. BALB/c mice received serum from L. major infected or naive mice. All mice were challenged with L. infantum and tissue parasite burdens were recorded. Animals that received anti-L. major serum exhibited significantly higher parasite burdens. Surprisingly, these parasite burdens were higher than those of mice infected with L. major and challenged with L. infantum. In vitro phagocytosis assays were carried out to measure parasite uptake in the presence of naive vs. anti-L. major serum. J774A.1 murine monocytes were cultured with either L. major or L. infantum in the presence of anti-L. major serum, naive serum, or no serum. Significantly higher rates of L. major uptake by J774A.1 cells occurred in the presence of anti-L. major serum, but no measurable increase of L. infantum phagocytosis was seen. Our results suggest that increased disease severity observed in vivo in mice previously exposed to L. major and challenged with L infantum is not a result of extrinsic ADE. We speculate that intrinsic ADE, due to biased memory T cell responses caused by Fcγ signaling, could account for disease exacerbation seen in the animal model.
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Leishmania infantum/imunologia , Leishmania major/imunologia , Leishmaniose/parasitologia , Animais , Anticorpos Antiprotozoários/sangue , Anticorpos Antiprotozoários/imunologia , Linhagem Celular , Modelos Animais de Doenças , Imunização Passiva , Memória Imunológica , Leishmaniose/imunologia , Leishmaniose Cutânea/complicações , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/parasitologia , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Psychodidae , Linfócitos T/imunologiaRESUMO
INTRODUCTION: Brain bioenergetics are defective in Alzheimer's disease (AD). Preclinical studies find oxaloacetate (OAA) enhances bioenergetics, but human safety and target engagement data are lacking. METHODS: We orally administered 500 or 1000 mg OAA, twice daily for 1 month, to AD participants (n = 15 each group) and monitored safety and tolerability. To assess brain metabolism engagement, we performed fluorodeoxyglucose positron emission tomography (FDG PET) and magnetic resonance spectroscopy before and after the intervention. We also assessed pharmacokinetics and cognitive performance. RESULTS: Both doses were safe and tolerated. Compared to the lower dose, the higher dose benefited FDG PET glucose uptake across multiple brain regions (P < .05), and the higher dose increased parietal and frontoparietal glutathione (P < .05). We did not demonstrate consistent blood level changes and cognitive scores did not improve. CONCLUSIONS: 1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.
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Doença de Alzheimer/tratamento farmacológico , Ácido Oxaloacético/administração & dosagem , Ácido Oxaloacético/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Metabolismo Energético/efeitos dos fármacos , Feminino , Fluordesoxiglucose F18 , Glucose/metabolismo , Glutationa/metabolismo , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Ácido Oxaloacético/efeitos adversos , Tomografia por Emissão de Pósitrons , Compostos RadiofarmacêuticosRESUMO
Rare endothelial cells in the aorta-gonad-mesonephros (AGM) transition into hematopoietic stem cells (HSCs) during embryonic development. Lineage tracing experiments indicate that HSCs emerge from cadherin 5 (Cdh5; vascular endothelial-cadherin)(+) endothelial precursors, and isolated populations of Cdh5(+) cells from mouse embryos and embryonic stem cells can be differentiated into hematopoietic cells. Cdh5 has also been widely implicated as a marker of AGM-derived hemogenic endothelial cells. Because Cdh5(-/-) mice embryos die before the first HSCs emerge, it is unknown whether Cdh5 has a direct role in HSC emergence. Our previous genetic screen yielded malbec (mlb(bw306)), a zebrafish mutant for cdh5, with normal embryonic and definitive blood. Using time-lapse confocal imaging, parabiotic surgical pairing of zebrafish embryos, and blastula transplantation assays, we show that HSCs emerge, migrate, engraft, and differentiate in the absence of cdh5 expression. By tracing Cdh5(-/-)green fluorescent protein (GFP)(+/+) cells in chimeric mice, we demonstrated that Cdh5(-/-)GFP(+/+) HSCs emerging from embryonic day 10.5 and 11.5 (E10.5 and E11.5) AGM or derived from E13.5 fetal liver not only differentiate into hematopoietic colonies but also engraft and reconstitute multilineage adult blood. We also developed a conditional mouse Cdh5 knockout (Cdh5(flox/flox):Scl-Cre-ER(T)) and demonstrated that multipotent hematopoietic colonies form despite the absence of Cdh5. These data establish that Cdh5, a marker of hemogenic endothelium in the AGM, is dispensable for the transition of hemogenic endothelium to HSCs.
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Antígenos CD/metabolismo , Caderinas/metabolismo , Diferenciação Celular/fisiologia , Hemangioblastos/citologia , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/citologia , Animais , Linhagem da Célula/fisiologia , Eletroporação , Embrião de Mamíferos , Embrião não Mamífero , Citometria de Fluxo , Imuno-Histoquímica , Mesonefro/embriologia , Camundongos , Camundongos Knockout , Microscopia Confocal , Peixe-ZebraRESUMO
Genetic mapping of mutations in model systems has facilitated the identification of genes contributing to fundamental biological processes including human diseases. However, this approach has historically required the prior characterization of informative markers. Here we report a fast and cost-effective method for genetic mapping using next-generation sequencing that combines single nucleotide polymorphism discovery, mutation localization, and potential identification of causal sequence variants. In contrast to prior approaches, we have developed a hidden Markov model to narrowly define the mutation area by inferring recombination breakpoints of chromosomes in the mutant pool. In addition, we created an interactive online software resource to facilitate automated analysis of sequencing data and demonstrate its utility in the zebrafish and mouse models. Our novel methodology and online tools will make next-generation sequencing an easily applicable resource for mutation mapping in all model systems.
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Análise Mutacional de DNA/métodos , Software , Peixe-Zebra/genética , Alelos , Animais , Mapeamento Cromossômico/métodos , Cromossomos/genética , Cruzamentos Genéticos , Feminino , Frequência do Gene , Genômica/métodos , Homozigoto , Masculino , Cadeias de Markov , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Polimorfismo de Nucleotídeo Único , Recombinação Genética , Fatores de TempoRESUMO
Growth Factor Independence (Gfi) transcription factors play essential roles in hematopoiesis, differentially activating and repressing transcriptional programs required for hematopoietic stem/progenitor cell (HSPC) development and lineage specification. In mammals, Gfi1a regulates hematopoietic stem cells (HSC), myeloid and lymphoid populations, while its paralog, Gfi1b, regulates HSC, megakaryocyte and erythroid development. In zebrafish, gfi1aa is essential for primitive hematopoiesis; however, little is known about the role of gfi1aa in definitive hematopoiesis or about additional gfi factors in zebrafish. Here, we report the isolation and characterization of an additional hematopoietic gfi factor, gfi1b. We show that gfi1aa and gfi1b are expressed in the primitive and definitive sites of hematopoiesis in zebrafish. Our functional analyses demonstrate that gfi1aa and gfi1b have distinct roles in regulating primitive and definitive hematopoietic progenitors, respectively. Loss of gfi1aa silences markers of early primitive progenitors, scl and gata1. Conversely, loss of gfi1b silences runx-1, c-myb, ikaros and cd41, indicating that gfi1b is required for definitive hematopoiesis. We determine the epistatic relationships between the gfi factors and key hematopoietic transcription factors, demonstrating that gfi1aa and gfi1b join lmo2, scl, runx-1 and c-myb as critical regulators of teleost HSPC. Our studies establish a comparative paradigm for the regulation of hematopoietic lineages by gfi transcription factors.
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Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Hematopoese/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Sequência de Aminoácidos , Animais , Clonagem Molecular , Sequência Conservada/genética , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Embrião não Mamífero/metabolismo , Epistasia Genética , Eritropoese/genética , Evolução Molecular , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Sistema Hematopoético/embriologia , Sistema Hematopoético/metabolismo , Modelos Biológicos , Dados de Sequência Molecular , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/metabolismoRESUMO
The promising clinical effects of mesenchymal stromal/stem cells (MSCs) rely especially on paracrine and nonimmunogenic mechanisms. Delivery routes are essential for the efficacy of cell therapy and systemic delivery by infusion is the obvious goal for many forms of MSC therapy. Lung adhesion of MSCs might, however, be a major obstacle yet to overcome. Current knowledge does not allow us to make sound conclusions whether MSC lung entrapment is harmful or beneficial, and thus we wanted to explore MSC lung adhesion in greater detail. We found a striking difference in the lung clearance rate of systemically infused MSCs derived from two different clinical sources, namely bone marrow (BM-MSCs) and umbilical cord blood (UCB-MSCs). The BM-MSCs and UCB-MSCs used in this study differed in cell size, but our results also indicated other mechanisms behind the lung adherence. A detailed analysis of the cell surface profiles revealed differences in the expression of relevant adhesion molecules. The UCB-MSCs had higher expression levels of α4 integrin (CD49d, VLA-4), α6 integrin (CD49f, VLA-6), and the hepatocyte growth factor receptor (c-Met) and a higher general fucosylation level. Strikingly, the level of CD49d and CD49f expression could be functionally linked with the lung clearance rate. Additionally, we saw a possible link between MSC lung adherence and higher fibronectin expression and we show that the expression of fibronectin increases with MSC culture confluence. Future studies should aim at developing methods of transiently modifying the cell surface structures in order to improve the delivery of therapeutic cells.
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Células da Medula Óssea/citologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Sangue Fetal/citologia , Pulmão/citologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Animais , Biomarcadores/metabolismo , Células da Medula Óssea/metabolismo , Adesão Celular , Diferenciação Celular , Feminino , Sangue Fetal/metabolismo , Expressão Gênica , Meia-Vida , Humanos , Infusões Intravenosas , Integrina alfa4/genética , Integrina alfa4/metabolismo , Integrina alfa4beta1/genética , Integrina alfa4beta1/metabolismo , Integrina alfa6/genética , Integrina alfa6/metabolismo , Integrina alfa6beta1/genética , Integrina alfa6beta1/metabolismo , Marcação por Isótopo , Pulmão/imunologia , Pulmão/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Compostos de Tecnécio , Transplante HeterólogoRESUMO
The mitochondria-ER-cortex anchor (MECA) forms a tripartite membrane contact site between mitochondria, the endoplasmic reticulum (ER), and the plasma membrane (PM). The core component of MECA, Num1, interacts with the PM and mitochondria via two distinct lipid-binding domains; however, the molecular mechanism by which Num1 interacts with the ER is unclear. Here, we demonstrate that Num1 contains a FFAT motif in its C-terminus that interacts with the integral ER membrane protein Scs2. While dispensable for Num1's functions in mitochondrial tethering and dynein anchoring, the FFAT motif is required for Num1's role in promoting mitochondrial division. Unexpectedly, we also reveal a novel function of MECA in regulating the distribution of phosphatidylinositol-4-phosphate (PI(4)P). Breaking Num1 association with any of the three membranes it tethers results in an accumulation of PI(4)P on the PM, likely via disrupting Sac1-mediated PI(4)P turnover. This work establishes MECA as an important regulatory hub that spatially organizes mitochondria, ER, and PM to coordinate crucial cellular functions.
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Retículo Endoplasmático , Mitocôndrias , Fosfatos de Fosfatidilinositol , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Membrana Celular/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Mitocôndrias/metabolismo , Mitocôndrias/genética , Dinâmica Mitocondrial , Fosfatos de Fosfatidilinositol/metabolismo , Ligação Proteica , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genéticaRESUMO
[This corrects the article DOI: 10.3389/fvets.2024.1327081.].
RESUMO
Introduction: The correct labeling of a genetic variant as pathogenic is important as breeding decisions based on incorrect DNA tests can lead to the unwarranted exclusion of animals, potentially compromising the long-term health of a population. In human medicine, the American college of Medical Genetics (ACMG) guidelines provide a framework for variant classification. This study aims to apply these guidelines to six genetic variants associated with hypertrophic cardiomyopathy (HCM) in certain cat breeds and to propose a modified criterion for variant classification. Methods: Genetic samples were sourced from five cat breeds: Maine Coon, Sphynx, Ragdoll, Devon Rex, and British Short- and Longhair. Allele frequencies were determined, and in the subset with phenotypes available, odds ratios to determine the association with HCM were calculated. In silico evaluation followed with joint evidence and data from other publications assisting in the classification of each variant. Results: Two variants, MYBPC3:c.91G > C [A31P] and MYBPC3:c.2453C > T [R818W], were designated as pathogenic. One variant, MYH7:c.5647G > A [E1883K], was found likely pathogenic, while the remaining three were labeled as variants of unknown significance. Discussion: Routine genetic testing is advised solely for the MYBPC3:c.91G > C [A31P] in the Maine Coon and MYBPC3:c.2453C > T [R818W] in the Ragdoll breed. The human ACMG guidelines serve as a suitable foundational tool to ascertain which variants to include; however, refining them for application in veterinary medicine might be beneficial.