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Toxoplasmosis, caused by the protozoan parasite Toxoplasma gondii, is a globally distributed zoonotic infection with significant implications for human and animal health. This study investigated the prevalence of T. gondii infection in a population of beef cattle at three different stages of their productive lifespan and examined the impact of T. gondii serological status on blood parameters. A commercial beef fattening unit in Italy was the setting for this research, which involved a biosecurity assessment upon cattle arrival, blood sampling at three time points and Toxoplasma-specific serological testing using indirect fluorescent antibody tests (IFAT). Results revealed a dynamic pattern of T. gondii seropositivity in cattle, with an initial prevalence of 30.6% at arrival (T0) that increased to 44.6% at 14 days (T1) and then decreased slightly to 39.3% at slaughter after 5 months (T2). Interestingly, seroconversion was observed during the study, indicating ongoing infections, and antibody waning occurred in some animals. In terms of blood parameters, seropositive cattle exhibited significantly lower mean corpuscular volume (MCV) and a higher neutrophil–lymphocyte (N/L) ratio, suggesting an activation of the innate immune response. Furthermore, cattle with higher antibody titres displayed higher neutrophil counts. However, all blood parameters with a statistical significance were within the reference range. This study provides for the first time a longitudinal investigation on the serological status for T. gondii in naturally exposed beef cattle. These findings provide valuable insights into the clinico-pathological aspects of natural T. gondii exposure in cattle and underscore the importance of monitoring and managing T. gondii infection in livestock production systems. [ABSTRACT FROM AUTHOR]

Hepatic fibrinogen storage disease (HFSD) was diagnosed in a 5‐month‐old Wagyu calf with a history of recurrent respiratory disease. It was characterized by lethargy, dehydration, acidemia, and increased liver enzyme activities. Histologically, disseminated hepatocytes were swollen and showed a single, sharply demarcated, faintly eosinophilic cytoplasmic inclusion with a ground‐glass appearance, with the nucleus in an eccentric position. Cytoplasmic inclusions did not stain with the periodic acid‐Schiff (PAS) reaction. Using a rabbit polyclonal antibody against fibrinogen, the cytoplasmic vacuoles in the hepatocytes stained intensely. Electron microscopy disclosed hepatocytes with membrane‐bound cytoplasmic inclusions filled with fine granular material interspersed with a few coarse‐grained electron‐dense granules. A trio whole‐genome sequencing approach identified a deleterious homozygous missense variant in DGKG (p.Thr721Ile). The allele frequency in 209 genotyped Wagyu was 7.2%. This is a report of a DGKG‐related recessive inherited disorder in cattle and adds DGKG to the list of candidate genes for HFSD in other species. [ABSTRACT FROM AUTHOR]

Background: A recessive form of MOCOS‐associated xanthinuria type II is described in Tyrolean grey cattle. A similar case was identified in a 5‐month‐old Brown Swiss calf with hoof overgrowth, rough coat, urine sediment, and pneumonia. Hypothesis/Objectives: To characterize the disease phenotype, to evaluate its genetic etiology, and to determine the prevalence of the deleterious allele in the Brown Swiss population. Animals: An affected calf, its parents, and 65 441 Swiss dairy cattle. Methods: The affected animal was clinically examined and necropsied. Microarray genotyping was used to determine the genotypes and to assess the frequency of the MOCOS allele in a Brown Swiss control cohort. Results: Ultrasonography revealed hyperechoic renal pyramids with multifocal distal shadowing and echogenic sediment in the urinary bladder. Necropsy revealed suppurative bronchopneumonia and urolithiasis. Histology revealed numerous nephroliths with multifocal chronic lymphohistiocytic interstitial infiltrates, fibrosis, tubular degeneration, chronic multifocal glomerulonephritis with sclerosis, and bilateral hydronephrosis. Dysplastic changes were observed in the corium of the claw and the cornea. Genetic testing identified the homozygous presence of a known MOCOS frameshift variant in the case. Both parents were heterozygous and the prevalence of carriers in genotyped Brown Swiss cattle was 1.4% (342/24337). Conclusions and Clinical Importance: The findings were consistent with the diagnosis of a recessive renal syndrome similar to xanthinuria type II described in Tyrolean grey cattle. The prevalence of the deleterious MOCOS allele is low in the Brown Swiss breed. However, mating of carriers should be avoided to prevent further losses. [ABSTRACT FROM AUTHOR]

In this study, epilepsy with focal seizures progressing to generalized seizures was diagnosed in a 6‐month‐old Holstein heifer. The seizures were characterized by a brief pre‐ictal phase with depression and vocalization. During the ictal phase eyelid spasms, tongue contractions, nodding and abundant salivation were observed, rapidly followed by a convulsive phase with bilateral tonic, clonic or tonic–clonic activity and loss of consciousness. Finally, during the postictal phase the heifer was obtunded and disorientated, unable to perceive obstacles and hypermetric, and pressed its head against objects. In the inter‐seizure phase, the heifer was clinically normal. Neuropathology revealed axonal degeneration in the brainstem and diffuse astrocytic hypertrophic gliosis. Whole genome sequencing of the affected heifer identified a private heterozygous splice‐site variant in DYRK1B (NM_001081515.1: c.‐101‐1G>A), most likely resulting in haploinsufficiency owing to loss‐of‐function. This represents a report of a DYRK1B‐associated disease in cattle and adds DYRK1B to the candidate genes for epilepsy. [ABSTRACT FROM AUTHOR]

Simple Summary: Congenital mast cell tumor is an uncommon disease in both human and veterinary medicine. In cattle, usually, such anomalies are not further investigated at the molecular genetic level, mainly because of a lack of resources and diagnostic tools and the low value and short life expectancy of the affected animals. Here we reported the clinical, pathological and genetic findings of a Holstein calf that had multiple cutaneous and visceral poorly differentiated embryonal mast cell tumors consistent with a form of congenital mast cell tumor. Whole-genome sequencing identified a single X-linked recessive protein-changing variant in the PLP2 gene that was unique to the affected male calf and its dam and absent in a representative control cohort. Given the rarity of the identified variant, its predicted deleterious effect and the known function of proteolipid protein 2, a small transmembrane lipoprotein associated with skin cancer, we proposed a novel candidate gene associated with mast cell tumors. Congenital tumors occur infrequently in cattle. The aim of this study was to detail the clinicopathological phenotype of a Holstein calf with a congenital mast cell tumor and to identify the genetic cause by a whole-genome sequencing (WGS) trio-approach. An 18-day-old male Holstein calf was clinically examed and revealed multifocal, alopecic, thick and wrinkled skin lesions over the entire body. At 6 months of age, the general condition of the calf was characterized by retarded growth, poor nutritional status, and ulceration of the skin lesions. Histopathological examination revealed a primary cutaneous, poorly differentiated embryonal mast cell tumor with metastases in the lymph nodes and liver. Genetic analysis revealed a private X-linked variant in the PLP2 gene (chrX:87216480C > T; c.50C > T), which was present only in the genomes of the case (hemizygous) and his mother (heterozygous). It was absent in the sire as well as in 5365 control genomes. The identified missense variant exchanges the encoded amino acid of PLP2 at position 17 (p.Thr17Ile), which is classified as deleterious and affects a protein that plays a role in tumor growth and metastasis. Therefore, we suggested that the detected PLPL2 variant could be a plausible cause for this congenital condition in the affected calf. [ABSTRACT FROM AUTHOR]

Hemifacial microsomia (HFM) was diagnosed in a 9‐day‐old Romagnola calf. The condition was characterized by microtia of the left ear, anotia of the right ear, asymmetry of the face, and deafness. Magnetic resonance imaging revealed agenesis of the right pinna and both tympanic bullae, asymmetry of the temporal bones and temporomandibular joints, and right pontine meningocele. Brainstem auditory evoked responses confirmed the impaired auditory capacity. At gross post mortem examination, there was agenesis and hypoplasia of the right and the left external ear, respectively. No histological abnormalities were detected in the inner ears. A trio whole‐genome sequencing approach was carried out and identified a private homozygous missense variant in LAMB1 affecting a conserved residue (p.Arg668Cys). Genotyping of 221 Romagnola bulls revealed a carrier prevalence <2%. This represents a report of a LAMB1‐related autosomal recessive inherited disorder in domestic animals and adds LAMB1 to the candidate genes for HFM. [ABSTRACT FROM AUTHOR]

The aim of this study was to characterize the phenotype and to identify the genetic etiology of a syndromic form of ichthyosis congenita (IC) observed in Italian Chianina cattle and to estimate the prevalence of the deleterious allele in the population. Sporadic occurrence of different forms of ichthyosis including IC have been previously reported in cattle. However, so far, no causative genetic variant has been found for bovine IC. Nine affected cattle presenting congenital xerosis, hyperkeratosis and scaling of the skin as well as urolithiasis and cystitis associated with retarded growth were examined. Skin histopathology revealed a severe, diffuse orthokeratotic hyperkeratosis with mild to moderate epidermal hyperplasia. The pedigree records indicated a monogenic recessive trait. Homozygosity mapping and whole-genome sequencing allowed the identification of a homozygous frameshift 1 bp insertion in the FA2H gene (c.9dupC; p.Ala4ArgfsTer142) located in a 1.92 Mb shared identical-by-descent region on chromosome 18 present in all cases, while the parents were heterozygous as expected for obligate carriers. These findings enable the selection against this sub-lethal allele showing an estimated frequency of ~ 7.5% in Chianina top sires. A sporadic incidence of mild clinical signs in the skin of heterozygous carriers was observed. So far, pathogenic variants affecting the encoded fatty acid 2-hydroxylase catalyzing the synthesis of 2-hydroxysphingolipids have been associated with myelin disorders. In conclusion, this study represents the first report of an FA2H-related autosomal recessive inherited skin disorder in a mammalian species and adds FA2H to the list of candidate genes for ichthyosis in humans and animals. Furthermore, this study provides a DNA-based diagnostic test that enables selection against the identified pathogenic variant in the Chianina cattle population. However, functional studies are needed to better understand the expression of FA2H in IC-affected Chianina cattle. [ABSTRACT FROM AUTHOR]

Palatoschisis (also called cleft palate, CP) is an opening or cleft in the upper lip, the roof of the palate, or both, and is a common defect in both humans and domestic animals (Mossey & Modell, [4]; Mulvihill et al., [5]). Inherited forms of I MYH3 i -related human syndromes, including cleft palate, are known (OMIM 160720). The affected gene, I MYH3 i , encodes the myosin heavy chain 3 protein, which is known to be responsible for muscle contraction. [Extracted from the article]

A 6‐day‐old Belgian Blue‐Holstein calf was referred because of a syndrome resembling epidermolysis bullosa simplex (EBS). The clinical phenotype included irregular and differently sized erosions and ulcerations spread over the body, in particular on the limbs and over bone prominences, as well as in the nasal planum and oral mucosa. Blisters were easily induced by rubbing the skin. The skin lesions displayed a clear dermal‐epidermal separation at the level of the basal cell layer. Post mortem examination revealed erosions in the pharynx, proximal esophagus, and rumen. Whole‐genome sequencing revealed a heterozygous disruptive in‐frame deletion variant in KRT5 (c.534_536delCAA). Genotyping of both parents confirmed the variant as de novo mutation. Clinicopathological and genetic findings were consistent with the diagnosis of KRT5‐related EBS providing the second example of a spontaneous mutation causing epidermolysis bullosa in cattle. [ABSTRACT FROM AUTHOR]

This identified two heterozygous private protein-changing variants present exclusively in the genome of the affected calf and absent in both parental genomes as well as in 5365 controls (Table S1). Sanger sequencing confirmed the presence of the heterozygous I NUMB i variant in the affected calf and its sire, which clearly carried the mutant allele at a low level in comparison with the wild type allele, representing a germinal mosaic (Figure S1). A germline de novo variant in NUMB associated with a double-outlet right ventricle in Chianina cattle. [Extracted from the article]

These variants were absent from a total of 5365 controls and a single variant affects I SGSH i , a putative candidate gene for the observed congenital anomaly. Congenital amastia is a rare developmental disorder characterised by the complete absence of the mammary gland and teats (Huppert & Zidenberg, 2008). [Extracted from the article]

Osteochondrodysplasias comprise a broad spectrum of hereditary developmental disorders of bone and cartilage, but can also have significant effects on tendons, ligaments, and muscles (Warman et al., 2011). This heterozygous variant at chr1:152807533C>CA represents a 1-bp insertion in exon 2 of the I ANKRD28 i gene that directly affect the translation initiation (start) codon (XM 024989836.1: c.2dupT; Figure S1). COMMENTS We propose the heterozygous c.2dupT variant as a candidate causative variant for the observed congenital disorder and I ANKRD28 i as a novel candidate gene for dwarfism phenotypes. [Extracted from the article]

The deletion spanning 19 coding exons of the I COL2A1 i gene was subsequently evaluated by performing a multiplex PCR across both breakpoints, revealing an additional PCR product only in the affected calf (Fig. The I COL2A1 i gene has a probability of loss-of-function intolerance score of 1, meaning that it clearly falls into the class of loss-of-function haploinsufficient genes.11 Consequently, the observed phenotype could be explained by the non-expression of the mutant allele. This report presents another large structural variant affecting the I COL2A1 i gene causing a novel form of bovine achondrogenesis type II that occurred in combination with the perosomus elumbis (PE) phenotype (OMIA 000789-9913). [Extracted from the article]

Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to characterize the clinicopathologic features of a Belgian Blue x Holstein crossbred calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, and to identify the most likely genetic etiology. The calf displayed episodes of exercise-induced generalized myotonic muscle stiffness accompanied by increase in serum potassium. It also showed slight flattening of the splanchnocranium with deviation to the right side. On gross pathology, myelodysplasia (hydrosyringomielia and segmental hypoplasia) in the lumbosacral intumescence region was noticed. Histopathology of the muscle profile revealed loss of the main shape in 5.3% of muscle fibers. Whole-genome sequencing revealed a heterozygous missense variant in KCNG1 affecting an evolutionary conserved residue (p.Trp416Cys). The mutation was predicted to be deleterious and to alter the pore helix of the ion transport domain of the transmembrane protein. The identified variant was present only in the affected calf and not seen in more than 5200 other sequenced bovine genomes. We speculate that the mutation occurred either as a parental germline mutation or post-zygotically in the developing embryo. This study implicates an important role for KCNG1 as a member of the potassium voltage-gated channel group in neurodegeneration. Providing the first possible KCNG1-related disease model, we have, therefore, identified a new potential candidate for related conditions both in animals and in humans. This study illustrates the enormous potential of phenotypically well-studied spontaneous mutants in domestic animals to provide new insights into the function of individual genes. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, a peculiar case of bovine eosinophilic myositis (BEM) observed in a beef cattle is described. BEM is a specific inflammatory myopathy, often associated with Sarcocystis spp., with multifocal gray-green lesions that can lead to considerable economic losses and public health issues. Through histological, molecular, and serological analyses, we confirmed the first detection of T. gondii DNA in a case of BEM, associated with the coinfection by S. hominis. Molecular results highlighted DNA of both pathogens within the lesion, in healthy muscle and or in the meat juice pellets, drawing attention to the possible role that a co-infection of T. gondii with Sarcocystis sp. may play in evoking BEM lesions. Bovine eosinophilic myositis (BEM) is a specific inflammatory myopathy, often associated with Sarcocystis spp., with multifocal gray-green lesions leading to carcass condemnation with considerable economic losses. Here is described a peculiar case of BEM that occurred in an adult (16 month) cattle, born in France, bred, and slaughtered in Italy at the end of 2021. On inspection, muscles showed the typical multifocal gray-green lesions that were sampled for, cytological, histological, and molecular investigations, while meat juice was subjected to IFAT for Toxoplasma IgG. Genomic DNA was extracted from lesions, portions of healthy muscle and from meat juice pellet and analyzed by PCR targeting 18S rDNA, COI mtDNA and B1 genes, and sequenced. The cytology showed inflammatory cells mostly referable to eosinophils; at histology, protozoan cysts and severe granulomatous myositis were observed. A BEM lesion and meat juice pellet subjected to PCR showed, concurrently, sequences referable both to S. hominis and T. gondii. Meat juice IFAT resulted negative for T. gondii IgG. Our findings highlight the first detection of T. gondii DNA in association with S. hominis in a BEM case, suggesting a multiple parasite infection associated with this pathology, although the actual role of T. gondii infection in the pathophysiology of the diseases should be clarified. [ABSTRACT FROM AUTHOR]

Simple Summary: Skeletal dysplasias encompass a clinical-, pathological- and genetically heterogeneous group of disorders characterized by abnormal cartilage and/or bone formation, growth, and remodeling. They may belong to the so-called RASopathies, congenital conditions caused by heterozygous variants in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) cell signaling pathway. Herein, an affected calf of the Italian Romagnola breed was reported showing a skeletal-cardio-enteric dysplasia. We identified a most likely disease-causing mutation in the MAP2K2 gene by whole-genome sequencing (WGS). The MAP2K2 gene is known to be related with dominant inherited cardio-facio-cutaneous syndrome in humans, but it was so far unknown to cause a similar disease in domestic animals. We assume that the identified missense variant that was predicted to impair the function of the protein, occurred either within the germline of the dam or post-zygotically in the embryo. Rare lethal diseases such as the skeletal-cardio-enteric dysplasia in livestock are usually not characterized to the molecular level, mainly because of the lack of funds and diagnostic opportunities. Precise WGS-based diagnostics enables the understanding of rare diseases and supports the value of monitoring cattle breeding populations for fatal genetic defects. RASopathies are a group of developmental disorders caused by dominant mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) cell signaling pathway. The goal of this study was to characterize the pathological phenotype of a Romagnola stillborn calf with skeletal-cardio-enteric dysplasia and to identify a genetic cause by whole-genome sequencing (WGS). The calf showed reduced fetal growth, a short-spine, a long and narrow face, cardiac defects and heterotopy of the spiral colon. Genetic analysis revealed a private heterozygous missense variant in MAP2K2:p.Arg179Trp, located in the protein kinase domain in the calf, and not found in more than 4500 control genomes including its sire. The identified variant affecting a conserved residue was predicted to be deleterious and most likely occurred de novo. This represents the first example of a dominant acting, and most likely pathogenic, variant in MAP2K2 in domestic animals, thereby providing the first MAP2K2-related large animal model, especially in respect to the enteric malformation. In addition, this study demonstrates the utility of WGS-based precise diagnostics for understanding sporadic congenital syndromic anomalies in cattle and the general utility of continuous surveillance for rare hereditary defects in cattle. [ABSTRACT FROM AUTHOR]

Genodermatoses, such as heritable skin disorders, mostly represent Mendelian conditions. Congenital hypotrichosis (HY) characterize a condition of being born with less hair than normal. The purpose of this study was to characterize the clinicopathological phenotype of a breed-specific non-syndromic form of HY in Hereford cattle and to identify the causative genetic variant for this recessive disorder. Affected calves showed a very short, fine, wooly, kinky and curly coat over all parts of the body, with a major expression in the ears, the inner part of the limbs, and in the thoracic-abdominal region. Histopathology showed a severely altered morphology of the inner root sheath (IRS) of the hair follicle with abnormal Huxley and Henle's layers and severely dysplastic hair shafts. A genome-wide association study revealed an association signal on chromosome 5. Homozygosity mapping in a subset of cases refined the HY locus to a 690 kb critical interval encompassing a cluster of type II keratin encoding genes. Protein-coding exons of six positional candidate genes with known hair or hair follicle function were re-sequenced. This revealed a protein-changing variant in the KRT71 gene that encodes a type II keratin specifically expressed in the IRS of the hair follicle (c.281delTGTGCCCA; p.Met94AsnfsX14). Besides obvious phenocopies, a perfect concordance between the presence of this most likely pathogenic loss-of-function variant located in the head domain of KRT71 and the HY phenotype was found. This recessive KRT71-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002114-9913). [ABSTRACT FROM AUTHOR]

Simple Summary: Vascular anomalies represent a heterogeneous group of rare disorders encompassing both vascular malformations and tumors, which can be congenital or arise shortly after birth. They often pose a diagnostic challenge in human and veterinary medicine, and the referring nomenclature is equivocal. Bovine juvenile angiomatosis (BJA), a clinical condition belonging to this group of disorders, encompasses vascular malformations and tumors arising in calves. Usually, such vascular anomalies are not further investigated on a molecular genetic level, mainly because of a lack of resources and diagnostic tools, as well as the low value and short lifespan of the affected animals. Here we report the clinical, pathological, immunohistochemical, and genetic features of a Simmental calf that displayed multiple cutaneous, subcutaneous, and visceral vascular hamartomas compatible with a generalized form of BJA. Whole-genome sequencing identified six coding variants, including four heterozygous variants in the PREX1, UBE3B, PCDHGA2, and ZSWIM6 genes, which occurred only in the BJA-affected calf and were absent in the global control cohort of more than 4500 cattle. Assuming a germline mutation as etiology, one of these variants might be responsible for the vascular malformations identified in this calf. Bovine juvenile angiomatosis (BJA) comprises a group of single or multiple proliferative vascular anomalies in the skin and viscera of affected calves. The purpose of this study was to characterize the clinicopathological phenotype of a 1.5-month-old Simmental calf with multiple cutaneous, subcutaneous, and visceral vascular hamartomas, which were compatible with a generalized form of BJA, and to identify genetic cause for this phenotype by whole-genome sequencing (WGS). The calf was referred to the clinics as a result of its failure to thrive and the presence of multiple cutaneous and subcutaneous nodules, some of which bled abundantly following spontaneous rupture. Gross pathology revealed similar lesions at the inner thoracic wall, diaphragm, mediastinum, pericardium, inner abdominal wall, and mesentery. Histologically, variably sized cavities lined by a single layer of plump cells and supported by a loose stroma with occasional acute hemorrhage were observed. Determined by immunochemistry, the plump cells lining the cavities displayed a strong cytoplasmic signal for PECAM-1, von Willebrand factor, and vimentin. WGS revealed six private protein-changing variants affecting different genes present in the calf and absent in more than 4500 control genomes. Assuming a spontaneous de novo mutation event, one of the identified variants found in the PREX1, UBE3B, PCDHGA2, and ZSWIM6 genes may represent a possible candidate pathogenic variant for this rare form of vascular malformation. [ABSTRACT FROM AUTHOR]

Simple Summary: Skeletal connective tissue disorders represent a heterogeneous group of inherited disorders mostly monogenically inherited. Heritable connective tissue disorders such as osteogenesis imperfecta (OI) belong to this group. Herein, an affected calf showing congenital bone lesions such as intrauterine fractures, abnormally shaped long bones and localized arthrogryposis resembling OI type II is reported. Whole-genome sequencing (WGS) identified a most likely disease-causing mutation in the COL1A1 gene. The COL1A1 gene is known to be associated with dominant inherited OI type II forms in humans and sporadically in dogs and cattle, but so far, a variant in the fibrillar collagen NC1 domain has not been shown to cause a similar phenotype in domestic animals. We assume that the herein identified most-likely causative variant occurred either within the parental germlines or post-zygotically in the developing embryo. Rare lethal disorders such as OI in livestock are usually not diagnosed to the molecular level, mainly because of the lack of resources and diagnostic tools. WGS-based precision diagnostics allows understanding rare disorders and supports the value of surveillance of cattle breeding populations for harmful genetic disorders. Osteogenesis imperfecta (OI) type II is a genetic connective tissue disorder characterized by bone fragility, severe skeletal deformities and shortened limbs. OI usually causes perinatal death of affected individuals. OI type II diagnosis in humans is established by the identification of heterozygous mutations in genes coding for collagens. The purpose of this study was to characterize the pathological phenotype of an OI type II-affected neonatal Holstein calf and to identify the causative genetic variant by whole-genome sequencing (WGS). The calf had acute as well as intrauterine fractures, abnormally shaped long bones and localized arthrogryposis. Genetic analysis revealed a private heterozygous missense variant in COL1A1 (c.3917T>A) located in the fibrillar collagen NC1 domain (p.Val1306Glu) that most likely occurred de novo. This confirmed the diagnosis of OI type II and represents the first report of a pathogenic variant in the fibrillar collagen NC domain of COL1A1 associated to OI type II in domestic animals. Furthermore, this study highlights the utility of WGS-based precise diagnostics for understanding congenital disorders in cattle and the need for continued surveillance for rare lethal genetic disorders in cattle. [ABSTRACT FROM AUTHOR]

Simple Summary: Congenital tumours are rare conditions in both veterinary and human medicine. Undifferentiated sarcomas represent a recently introduced section that encompasses unclassified sarcomas that have no distinct histologic, immunohistochemical, or genetic features. The aim of this study is to describe the clinical and pathological phenotype of a 3-day-old male crossbred calf presenting a congenital suborbital mass that infiltrated the underlying muscle and bone, and suggestive of undifferentiated sarcoma. To the best of our knowledge, our report constitutes the first clinical, ultrasonographic, radiographic, endoscopic and pathological study of a congenital undifferentiated sarcoma, a condition that has been rarely reported in the veterinary literature. Undifferentiated sarcomas are rare conditions that represent a group of unclassified sarcomas. The purpose of this study is to describe the clinical and pathological features of a calf showing a congenital infiltrating suborbital mass suggestive of undifferentiated sarcoma. The animal was referred because of respiratory distress and the presence of a right suborbital mass since birth. At ultrasonography, the mass displayed an irregular shape with multiple cavities. Radiographs revealed a diffuse, poorly defined mass with different densities overlying the bony structures of the skull. Endoscopy showed a co-involution of the mass in the right side with extension into the nasopharynx. Post-mortem examination showed a round, poorly demarcated neoplasia infiltrating the nasal turbinate and displacing the nasal septum. Histologically, the subcutis was expanded by lobules and bundles of densely cellular neoplastic spindle cells. The neoplasm infiltrated the underlying muscles, bone and the right retromandibular lymph node. The neoplastic cells had a diffuse intense cytoplasmic immunexpression to vimentin, and were negative to cytokeratin AE1/AE3, desmin, MUM1, IBA1, melan A, chromogranin and synaptophysin. [ABSTRACT FROM AUTHOR]

Simple Summary: Genodermatoses represent inherited disorders of the skin that mostly follow a monogenic mode of inheritance. Heritable connective tissue disorders such as classical Ehlers–Danlos syndrome (cEDS) belong to this group of human rare diseases that sporadically occur in other species. Herein, affected cattle are reported showing skin lesions including cutis laxa clinically and pathologically resembling cEDS in humans. Microscopic findings in the deeper dermis were consistent with collagen dysplasia. Whole-genome sequencing (WGS) identified a most likely disease-causing mutation in the COL5A2 gene. The COL5A2 gene is known to be associated with dominant inherited cEDS forms in mice and humans, but so far, it was not shown to cause a similar phenotype in domestic animals. The disease phenotype examined herein showed co-segregation with the identified missense variant within the maternal line across two generations and is most likely due to a spontaneous mutation event. Rare non-lethal disorders such as cEDS in livestock are mostly not diagnosed, but might affect animal welfare and thus lower the value of affected animals. WGS-based precision diagnostics allows understanding rare disorders and supports the value of surveillance of cattle breeding populations for harmful genetic disorders. Classical Ehlers–Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by variable degrees of skin hyperextensibility and fragility, atrophic scarring, and generalized joint hypermobility. The purpose of this study was to characterize the clinicopathological phenotype of a cEDS-affected Holstein calf and to identify the causative genetic variant associated with the disorder by whole-genome sequencing (WGS). A 3-day-old female Holstein calf was referred because of easily induced skin detachment and hyperextensibility in the neck. A complete clinical investigation was performed in the calf, dam, and maternal-grandmother. The calf and dam showed hyperextensibility of the neck skin and atrophic scarring; additionally, the calf presented skin fragility. Moreover, the histopathology of biopsies from the calf and its dam showed that the collagen bundles in affected skin areas were wavy, short, thin, and surrounded by edema and moderate to severe acute hemorrhages. Genetic analysis revealed a private heterozygous missense variant in COL5A2 (c.2366G>T; p.Gly789Val) that was present only in the calf and dam. This confirmed the diagnosis of cEDS and represents the first report of a causal variant for cEDS in cattle and the first COL5A2-related large animal model. [ABSTRACT FROM AUTHOR]

Genodermatosis such as hair disorders mostly follow a monogenic mode of inheritance. Congenital hypotrichosis (HY) belong to this group of disorders and is characterized by abnormally reduced hair since birth. The purpose of this study was to characterize the clinical phenotype of a breed-specific non-syndromic form of HY in Belted Galloway cattle and to identify the causative genetic variant for this recessive disorder. An affected calf born in Switzerland presented with multiple small to large areas of alopecia on the limbs and on the dorsal part of the head, neck, and back. A genome-wide association study using Swiss and US Belted Galloway cattle encompassing 12 cases and 61 controls revealed an association signal on chromosome 29. Homozygosity mapping in a subset of cases refined the HY locus to a 1.5 Mb critical interval and subsequent Sanger sequencing of protein-coding exons of positional candidate genes revealed a stop gain variant in the HEPHL1 gene that encodes a multi-copper ferroxidase protein so-called hephaestin like 1 (c.1684A>T; p.Lys562*). A perfect concordance between the homozygous presence of this most likely pathogenic loss-of-function variant and the HY phenotype was found. Genotyping of more than 700 purebred Swiss and US Belted Galloway cattle showed the global spread of the mutation. This study provides a molecular test that will permit the avoidance of risk matings by systematic genotyping of relevant breeding animals. This rare recessive HEPHL1-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002230-9913). [ABSTRACT FROM AUTHOR]

Sporadic occurrence of inherited eye disorders has been reported in cattle but so far pathogenic variants were found only for rare forms of cataract but not for retinopathies. The aim of this study was to characterize the phenotype and the genetic aetiology of a recessive form of congenital day-blindness observed in several cases of purebred Original Braunvieh cattle. Electroretinography in an affected calf revealed absent cone-mediated function, whereas the rods continue to function normally. Brain areas involved in vision were morphologically normal. When targeting cones by immunofluorescence, a decrease in cone number and an accumulation of beta subunits of cone cyclic-nucleotide gated channel (CNGB3) in the outer plexiform layer of affected animals was obvious. Achromatopsia is a monogenic Mendelian disease characterized by the loss of cone photoreceptor function resulting in day-blindness, total color-blindness, and decreased central visual acuity. After SNP genotyping and subsequent homozygosity mapping with twelve affected cattle, we performed whole-genome sequencing and variant calling of three cases. We identified a single missense variant in the bovine CNGB3 gene situated in a ~2.5 Mb homozygous genome region on chromosome 14 shared between all cases. All affected cattle were homozygous carriers of the p.Asp251Asn mutation that was predicted to be deleterious, affecting an evolutionary conserved residue. In conclusion, we have evidence for the occurrence of a breed-specific novel CNGB3-related form of recessively inherited achromatopsia in Original Braunvieh cattle which we have designated OH1 showing an allele frequency of the deleterious allele of ~8%. The identification of carriers will enable selection against this inherited disorder. The studied cattle might serve as an animal model to further elucidate the function of CNGB3 in mammals. [ABSTRACT FROM AUTHOR]