Dataset Information

A Missense Variant in PLP2 in Holstein Cattle with X-Linked Congenital Mast Cell Tumor.

ABSTRACT: 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.

SUBMITTER: Jacinto JGP

PROVIDER: S-EPMC9494957 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Missense Variant in PLP2 in Holstein Cattle with X-Linked Congenital Mast Cell Tumor.

Jacinto Joana G P JGP Muscatello Luisa Vera LV Häfliger Irene M IM Benazzi Cinzia C Bolcato Marilena M Gentile Arcangelo A Drögemüller Cord C

Animals : an open access journal from MDPI 20220907 18

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 nutr ...[more]

PMID: 36139188

Similar Datasets

Project description:BackgroundSurveillance for bovine genetic diseases in Denmark identified a hitherto unreported congenital syndrome occurring among progeny of a Holstein sire used for artificial breeding. A genetic aetiology due to a dominant inheritance with incomplete penetrance or a mosaic germline mutation was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause.ResultsSeven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial dysplasia and complete prolapse of the eyes. Consequently the syndrome was named facial dysplasia syndrome (FDS). Furthermore, extensive brain malformations, including microencephaly, hydrocephalus, lobation of the cerebral hemispheres and compression of the brain were present. Subsequent data analysis of progeny of the sire revealed that around 0.5% of his offspring suffered from FDS. High density single nucleotide polymorphism (SNP) genotyping data of the seven cases and their parents were used to map the defect in the bovine genome. Significant genetic linkage was obtained for three regions, including chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events in the germline of the sire.ConclusionsFDS is a novel genetic disorder of Holstein cattle. Mutations in the human FGFR2 gene are associated with various dominant inherited craniofacial dysostosis syndromes. Given the phenotypic similarities in FDS affected calves, the genetic mapping and absence of further high impact variants in the critical genome regions, it is highly likely that the missense mutation in the FGFR2 gene caused the FDS phenotype in a dominant mode of inheritance.

Project description:BackgroundStructural variants (SVs) such as deletions, duplications, and insertions are known to contribute to phenotypic variation but remain challenging to identify and genotype. A more complete, accessible, and assessable collection of SVs will assist efforts to study SV function in cattle and to incorporate SV genotyping into animal evaluation.ResultsIn this work we produced a large and deeply characterized collection of SVs in Holstein cattle using two popular SV callers (Manta and Smoove) and publicly available Illumina whole-genome sequence (WGS) read sets from 310 samples (290 male, 20 female, mean 20X coverage). Manta and Smoove identified 31 K and 68 K SVs, respectively. In total the SVs cover 5% (Manta) and 6% (Smoove) of the reference genome, in contrast to the 1% impacted by SNPs and indels. SV genotypes from each caller were confirmed to accurately recapitulate animal relationships estimated using WGS SNP genotypes from the same dataset, with Manta genotypes outperforming Smoove, and deletions outperforming duplications. To support efforts to link the SVs to phenotypic variation, overlapping and tag SNPs were identified for each SV, using genotype sets extracted from the WGS results corresponding to two bovine SNP chips (BovineSNP50 and BovineHD). 9% (Manta) and 11% (Smoove) of the SVs were found to have overlapping BovineHD panel SNPs, while 21% (Manta) and 9% (Smoove) have BovineHD panel tag SNPs. A custom interactive database ( https://svdb-dc.pslab.ca ) containing the identified sequence variants with extensive annotations, gene feature information, and BAM file content for all SVs was created to enable the evaluation and prioritization of SVs for further study. Illustrative examples involving the genes POPDC3, ORM1, G2E3, FANCI, TFB1M, FOXC2, N4BP2, GSTA3, and COPA show how this resource can be used to find well-supported genic SVs, determine SV breakpoints, design genotyping approaches, and identify processed pseudogenes masquerading as deletions.ConclusionsThe resources developed through this study can be used to explore sequence variation in Holstein cattle and to develop strategies for studying SVs of interest. The lack of overlapping and tag SNPs from commonly used SNP chips for most of the SVs suggests that other genotyping approaches will be needed (for example direct genotyping) to understand their potential contributions to phenotype. The included SV genotype assessments point to challenges in characterizing SVs, especially duplications, using short-read data and support ongoing efforts to better characterize cattle genomes through long-read sequencing. Lastly, the identification of previously known functional SVs and additional CDS-overlapping SVs supports the phenotypic relevance of this dataset.

Project description:BackgroundChiari malformation type II (CMII) was originally reported in humans as a rare disorder characterized by the downward herniation of the hindbrain and towering cerebellum. The congenital brain malformation is usually accompanied by spina bifida, a congenital spinal anomaly resulting from incomplete closure of the dorsal aspect of the spinal neural tube, and occasionally by other lesions. A similar disorder has been reported in several animal species, including cattle, particularly as a congenital syndrome. A cause of congenital syndromic Chiari-like malformation (CSCM) in cattle has not been reported to date. We collected a series of 14 CSCM-affected Holstein calves (13 purebred, one Red Danish Dairy F1 cross) and performed whole-genome sequencing (WGS). WGS was performed on 33 cattle, including eight cases with parents (trio-based; group 1), three cases with one parent (group 2), and three single cases (solo-based; group 3).ResultsSequencing-based genome-wide association study of the 13 Holstein calves with CSCM and 166 controls revealed no significantly associated genome region. Assuming a single Holstein breed-specific recessive allele, no region of shared homozygosity was detected suggesting heterogeneity. Subsequent filtering for protein-changing variants that were only homozygous in the genomes of the individual cases allowed the identification of two missense variants affecting different genes, SHC4 in case 4 in group 1 and WDR45B in case 13 in group 3. Furthermore, these two variants were only observed in Holstein cattle when querying WGS data of > 5,100 animals. Alternatively, potential de novo mutational events were assessed in each case. Filtering for heterozygous private protein-changing variants identified one DYNC1H1 frameshift variant as a candidate causal dominant acting allele in case 12 in group 3. Finally, the presence of larger structural DNA variants and chromosomal abnormalities was investigated in all cases. Depth of coverage analysis revealed two different partial monosomies of chromosome 2 segments in cases 1 and 7 in group 1 and a trisomy of chromosome 12 in the WDR45B homozygous case 13 in group 3.ConclusionsThis study presents for the first time a detailed genomic evaluation of CSCM in Holstein cattle and suggests an unexpected genetic and allelic heterogeneity considering the mode of inheritance, as well as the type of variant. For the first time, we propose candidate causal variants that may explain bovine CSCM in a certain proportion of affected calves. We present cattle as a large animal model for human CMII and propose new genes and genomic variants as possible causes for related diseases in both animals and humans.

Dataset Information

A Missense Variant in PLP2 in Holstein Cattle with X-Linked Congenital Mast Cell Tumor.

Publications

A Missense Variant in PLP2 in Holstein Cattle with X-Linked Congenital Mast Cell Tumor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets