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BMC Medical Genomics Jul 2024Intellectual disability (ID) is a neurodevelopmental condition affecting around 2% of children and young adults worldwide, characterized by deficits in intellectual...
BACKGROUND
Intellectual disability (ID) is a neurodevelopmental condition affecting around 2% of children and young adults worldwide, characterized by deficits in intellectual functioning and adaptive behavior. Genetic factors contribute to the development of ID phenotypes, including mutations and structural changes in chromosomes. Pathogenic variants in the HCFC1 gene cause X-linked mental retardation syndrome, also known as Siderius type X-linked mental retardation. The MN1 gene is necessary for palate development, and mutations in this gene result in a genetic condition called CEBALID syndrome.
METHODS
Exome sequencing was used to identify the disease-causing variants in two affected families, A and B, from various regions of Pakistan. Affected individuals in these two families presented ID, developmental delay, and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing.
RESULTS
In an X-linked family A, a novel hemizygous missense variant (c.5705G > A; p.Ser1902Asn) in the HCFC1 gene (NM_005334.3) was identified, while in family B exome sequencing revealed a heterozygous nonsense variant (c.3680 G > A; p. Trp1227Ter) in exon-1 of the MN1 gene (NM_032581.4). Sanger sequencing confirmed the segregation of these variants with ID in each family.
CONCLUSIONS
The investigation of two Pakistani families revealed pathogenic genetic variants in the HCFC1 and MN1 genes, which cause ID and expand the mutational spectrum of these genes.
Topics: Humans; Pakistan; Male; Pedigree; Intellectual Disability; Female; Host Cell Factor C1; Tumor Suppressor Proteins; Trans-Activators; Child; Exome Sequencing; Child, Preschool
PubMed: 38956580
DOI: 10.1186/s12920-024-01943-2 -
Cancer Cell International Jul 2024Secretory cells in the fallopian tube fimbria epithelium (FTE) are regarded as the main cells of origin of ovarian high-grade serous carcinoma (HGSC). Ovulation is the...
Secretory cells in the fallopian tube fimbria epithelium (FTE) are regarded as the main cells of origin of ovarian high-grade serous carcinoma (HGSC). Ovulation is the main cause of FTE oncogenesis, which proceeds through a sequence of TP53 mutations, chromosomal instability due to Rb/cyclin E aberration, in situ carcinoma (STIC), and metastasis to the ovary and peritoneum (metastatic HGSC). Previously, we have identified multiple oncogenic activities of the ovulatory follicular fluid (FF), which exerts the full spectrum of transforming activity on FTE cells at different stages of transformation. After ovulation, the FF is transfused into the peritoneal fluid (PF), in which the FTE constantly bathes. We wondered whether PF exerts the same spectrum of oncogenic activities as done by FF and whether these activities are derived from FF. By using a panel of FTE cell lines with p53 mutation (FT282-V), p53/CCNE1 aberrations (FT282-CCNE1), and p53/Rb aberrations plus spontaneous transformation, and peritoneal metastasis (FEXT2), we analyzed the changes of different transformation phenotypes after treating with FF and PF collected before or after ovulation. Similar to effects exhibited by FF, we found that, to a lesser extent, PF promoted anchorage-independent growth (AIG), migration, anoikis resistance, and peritoneal attachment in transforming FTE cells. The more transformed cells were typically more affected. Among the transforming activities exhibited by PF treatment, AIG, Matrigel invasion, and peritoneal attachment growth were higher with luteal-phase PF treatment than with the proliferative-phase PF treatment, suggesting an ovulation source. In contrast, changes in anoikis resistance and migration activities were similar in response to treatment with PF collected before and after ovulation, suggesting an ovulation-independent source. The overall transforming activity of luteal-phase PF was verified in an i.p. co-injection xenograft mouse model. Co-injection of Luc-FEXT2 cells with either FF or luteal-phase PF supported early peritoneal implantation, whereas co-injection with follicular-phase PF did not. This study, for the first time, demonstrates that PF from ovulating women can promote different oncogenic phenotypes in FTE cells at different stages of malignant transformation. Most of these activities, other than anoikis resistance and cell migration, are sourced from ovulation.
PubMed: 38956560
DOI: 10.1186/s12935-024-03406-1 -
BMC Women's Health Jul 2024The aim of this study is to assess the efficacy of a multiparametric ultrasound imaging omics model in predicting the risk of postoperative recurrence and molecular...
BACKGROUND
The aim of this study is to assess the efficacy of a multiparametric ultrasound imaging omics model in predicting the risk of postoperative recurrence and molecular typing of breast cancer.
METHODS
A retrospective analysis was conducted on 534 female patients diagnosed with breast cancer through preoperative ultrasonography and pathology, from January 2018 to June 2023 at the Affiliated Cancer Hospital of Xinjiang Medical University. Univariate analysis and multifactorial logistic regression modeling were used to identify independent risk factors associated with clinical characteristics. The PyRadiomics package was used to delineate the region of interest in selected ultrasound images and extract radiomic features. Subsequently, radiomic scores were established through Least Absolute Shrinkage and Selection Operator (LASSO) regression and Support Vector Machine (SVM) methods. The predictive performance of the model was assessed using the receiver operating characteristic (ROC) curve, and the area under the curve (AUC) was calculated. Evaluation of diagnostic efficacy and clinical practicability was conducted through calibration curves and decision curves.
RESULTS
In the training set, the AUC values for the postoperative recurrence risk prediction model were 0.9489, and for the validation set, they were 0.8491. Regarding the molecular typing prediction model, the AUC values in the training set and validation set were 0.93 and 0.92 for the HER-2 overexpression phenotype, 0.94 and 0.74 for the TNBC phenotype, 1.00 and 0.97 for the luminal A phenotype, and 1.00 and 0.89 for the luminal B phenotype, respectively. Based on a comprehensive analysis of calibration and decision curves, it was established that the model exhibits strong predictive performance and clinical practicability.
CONCLUSION
The use of multiparametric ultrasound imaging omics proves to be of significant value in predicting both the risk of postoperative recurrence and molecular typing in breast cancer. This non-invasive approach offers crucial guidance for the diagnosis and treatment of the condition.
Topics: Humans; Female; Breast Neoplasms; Neoplasm Recurrence, Local; Middle Aged; Retrospective Studies; Adult; Risk Assessment; Predictive Value of Tests; Risk Factors; Ultrasonography; Aged; Ultrasonography, Mammary; ROC Curve
PubMed: 38956552
DOI: 10.1186/s12905-024-03231-8 -
BMC Biology Jul 2024Microbes in the cold polar and alpine environments play a critical role in feedbacks that amplify the effects of climate change. Defining the cold adapted ecotype is one...
BACKGROUND
Microbes in the cold polar and alpine environments play a critical role in feedbacks that amplify the effects of climate change. Defining the cold adapted ecotype is one of the prerequisites for understanding the response of polar and alpine microbes to climate change.
RESULTS
Here, we analysed 85 high-quality, de-duplicated genomes of Deinococcus, which can survive in a variety of harsh environments. By leveraging genomic and phenotypic traits with reverse ecology, we defined a cold adapted clade from eight Deinococcus strains isolated from Arctic, Antarctic and high alpine environments. Genome-wide optimization in amino acid composition and regulation and signalling enable the cold adapted clade to produce CO from organic matter and boost the bioavailability of mineral nitrogen.
CONCLUSIONS
Based primarily on in silico genomic analysis, we defined a potential cold adapted clade in Deinococcus and provided an updated view of the genomic traits and metabolic potential of Deinococcus. Our study would facilitate the understanding of microbial processes in the cold polar and alpine environments.
Topics: Deinococcus; Cold Temperature; Genomics; Genome, Bacterial; Adaptation, Physiological; Phylogeny
PubMed: 38956546
DOI: 10.1186/s12915-024-01944-8 -
BMC Medical Genomics Jul 2024Autosomal recessive non-syndromic hearing loss (NSHL) and cone dystrophies (CODs) are highly genetically and phenotypically heterogeneous disorders. In this study, we...
Clinical characterizations and molecular genetic study of two co-segregating variants in PDZD7 and PDE6C genes leading simultaneously to non-syndromic hearing loss and achromatopsia.
BACKGROUND
Autosomal recessive non-syndromic hearing loss (NSHL) and cone dystrophies (CODs) are highly genetically and phenotypically heterogeneous disorders. In this study, we applied the whole exome sequencing (WES) to find the cause of HL and COD in an Iranian consanguineous family with three affected individuals.
METHODS
Three members from an Iranian consanguineous family who were suffering from NSHL and visual impairment were ascertained in this study. Comprehensive clinical evaluations and genetic analysis followed by bioinformatic and co-segregation studies were performed to diagnose the cause of these phenotypes. Data were collected from 2020 to 2022.
RESULTS
All cases showed congenital bilateral NSHL, decreased visual acuity, poor color discrimination, photophobia and macular atrophy. Moreover, cornea, iris and anterior vitreous were within normal limit in both eyes, decreased foveal sensitivity, central scotoma and generalized depression of visual field were seen in three cases. WES results showed two variants, a novel null variant (p.Trp548Ter) in the PDE6C gene causing COD type 4 (Achromatopsia) and a previously reported variant (p.Ile84Thr) in the PDZD7 gene causing NSHL. Both variants were found in the cis configuration on chromosome 10 with a genetic distance of about 8.3 cM, leading to their co-inheritance. However, two diseases could appear independently in subsequent generations due to crossover during meiosis.
CONCLUSIONS
Here, we could successfully determine the etiology of a seemingly complex phenotype in two adjacent genes. We identified a novel variant in the PDE6C gene, related to achromatopsia. Interestingly, this variant could cooperatively cause visual disorders: cone dystrophy and cone-rod dystrophy.
Topics: Humans; Color Vision Defects; Cyclic Nucleotide Phosphodiesterases, Type 6; Male; Female; Pedigree; Exome Sequencing; Adult; Hearing Loss; Mutation; Consanguinity; Child; Iran; Phenotype; Eye Proteins
PubMed: 38956522
DOI: 10.1186/s12920-024-01942-3 -
BMC Genomics Jul 2024Breeding polled goats is a welfare-friendly approach for horn removal in comparison to invasive methods. To gain a comprehensive understanding of the genetic basis...
BACKGROUND
Breeding polled goats is a welfare-friendly approach for horn removal in comparison to invasive methods. To gain a comprehensive understanding of the genetic basis underlying polledness in goats, we conducted whole-genome sequencing of 106 Xinong Saanen dairy goats, including 33 horned individuals, 70 polled individuals, and 3 polled intersexuality syndrome (PIS) individuals.
METHODS
The present study employed a genome-wide association study (GWAS) and linkage disequilibrium (LD) analysis to precisely map the genetic locus underlying the polled phenotype in goats.
RESULTS
The analysis conducted in our study revealed a total of 320 genome-wide significant single nucleotide polymorphisms (SNPs) associated with the horned/polled phenotype in goats. These SNPs exhibited two distinct peaks on chromosome 1, spanning from 128,817,052 to 133,005,441 bp and from 150,336,143 to 150,808,639 bp. The present study identified three genome-wide significant SNPs, namely Chr1:129789816, Chr1:129791507, and Chr1:129791577, as potential markers of PIS-affected goats. The results of our LD analysis suggested a potential association between MRPS22 and infertile intersex individuals, as well as a potential association between ERG and the polled trait in goats.
CONCLUSION
We have successfully identified three marker SNPs closely linked to PIS, as well as several candidate genes associated with the polled trait in goats. These results may contribute to the development of SNP chips for early prediction of PIS in goats, thereby facilitating breeding programs aimed at producing fertile herds with polled traits.
Topics: Animals; Goats; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Phenotype; Linkage Disequilibrium; Disorders of Sex Development; Female; Male; Whole Genome Sequencing; Horns
PubMed: 38956513
DOI: 10.1186/s12864-024-10568-9 -
BMC Genomics Jul 2024Neither a TYRP1-mediated highly conserved genetic network underlying skin color towards optimum defense nor the pathological tendency of its mutation is well understood....
BACKGROUND
Neither a TYRP1-mediated highly conserved genetic network underlying skin color towards optimum defense nor the pathological tendency of its mutation is well understood. The Oujiang Color Common Carp (Cyprinus carpio var. color) as a model organism, offering valuable insights into genetics, coloration, aquaculture practices, and environmental health. Here, we performed a comparative skin transcriptome analysis on TYRP1 mutant and wild fishes by applying a conservative categorical approach considering different color phenotypes.
RESULTS
Our results reveal that an unusual color phenotype may be sensitized with TYRP1 mutation as a result of upregulating several genes related to an anti-inflammatory autoimmune system in response to the COMT-mediated catecholamine neurotransmitters in the skin. Particularly, catecholamines-derived red/brown, red with blue colored membrane attack complex, and brown/grey colored reduced eumelanin are expected to be aggregated in the regenerated cells.
CONCLUSIONS
It is, thus, concluded that the regenerated cells with catecholamines, membrane attack complex, and eumelanin altogether may contribute to the formation of the unusual (coffee-like) color phenotype in TYRP1 mutant.
Topics: Animals; Carps; Gene Regulatory Networks; Mutation; Skin Pigmentation; Phenotype; Fish Proteins; Gene Expression Profiling; Transcriptome
PubMed: 38956500
DOI: 10.1186/s12864-024-10550-5 -
BMC Genomics Jul 2024The cashmere goat industry is one of the main pillars of animal husbandry in Inner Mongolia Autonomous Region, and plays an irreplaceable role in local economic...
BACKGROUND
The cashmere goat industry is one of the main pillars of animal husbandry in Inner Mongolia Autonomous Region, and plays an irreplaceable role in local economic development. With the change in feeding methods and environment, the cashmere produced by Inner Mongolia cashmere goats shows a tendency of coarser, and the cashmere yield can not meet the consumption demand of people. However, the genetic basis behind these changes is not fully understood. We measured cashmere traits, including cashmere yield (CY), cashmere diameter (CD), cashmere thickness (CT), and fleece length (FL) traits for four consecutive years, and utilized Genome-wide association study of four cashmere traits in Inner Mongolia cashmere goats was carried out using new genomics tools to infer genomic regions and functional loci associated with cashmere traits and to construct haplotypes that significantly affect cashmere traits.
RESULTS
We estimated the genetic parameters of cashmere traits in Inner Mongolia cashmere goats. The heritability of cashmere yield, cashmere diameter, and fleece length traits of Inner Mongolia cashmere goats were 0.229, 0.359, and 0.250, which belonged to the medium heritability traits (0.2 ~ 0.4). The cashmere thickness trait has a low heritability of 0.053. We detected 151 genome-wide significantly associated SNPs with four cashmere traits on different chromosomes, which were very close to the chromosomes of 392 genes (located within the gene or within ± 500 kb). Notch3, BMPR1B, and CCNA2 have direct functional associations with fibroblasts and follicle stem cells, which play important roles in hair follicle growth and development. Based on GO functional annotation and KEGG enrichment analysis, potential candidate genes were associated with pathways of hair follicle genesis and development (Notch, P13K-Akt, TGF-beta, Cell cycle, Wnt, MAPK). We calculated the effective allele number of the Inner Mongolia cashmere goat population to be 1.109-1.998, the dominant genotypes of most SNPs were wild-type, the polymorphic information content of 57 SNPs were low polymorphism (0 < PIC < 0.25), and the polymorphic information content of 79 SNPs were moderate polymorphism (0.25 < PIC < 0.50). We analyzed the association of SNPs with phenotypes and found that the homozygous mutant type of SNP1 and SNP3 was associated with the highest cashmere yield, the heterozygous mutant type of SNP30 was associated with the lowest cashmere thickness, the wild type of SNP76, SNP77, SNP78, SNP80, and SNP81 was associated with the highest cashmere thickness, and the wild type type of SNP137 was associated with the highest fleece length. 21 haplotype blocks and 68 haplotype combinations were constructed. Haplotypes A2A2, B2B2, C2C2, and D4D4 were associated with increased cashmere yield, haplotypes E2E2, F1F1, G5G5, and G1G5 were associated with decreased cashmere fineness, haplotypes H2H2 was associated with increased cashmere thickness, haplotypes I1I1, I1I2, J1J4, L5L3, N3N2, N3N3, O2O1, P2P2, and Q3Q3 were associated with increased cashmere length. We verified the polymorphism of 8 SNPs by KASP, and found that chr7_g.102631194A > G, chr10_g.82715068 T > C, chr1_g.124483769C > T, chr24_g.12811352C > T, chr6_g.114111249A > G, and chr6_g.115606026 T > C were significantly genotyped in verified populations (P < 0.05).
CONCLUSIONS
In conclusion, the genetic effect of single SNP on phenotypes is small, and SNPs are more inclined to be inherited as a whole. By constructing haplotypes from SNPs that are significantly associated with cashmere traits, it will help to reveal the complex and potential causal variations in cashmere traits of Inner Mongolia cashmere goats. This will be a valuable resource for genomics and breeding of the cashmere goat.
Topics: Animals; Goats; Genome-Wide Association Study; Haplotypes; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Phenotype; China; Quantitative Trait, Heritable
PubMed: 38956486
DOI: 10.1186/s12864-024-10543-4 -
Diagnosis of cystic fibrosis: a high heterogeneity of symptoms and genotypes in a Brazil population.BMC Pediatrics Jul 2024In highly multiracial populations with inadequate newborn screening, knowledge of the various phenotypic presentations of Cystic Fibrosis (CF) can help reach an early...
INTRODUCTION
In highly multiracial populations with inadequate newborn screening, knowledge of the various phenotypic presentations of Cystic Fibrosis (CF) can help reach an early diagnosis. This study aims to describe phenotypes and genotypes at the time of CF diagnosis in a state in the Northeast Region of Brazil.
METHODS
Retrospective cross-sectional study. Clinical data were extracted from the medical records of CF patients. Clinical, laboratory, and genotypic characteristics were described for patients admitted to a tertiary referral center between 2007 and 2021.
RESULTS
Fifty-eight (58) patients were included in the study, 53.5% of whom were diagnosed through clinical suspicion. The median age at diagnosis was 4.7 months (IQR: 1.5-14.8 months). Five patients had false-negative results in the newborn screening. Faltering growth was the most frequent clinical manifestation. Bronchiectasis and a history of pneumonia predominated in those older than ten, while thinness, underweight, and electrolyte imbalances were more frequent in children under two. Sequencing of the CFTR gene identified 27 genotypes, with at least one class I-III variant in all patients, and nine variants that are rare, previously undescribed, or have uncertain significance (619delA, T12991, K162Q, 3195del6, 1678del > T, 124del123bp, 3121-3113 A > T). The most frequent alleles were p.Phe508del, p.Gly542*, p.Arg334Trp, and p.Ser549Arg.
CONCLUSIONS
Malnutrition and electrolyte imbalances were the most frequent phenotypes for children < 2 years and were associated with genotypes including 2 class I-III variants. Rare and previously undescribed variants were identified. The p.Gly542*, p.Arg334Trp, and p.Ser549Arg alleles were among the most frequent variants in this population.
Topics: Humans; Cystic Fibrosis; Brazil; Cross-Sectional Studies; Retrospective Studies; Male; Female; Infant; Genotype; Cystic Fibrosis Transmembrane Conductance Regulator; Phenotype; Infant, Newborn; Neonatal Screening; Child, Preschool; Mutation
PubMed: 38956483
DOI: 10.1186/s12887-024-04891-z -
BMC Genomics Jul 2024Carcass weight (HCW) and marbling (MARB) are critical for meat quality and market value in beef cattle. In composite breeds like Brangus, which meld the genetics of...
BACKGROUND
Carcass weight (HCW) and marbling (MARB) are critical for meat quality and market value in beef cattle. In composite breeds like Brangus, which meld the genetics of Angus and Brahman, SNP-based analyses have illuminated some genetic influences on these traits, but they fall short in fully capturing the nuanced effects of breed of origin alleles (BOA) on these traits. Focus on the impacts of BOA on phenotypic features within Brangus populations can result in a more profound understanding of the specific influences of Angus and Brahman genetics. Moreover, the consideration of BOA becomes particularly significant when evaluating dominance effects contributing to heterosis in crossbred populations. BOA provides a more comprehensive measure of heterosis due to its ability to differentiate the distinct genetic contributions originating from each parent breed. This detailed understanding of genetic effects is essential for making informed breeding decisions to optimize the benefits of heterosis in composite breeds like Brangus.
OBJECTIVE
This study aims to identify quantitative trait loci (QTL) influencing HCW and MARB by utilizing SNP and BOA information, incorporating additive, dominance, and overdominance effects within a multi-generational Brangus commercial herd.
METHODS
We analyzed phenotypic data from 1,066 genotyped Brangus steers. BOA inference was performed using LAMP-LD software using Angus and Brahman reference sets. SNP-based and BOA-based GWAS were then conducted considering additive, dominance, and overdominance models.
RESULTS
The study identified numerous QTLs for HCW and MARB. A notable QTL for HCW was associated to the SGCB gene, pivotal for muscle growth, and was identified solely in the BOA GWAS. Several BOA GWAS QTLs exhibited a dominance effect underscoring their importance in estimating heterosis.
CONCLUSIONS
Our findings demonstrate that SNP-based methods may not detect all genetic variation affecting economically important traits in composite breeds. BOA inclusion in genomic evaluations is crucial for identifying genetic regions contributing to trait variation and for understanding the dominance value underpinning heterosis. By considering BOA, we gain a deeper understanding of genetic interactions and heterosis, which is integral to advancing breeding programs. The incorporation of BOA is recommended for comprehensive genomic evaluations to optimize trait improvements in crossbred cattle populations.
Topics: Animals; Polymorphism, Single Nucleotide; Cattle; Quantitative Trait Loci; Genome-Wide Association Study; Breeding; Phenotype; Genotype; Hybrid Vigor; Meat; Alleles
PubMed: 38956457
DOI: 10.1186/s12864-024-10465-1