OBJECTIVES: This study aims to identify factors possibly contributing to complications in children with acute leukaemia. Despite diverse etiological causes, similar processes trigger the process of cell malignancy. Genomic instability has received considerable attention in this context. METHOD: We conducted chromosomal analysis of bone marrow cells and measured the micronuclei (Mn) level in buccal cells over time. Statistical reliability assessment was performed using Analysis of variance (ANOVA), and the data were analyzed and visualized using the SPSS 12 statistical analysis software package. RESULTS: On the 15th day of treatment, our findings confirmed a statistically significant correlation (χ2=3.88, P=0.04) between the number of blasts in the bone marrow and unfavourable outcome in patients with a near-tetraploid chromosome clone. Additionally, on the 33rd day of treatment, we observed a correlation between an elevated number of Mn and relapses. DISCUSSION: While it is commonly believed that a hyperdiploid clone with >50 chromosomes in childhood acute lymphoblastic leukaemia confers favorable outcome, our study revealed partially heterogeneous results and poor prognosis in patients with a near-tetraploid clone. We have also identified a correlation between the Mn level on the 33rd day of treatment and the development of complications. It is possible that the increased Mn values and the occurrence of relapses were influenced by the individual patient's sensitivity to the genotoxic effect of the medication.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * genetics   MeSH
• Bone Marrow Cells pathology   MeSH
• Child MeSH
• Humans MeSH
• Micronucleus Tests MeSH
• Micronuclei, Chromosome-Defective * MeSH
• Adolescent MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• Tetraploidy MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

PURPOSE: Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations. METHODS: Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS. RESULTS: A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases. CONCLUSION: A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.

• MeSH
• Algorithms MeSH
• Child MeSH
• Genetic Testing * methods   MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation genetics   MeSH
• Dwarfism genetics   diagnosis   MeSH
• Consanguinity * MeSH
• Growth Disorders genetics   diagnosis   MeSH
• Child, Preschool MeSH
• Pedigree MeSH
• Exome Sequencing methods   MeSH
• Body Height genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Iraq MeSH

Necrotizing enterocolitis (NEC) is one of the most devastating intestinal diseases observed in preterm in the first days of life. Researchers have recently focused on potential predictive biomarkers for early and concomitant diagnoses. Thus, we inquired about the linkage of intestinal dysbiosis, one of the most important factors in NEC development to the gut microbiota. In this study, the systematic differences in the bacterial composition between neonates affected by NEC and healthy newborns were highlighted by metagenomic analysis. The next-generation sequencing of the V3-V4 variable region of the 16S rRNA gene and gene-specific qPCR analyzed the untargeted gut microbiota. Total bacteria, total and fecal coliform loads in stool samples with NEC were higher than control. OTU-level relative abundances of NEC infant was characterized by Firmicutes and Bacteroidetes at phylum levels. At the genus level, NEC stool was identified by the lack of Klebsiella and the presence of Roseburia, Blautia, and Parasutterella. Finally, Clostridium fessum was the predominant species of Clostridium genus in disease and healthy specimens at the species level, whereas Clostridium jeddahitimonense was at NEC diagnosis. Despite a strong relationship between pathophysiology and characterization of gut microbiota at a clinical diagnosis of NEC, our results emphasize the broad difficulty in identifying potential biomarkers.

• MeSH
• Bacteria * classification   genetics   isolation & purification   MeSH
• DNA, Bacterial genetics   MeSH
• Dysbiosis microbiology   MeSH
• Feces * microbiology   MeSH
• Humans MeSH
• Metagenomics MeSH
• Enterocolitis, Necrotizing * microbiology   MeSH
• Infant, Premature MeSH
• Infant, Newborn MeSH
• RNA, Ribosomal, 16S * genetics   MeSH
• Gastrointestinal Microbiome * MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Halophilic bacteria are extremophiles that thrive in saline environment. Their ability to withstand such harsh conditions makes them an ideal choice for industrial applications such as lignocellulosic biomass degradation. In this study, a halophilic bacterium with the ability to produce extracellular cellulases and hemicellulases, designated as Nesterenkonia sp. CL21, was isolated from mangrove sediment in Tanjung Piai National Park, Malaysia. Thus far, studies on lignocellulolytic enzymes concerning bacterial species under this genus are limited. To gain a comprehensive understanding of its lignocellulose-degrading potential, the whole genome was sequenced using the Illumina NovaSeq 6000 platform. The genome of strain CL21 was assembled into 25 contigs with 3,744,449 bp and a 69.74% GC content and was predicted to contain 3,348 coding genes. Based on taxonomy analysis, strain CL21 shares 73.8 to 82.0% average nucleotide identity with its neighbouring species, below the 95% threshold, indicating its possible status as a distinct species in Nesterenkonia genus. Through in-depth genomic mining, a total of 81 carbohydrate-active enzymes were encoded. Among these, 24 encoded genes were identified to encompass diverse cellulases (GH3), xylanases (GH10, GH11, GH43, GH51, GH127 and CE4), mannanases (GH38 and GH106) and pectinases (PL1, PL9, and PL11). The production of lignocellulolytic enzymes was tested in the presence of several substrates. This study revealed that strain CL21 can produce a diverse array of enzymes which are active at different time points. By combining experimental data with genomic information, the ability of strain CL21 to produce lignocellulolytic enzymes has been elucidated, with potential applications in biorefinery industry.

• MeSH
• Bacterial Proteins genetics   metabolism   MeSH
• Cellulases genetics   metabolism   MeSH
• Phylogeny * MeSH
• Genome, Bacterial * MeSH
• Genomics * MeSH
• Geologic Sediments microbiology   MeSH
• Glycoside Hydrolases * genetics   metabolism   MeSH
• Lignin * metabolism   MeSH
• RNA, Ribosomal, 16S genetics   MeSH
• Whole Genome Sequencing MeSH
• Base Composition MeSH
• Publication type
• Journal Article MeSH

Multidisciplinary molecular tumor boards (MTB) are already well established in many comprehensive cancer centers and play an important role in the individual treatment planning for cancer patients. Comprehensive genomic profiling of tumor tissue based on next-generation sequencing is currently performed for diagnostic and mainly predictive testing. If somatic genomic variants are identified, which are suspected to be pathogenic germline variants (PGVs), MTB propose genetic counseling and germline DNA testing. Commonly used comprehensive genomic profiling approaches of tumor tissue do not include a matched germline DNA control. Therefore, the detection of PGVs could be only predicted based on the content of tumor cells (CTC) in selected tumor area (%) and variant allele frequency score (%). For conclusion, the role of a medical geneticist is essential in these cases. The overall prevalence of PGVs in patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) is approximately 10%. In this single-center study, we present 37 patients with PDAC and 48 patients with CRC who were presented at MTB and tested using the large combined DNA/RNA sequencing panel. Content of tumor cells and variant allele frequency scores were evaluated in all tested patients. In case of suspicion of PGV and no previous genetic testing based on the standard guidelines, genetic counseling was recommended regardless of age, sex, and family history. In the PDAC subgroup, five patients were recommended by MTB for genetic counseling based on suspicious genetic findings. Based on a medical geneticist's decision, germline DNA sequencing was performed in four of these cases, and all of them tested positive for PGV in the following genes: ATM, ATM, BRCA1, and BRCA2. In the CRC subgroup, no PGV was confirmed in the two patients genetically tested based on the MTB recommendations. Furthermore, we present data from our center's registry of patients with PDAC and CRC who underwent genetic counseling and germline DNA testing based on the standard screening criteria. Our data confirm that comprehensive genomic profiling of tumor tissue can identify patients with hereditary forms of PDAC, who could remain unidentified by standard screening for hereditary forms of cancer.

• MeSH
• Adult MeSH
• Carcinoma, Pancreatic Ductal genetics   diagnosis   MeSH
• Genetic Counseling MeSH
• Genetic Testing methods   MeSH
• Genomics methods   MeSH
• Colorectal Neoplasms * genetics   diagnosis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Pancreatic Neoplasms * genetics   diagnosis   MeSH
• Incidental Findings MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• High-Throughput Nucleotide Sequencing methods   MeSH
• Germ-Line Mutation * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for 'actionable' genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in ~400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.86) for 8151 variants. Our information-dense mapping provides a generalizable approach to advance multiple dimensions of rare genetic disorders.

• MeSH
• Deep Learning * MeSH
• Child MeSH
• Adult MeSH
• Phenotype * MeSH
• Genetic Variation MeSH
• Genetic Association Studies MeSH
• Genomics methods   MeSH
• Thyroid Hormones metabolism   genetics   MeSH
• Humans MeSH
• X-Linked Intellectual Disability genetics   metabolism   MeSH
• Adolescent MeSH
• Loss of Function Mutation MeSH
• Child, Preschool MeSH
• Monocarboxylic Acid Transporters * genetics   metabolism   MeSH
• Severity of Illness Index MeSH
• Muscular Atrophy genetics   metabolism   pathology   MeSH
• Muscle Hypotonia genetics   metabolism   MeSH
• Symporters * genetics   metabolism   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Treponema pallidum subspecies pertenue (TPE) is the causative agent of human and nonhuman primate (NHP) yaws infection. The discovery of yaws bacterium in wild populations of NHPs opened the question of transmission mechanisms within NHPs, and this work aims to take a closer look at the transmission of the disease. METHODOLOGY/PRINCIPAL FINDINGS: Our study determined eleven whole TPE genomes from NHP isolates collected from three national parks in Tanzania: Lake Manyara National Park (NP), Serengeti NP, and Ruaha NP. The bacteria were isolated from four species of NHPs: Chlorocebus pygerythrus (vervet monkey), Cercopithecus mitis (blue monkey), Papio anubis (olive baboon), and Papio cynocephalus (yellow baboon). Combined with previously generated genomes of TPE originating from NHPs in Tanzania (n = 11), 22 whole-genome TPE sequences have now been analyzed. Out of 231 possible combinations of genome-to-genome comparisons, five revealed an unexpectedly high degree of genetic similarity in samples collected from different NHP species, consistent with inter-species transmission of TPE among NHPs. We estimated a substitution rate of TPE of NHP origin, ranging between 1.77 × 10-7 and 3.43 × 10-7 per genomic site per year. CONCLUSIONS/SIGNIFICANCE: The model estimations predicted that the inter-species transmission happened recently, within decades, roughly in an order of magnitude shorter time compared to time needed for the natural diversification of all tested TPE of Tanzanian NHP origin. Moreover, the geographical separation of the sampling sites (NPs) does not preclude TPE transmission between and within NHP species.

• MeSH
• Chlorocebus aethiops MeSH
• Cercopithecus microbiology   MeSH
• Yaws * microbiology   transmission   MeSH
• Phylogeny * MeSH
• Genome, Bacterial MeSH
• Humans MeSH
• Monkey Diseases microbiology   transmission   MeSH
• Papio anubis microbiology   MeSH
• Papio cynocephalus microbiology   genetics   MeSH
• Primates microbiology   MeSH
• Whole Genome Sequencing * MeSH
• Treponema pallidum genetics   isolation & purification   classification   MeSH
• Treponema MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Tanzania MeSH

BACKGROUND: Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease (CAD) that is characterized by concentric fibrous intimal hyperplasia along the length of coronary vessels, and is recognized as long-term complication after heart transplantation. The chromosomal loci 9p21, 6q25.1, and 2q36.3, represented by their respective leading variants rs10757274, rs6922269 and rs2943634, have been linked with a history of CAD by genome-wide association studies. We aimed to investigate the associations of genetic variants at the loci 9p21, 6q25.1, and 2q36.3 with CAV as genetic risk factors for early prediction. METHODS: Genomic DNA was extracted from paired aortic samples of 727 heart recipients (average age 50.8 ± 12.2 years; 21.3% women) and corresponding donors (average age 39.7 ± 12.0 years; 26.1% women). The variants within the loci 9p21, 6q25.1, and 2q36.3 were genotyped using PCR-RFLP. RESULTS: The recipients' variants of 9p21 (OR 1.97; 95% CI, 1.21-3.19 for GG vs. +A comparison, p = 0.0056) and 2q36.3 (OR 2.46; 95% CI, 1.12-6.17 for +C vs. AA comparison, p = 0.0186) were associated with higher incidence of CAV during the first year following heart transplantation. No such association was found for donor genotypes. CONCLUSIONS: Our data suggest that variants at the locus 9p21 (rs10757274) and 2q36.3 (rs2943634) are associated with early CAV development.

• MeSH
• Allografts * MeSH
• Genome-Wide Association Study MeSH
• Adult MeSH
• Genetic Predisposition to Disease MeSH
• Polymorphism, Single Nucleotide MeSH
• Middle Aged MeSH
• Humans MeSH
• Chromosomes, Human, Pair 2 genetics   MeSH
• Chromosomes, Human, Pair 6 genetics   MeSH
• Chromosomes, Human, Pair 9 genetics   MeSH
• Coronary Artery Disease * genetics   pathology   etiology   MeSH
• Heart Transplantation * adverse effects   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Rare, germline loss-of-function variants in a handful of DNA repair genes are associated with epithelial ovarian cancer. The aim of this study was to evaluate the role of rare, coding, loss-of-function variants across the genome in epithelial ovarian cancer. We carried out a gene-by-gene burden test with various histotypes using data from 2573 non-mucinous cases and 13,923 controls. Twelve genes were associated at a False Discovery Rate of less than 0.1 of which seven were the known ovarian cancer susceptibility genes BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH6 and PALB2. The other five genes were OR2T35, HELB, MYO1A and GABRP which were associated with non-high-grade serous ovarian cancer and MIGA1 which was associated with high-grade serous ovarian cancer. Further support for the association of HELB association comes from the observation that loss-of-function variants in HELB are associated with age at natural menopause and Mendelian randomisation analysis shows an association between genetically predicted age at natural menopause and endometrioid ovarian cancer, but not high-grade serous ovarian cancer.

• MeSH
• Adult MeSH
• Carcinoma, Ovarian Epithelial * genetics   pathology   MeSH
• Genetic Predisposition to Disease MeSH
• Middle Aged MeSH
• Humans MeSH
• Ovarian Neoplasms * genetics   pathology   MeSH
• Exome Sequencing MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Myelodysplastic neoplasms (MDS) are heterogeneous hematopoietic disorders characterized by ineffective hematopoiesis and genome instability. Mobilization of transposable elements (TEs) is an important source of genome instability leading to oncogenesis, whereas small PIWI-interacting RNAs (piRNAs) act as cellular suppressors of TEs. However, the roles of TEs and piRNAs in MDS remain unclear. METHODS: In this study, we examined TE and piRNA expression through parallel RNA and small RNA sequencing of CD34+ hematopoietic stem cells from MDS patients. RESULTS: Comparative analysis of TE and piRNA expression between MDS and control samples revealed several significantly dysregulated molecules. However, significant differences were observed between lower-risk MDS (LR-MDS) and higher-risk MDS (HR-MDS) samples. In HR-MDS, we found an inverse correlation between decreased TE levels and increased piRNA expression and these TE and piRNA levels were significantly associated with patient outcomes. Importantly, the upregulation of PIWIL2, which encodes a key factor in the piRNA pathway, independently predicted poor prognosis in MDS patients, underscoring its potential as a valuable disease marker. Furthermore, pathway analysis of RNA sequencing data revealed that dysregulation of the TE‒piRNA axis is linked to the suppression of processes related to energy metabolism, the cell cycle, and the immune response, suggesting that these disruptions significantly affect cellular activity. CONCLUSIONS: Our findings demonstrate the parallel dysregulation of TEs and piRNAs in HR-MDS patients, highlighting their potential role in MDS progression and indicating that the PIWIL2 level is a promising molecular marker for prognosis.

• Publication type
• Journal Article MeSH