BMC Medical Genomics[JOURNAL]
Sun
200 papers
Genetic disorders caused by consanguineous marriage in Radfan districts - Yemen.
Mehdi MAH, Ali NT, Saleh R
BMC Med Genomics · 2025 Dec · PMID 41444567 · Full text
BACKGROUND: Consanguineous marriage (≥ second cousins) is prevalent in Yemen (40-50%) and linked to increased genetic disorders. This study assesses its prevalence and health impacts in Radfan districts. METHODOLOGY: A 2...
BACKGROUND: Consanguineous marriage (≥ second cousins) is prevalent in Yemen (40-50%) and linked to increased genetic disorders. This study assesses its prevalence and health impacts in Radfan districts. METHODOLOGY: A 2024 cross-sectional study of 1065 randomly selected households. Data were collected via validated questionnaires supplemented by medical records where available. Analyses included consanguinity rates, inbreeding coefficients (F), sociocultural factors, and clinically validated genetic disorders. Statistical analysis employed χ² tests, multivariable logistic regression (adjusted ORs), and Cohen's d for effect sizes. RESULTS: The consanguinity rate was 57.46%, significantly higher in rural (37.09%) than urban areas (20.38%). Wives with a university education had a 71.9% lower likelihood of consanguineous marriage (adjusted OR = 0.28; 95% CI: 0.18-0.44). Consanguineous couples had significantly higher odds of adverse outcomes compared to non-consanguineous couples, including abortion (adjusted OR = 1.8; 95% CI: 1.4-2.3), child mortality (adjusted OR = 2.1; 95% CI: 1.6-2.8), blood disorders (adjusted OR = 3.5; 95% CI: 1.7-7.4), and disabilities (adjusted OR = 2.6; 95% CI: 1.4-4.8). Blood disorders were predominantly hemoglobinopathies (87%). The mean inbreeding coefficient was F = 0.0625 (first-cousin equivalent). CONCLUSIONS: The high prevalence of consanguineous marriages is a significant, modifiable risk factor for the increased burden of genetic disorders in the population. Addressing this urgent public health challenge requires a multi-faceted strategy: implementing mandatory premarital screening for hemoglobinopathies, launching community-based genetic literacy programs, and establishing economic incentives to encourage non-consanguineous unions.
Chromosome structural variation analysis reveals lung cancer-associated gene regulatory networks in rheumatoid arthritis patients.
Li H, Ding L, Liao R … +4 more , Li N, Hong X, Jiang Z, Liu D
BMC Med Genomics · 2025 Dec · PMID 41437054 · Full text
BACKGROUND: Chromosomal structural variations (CSVs) that comprise multiple gene mutations are important determinants for multiple diseases. However, the relationship between CSVs, rheumatoid arthritis (RA), and lung can...
BACKGROUND: Chromosomal structural variations (CSVs) that comprise multiple gene mutations are important determinants for multiple diseases. However, the relationship between CSVs, rheumatoid arthritis (RA), and lung cancer is not well understood. MATERIALS AND METHODS: In this study, we analyzed CSV associations and differences between RA and RA with lung cancer (RA LC) using genome sequencing, with RA-associated interstitial lung disease (RA ILD) as a disease control. First, we analyzed the CSVs of each individual. Then, we identified common CSVs within each disease group and finally analyzed specific CSVs between different diseases. Gene Ontology/KEGG terms, canonical pathways, and feature gene sets were used for the functional annotation and analysis of CSV-related pathways. RESULTS: Cell size regulation and axon guidance were mutated in all disease groups. Protein deubiquitination was mutated in RA LC, while the negative regulation of extractable stroma and protein catabolism was mutated in RA ILD. Characterization of clinical data also revealed correlations with these specific pathways. CONCLUSION: This study identifies common and specific CSVs and associated pathways for RA, LC, and ILD, uncovering key genetic factors that provide new insights into their diagnosis and treatment.
A novel Bi-Allelic pathogenic MCOLN1 variant underlying mucolipidosis type IV in an Iranian family: clinical, genetic, and molecular dynamics-based structural analysis.
Mohsenipour M, Nejati P, Khosravi T … +4 more , Alimoradi E, Salehi M, Oladnabi M, Alibakhshi R
BMC Med Genomics · 2025 Dec · PMID 41430707 · Full text
BACKGROUND: Mucolipidosis type IV (MLIV) is a rare autosomal recessive lysosomal storage disorder due to biallelic pathogenic variants in the MCOLN1 gene. Its main impact is on the central nervous system, leading to seve...
BACKGROUND: Mucolipidosis type IV (MLIV) is a rare autosomal recessive lysosomal storage disorder due to biallelic pathogenic variants in the MCOLN1 gene. Its main impact is on the central nervous system, leading to severe psychomotor delays, progressive visual impairment, and characteristic brain abnormalities. METHODS: A 12-year-old male from a consanguineous Iranian family underwent clinical and imaging evaluations for suspected MLIV. Exome sequencing identified the causative variant, confirmed by Sanger co-segregation analysis, in silico tools assessed pathogenicity, protein stability, and structural impact, followed by 3D modeling (I-TASSER) and protein interaction analysis (STRING). Molecular dynamics simulations were performed with GROMACS 2020.4 employing the GROMOS96 43a1 force field to compare wild-type and mutant structures, evaluating key parameters, including root mean square deviation (RMSD), radius of gyration (Rg), hydrogen bond profiles, and solvent-accessible surface area (SASA), were analyzed, and results which were visualized using GraphPad Prism. RESULTS: Exome sequencing revealed a previously unreported homozygous nonsense variant in MCOLN1 (NM_020533.3: c.1384G > T; p.Glu462). This variant introduces a premature termination codon predicted to yield a truncated protein if translated; however, it is likely subject to nonsense-mediated mRNA decay, leading to transcript degradation and consequent loss of functional protein. Sanger sequencing confirmed the variant and its co-segregation within the family, with both parents heterozygous carriers and the patient homozygous. Bioinformatic analysis classified the variant as likely pathogenic, with high deleteriousness scores. Structural modeling indicated disruption of a helical domain. STRING analysis demonstrated strong functional associations between MCOLN1 and its paralogs MCOLN2 and MCOLN3, supporting its biological relevance. This variant expands the known spectrum of genetic causes of MLIV. CONCLUSION: We report the first Iranian case of MLIV due to a novel homozygous nonsense variant in MCOLN1 (c.1384G > T; p.Glu462*). These findings expand the spectrum of MLIV, underscore phenotypic variability and the value of population-specific genetic data in rare disease diagnostics, and support the inclusion of this variant in targeted diagnostic panels for Iranian patients.
Expanding the clinical phenotype of DYNC1H1 -associated mutations: a Chinese family with autosomal dominant complex hereditary spastic paraplegia.
Yuan X, Zhang S, Tang Y
BMC Med Genomics · 2025 Dec · PMID 41430681 · Full text
BACKGROUND: Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases. To date, at least 84 distinct loci (SPGs) and 67 causative genes have been identified....
BACKGROUND: Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases. To date, at least 84 distinct loci (SPGs) and 67 causative genes have been identified. Even though the number of known causative genes is constantly increasing, a substantial portion of patients remains without a molecular diagnosis. Variants in the dynein, cytoplasmic 1, heavy chain 1(DYNC1H1)gene have been reported to cause a range of neurogenetic diseases, including spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease (CMT), and cortical malformations. This study aims to characterize the clinical spectrum of DYNC1H1-related disorders by reporting a rare missense variant (c.13763 C > T, p.Thr4588Met) identified in a Chinese family with autosomal dominant (AD) complex HSP. METHODS: The affected individuals underwent a comprehensive neurological evaluation, including assessment of clinical features, laboratory testing, brain magnetic resonance imaging (MRI), and electrophysiological studies. The repetition/deletions in the SPAST, ATL1 gene were detected using multiplex ligation-dependent probe analysis (MLPA). Whole-exome sequencing (WES) was performed to identify the disease-causing mutation in the proband, which was subsequently validated by Sanger sequencing in the proband and his parents. In silico analysis was performed to predict the pathogenicity of the identified mutations. RESULTS: A heterozygous missense variant (c.13763 C > T, p.Thr4588Met) in the DYNC1H1 gene was identified, which was classified as likely pathogenic according to ACMG guidelines. The family was affected by autosomal dominant complex HSP, presenting with marked spastic paraplegia and ataxia. In silico analyses (e.g., using PolyPhen-2, PROVEAN, Mutation Taster, and CADD) indicated a deleterious effect on protein function. CONCLUSIONS: This study reports a rare DYNC1H1 variant associated with autosomal dominant (AD) complex HSP, expanding the mutational and phenotypic spectrum of DYNC1H1-related disorders.
Construction and verification of a prognostic model for prostate cancer based on ribosome biogenesis-related genes.
Xie J, Tang Y, Wang Y … +10 more , Gao X, Fu F, Liu Y, Yi C, Zhou G, Wang Z, Chen C, Jin P, Cai Y, Zhou J
BMC Med Genomics · 2025 Dec · PMID 41419859 · Full text
BACKGROUND: Prostate cancer (PCa) is a prevalent and often aggressive malignancy. While ribosome production is a critical process in numerous cancers, the role of ribosome biogenesis-related genes (RB-RGs) in PCa remains...
BACKGROUND: Prostate cancer (PCa) is a prevalent and often aggressive malignancy. While ribosome production is a critical process in numerous cancers, the role of ribosome biogenesis-related genes (RB-RGs) in PCa remains underexplored. Therefore, this study aims to examine the expression characteristics of RB-RGs as potential prognostic markers in PCa. METHODS: Transcriptomic data were obtained from public databases to pinpoint differentially expressed genes (DEGs) associated with PCa. Among these, DEGs that were also identified as regulatory genes were selected as candidate genes and subjected to regression analysis to determine those with prognostic significance. A prognostic risk model was then created and subjected to validation. A standalone prognostic evaluation was performed. Additionally, analyses for enrichment, immune infiltration, and drug prediction were conducted for both high- and low-risk PCa cohorts. Finally, the levels of the prognostic genes were validated through reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western Blot (WB). RESULTS: SMARCA4, FBLL1, RRS1, and NVL were selected as prognostic genes. A risk model, exhibited considerable precision in evaluating the risk of PCa. The risk score, in conjunction with the prostate-specific antigen (PSA) score and Gleason score, has been recognized as independent prognostic factors for PCa. Analysis of biological pathways indicated notable variations in pathways, especially the cell cycle, when comparing the high- and low-risk groups. The expression of prognostic genes demonstrated a correlation with the presence of 21 distinct types of immune cells, notably including type-17 T helper cells, within PCa samples. Furthermore, notable variations in the levels of target genes (AKT1, CDK1, HIF1A, NFKB1, SRC, and TRIM24) were detected between the high- and low-risk cohorts in relation to different chemotherapeutic agents. PCR analysis showed that NVL and SMARCA4 were significantly upregulated in PCa samples (p < 0.05), with no significant difference in RRS 1. WB analysis showed that SMARCA4, FBLL 1, and RRS1 and NVL were differently expressed in both PCa and Control, with higher upregulation in PCa than in the control group. CONCLUSION: Among RB-RGs, SMARCA4, FBLL1, RRS1 and NVL were identified as prognostic genes for PCa, thereby providing a new direction for clinical disease treatment.
Molecular surveillance of antimalarial drug resistance genes in Nigeria: a systematic review and roadmap to malaria elimination.
Bamikole OJ, Fayehun AF, Uthman YA … +4 more , Salako IA, Adedeji BA, Olufeagba MB, Amodu OK
BMC Med Genomics · 2025 Dec · PMID 41413906 · Full text
BACKGROUND: Malaria remains a significant public health challenge in Nigeria, accounting for a substantial proportion of global malaria cases and deaths. Although artemisinin-based combination therapies (ACTs) are the re...
BACKGROUND: Malaria remains a significant public health challenge in Nigeria, accounting for a substantial proportion of global malaria cases and deaths. Although artemisinin-based combination therapies (ACTs) are the recommended first-line treatments, resistance to antimalarial drugs continues to threaten malaria control efforts. This systematic review provides an overview of the molecular surveillance of antimalarial drug resistance in Nigeria, aiming to identify prevalent resistance markers and inform future research and policy directions. METHODS: A systematic search was conducted using databases including PubMed, ScienceDirect, Ovid and Scopus. Studies published from 2010 to 2024 and focused on key resistance markers such as Pfcrt, Pfmdr, Pfdhfr, Pfdhps, and Pfk13 genes were included. RESULTS: A total of 26 studies met the inclusion criteria, revealing a high overall prevalence of mutations associated with resistance to chloroquine and sulfadoxine-pyrimethamine, particularly in Pfcrt and Pfdhfr genes. Although mutations associated with artemisinin resistance in the Pfk13 gene were less common, their presence warrants attention for future surveillance. Within this overall pattern, regional disparities were evident, with generally lower Pfcrt prevalence in northern Nigeria compared to the south, though levels varied across locations and time periods. CONCLUSION: Regional variability in CQ resistance mutations has been observed across Nigeria, with lower prevalence in some northern states but persistence in others. CQ may be reconsidered as an alternative to ACTs only in areas where resistance remains consistently low, contingent upon clinical trials confirming efficacy and safety, and accompanied by molecular surveillance to guide targeted policy decisions.
Novel LRF/ZBTB7A variants and known HbF-modulating SNPs in transfusion-dependent β-thalassemia.
Arikan Y, Mercan TK, Embel M … +1 more , Kurtoglu E
BMC Med Genomics · 2025 Dec · PMID 41413825 · Full text
BACKGROUND: β-Thalassemia is a hereditary blood disorder with a highly variable clinical presentation that is partly influenced by genetic modifiers that regulate fetal hemoglobin levels. Elevated HbF can ameliorate the...
BACKGROUND: β-Thalassemia is a hereditary blood disorder with a highly variable clinical presentation that is partly influenced by genetic modifiers that regulate fetal hemoglobin levels. Elevated HbF can ameliorate the clinical symptoms of β-thalassemia, making the identification of HbF-modifying loci crucial for understanding disease variability and developing potential therapeutic strategies. METHODS: In this study, we evaluated the distribution and effect of known HbF-associated single nucleotide polymorphisms within the BCL11A, HMIP, and XmnI-HBG2 loci in β-thalassemia patients. Our investigation was initiated by a hypothesis based on genomic data from the K562 cell line, which indicated the presence of a specific LRF/ZBTB7A variant. In addition, we explored the role of LRF/ZBTB7A, a transcription factor implicated in globin gene regulation, through Sanger sequencing and in silico analyses. A hypothetical Genetic Modifier Score was devised to quantify the cumulative effect of the five major HbF-associated QTLs. RESULTS: While we confirmed the previously reported associations of the common SNPs with HbF levels, we also identified novel rare variants in LRF/ZBTB7A (p.Pro241Leu, p.Asp344Asp, p.Glu277del) that may influence HbF expression. XmnI-HBG2 accounted for a small yet significant proportion (7%) of HbF variability. A significant positive correlation was found between the Genetic Modifier Score and HbF levels, yet the model explained only ~ 14% of the variance, highlighting a substantial role for other modifiers such as the novel LRF/ZBTB7A variants identified here. CONCLUSIONS: These results suggest LRF/ZBTB7A is a novel modifier of HbF. The discovery of the variants, against a backdrop of modest QTL effects, underscores its potential and warrants further functional investigation.
Novel TRIP12 variants in two Lebanese patients with neurodevelopmental delay.
Khalifeh S, Makhoul NJ, Trad S … +4 more , Amro S, Siddik M, Bedran J, Boustany RM
BMC Med Genomics · 2025 Dec · PMID 41413819 · Full text
BACKGROUND: The TRIP12 gene, encoding an E3 ligase involved in the ubiquitin-proteasome pathway, is implicated in Clark-Baraitser syndrome which causes neurodevelopmental delay and intellectual disability (ID). This stud...
BACKGROUND: The TRIP12 gene, encoding an E3 ligase involved in the ubiquitin-proteasome pathway, is implicated in Clark-Baraitser syndrome which causes neurodevelopmental delay and intellectual disability (ID). This study aims to present and characterize two distinct novel TRIP12 variants in two unrelated Lebanese children with neurodevelopmental delay. METHODS: Exome sequencing (ES) was performed, followed by in silico assessment of variant impact on protein structure. Clinical and molecular findings were described. Literature review was carried out on previously published TRIP12 variants. RESULTS: Patients demonstrated hypotonia, speech and motor delay. ES uncovered a paternally inherited missense variant in the TRIP12 gene (c.5905T > A nucleotide substitution) in patient 1, and a de novo indel variant causing an in-frame change (c.4532_4538delinsC) in patient 2. Affected amino acids in both variants were highly conserved, and structural analyses of mutant variants suggested altered TRIP12 protein structure. No phenotypic distinction emerged in comparison to 70 published TRIP12 variants. CONCLUSION: This study introduces the first Lebanese TRIP12 variants in developmentally delayed patients. It expands the genotypic spectrum of TRIP12-related neurodevelopmental disorders and underscores their variable expressivity.
Heterogeneity study on MiRNA expression in islet cells of rat pancreatic head and tail.
Lu X, Liu Y, Chen J … +3 more , Huang P, Wang K, Han J
BMC Med Genomics · 2025 Dec · PMID 41413515 · Full text
BACKGROUND: As a vital endocrine organ, the pancreas exhibits differences in anatomical structure and microenvironment between its head and tail. However, whether there is heterogeneity in miRNA expression within the isl...
BACKGROUND: As a vital endocrine organ, the pancreas exhibits differences in anatomical structure and microenvironment between its head and tail. However, whether there is heterogeneity in miRNA expression within the islet cells of these two regions and what biological significance this heterogeneity may entail remain unclear. METHODS: This study utilized high-throughput sequencing to analyze the miRNA expression profiles in the islet cells from the pancreatic head and tail in rats. The TargetScan and miRDB databases were used to predict target genes of the differentially expressed miRNAs (DEmiRNAs). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were utilized to analyze the target genes. The key miRNA was verified by qRT-PCR. RESULT: A total of 445 miRNAs were detected in the islet cells of the pancreatic head and tail, among which 69 showed significant differences (|log2 fold change|>0.585 and P<0.05). Compared with the pancreatic tail, 28 miRNAs were upregulated and 41 miRNAs were downregulated in the pancreatic head. Bioinformatics analysis revealed that these target genes were significantly enriched in functions such as negative regulation of cellular process, anatomical structure development, intracellular organelle, pancreatic cancer, insulin resistance, MAPK signaling, Wnt signaling, and Hippo signaling. In addition, KEGG analysis of target genes showed that miR-124-3p was in several pathways, such as the insulin signaling pathway, endocrine resistance, small cell lung cancer, and other pathways in cancer. qRT-PCR results showed that miR-124-3p was significantly upregulated in the pancreatic head. CONCLUSIONS: Our findings provide novel insights into the heterogeneity of miRNA expression in the pancreas and the molecular mechanisms underlying pancreatic cancer, offering potential targets for future diagnostic and therapeutic strategies.
Biobank participants' perspectives on receiving genetic risk information from a biobank - the case of haemochromatosis.
Clancy J, Forstén J, Koskinen E … +4 more , Arvas M, Åberg F, Pitkänen K, Castrén J
BMC Med Genomics · 2025 Dec · PMID 41408552 · Full text
In the era of genomic medicine, utilizing genetic information in the concept of personalized medicine has become widely attractive. In addition to the large-scale population level data sets, professional, standardized an...
In the era of genomic medicine, utilizing genetic information in the concept of personalized medicine has become widely attractive. In addition to the large-scale population level data sets, professional, standardized and legislated operating environment of the biobanks has enabled their growing footprint in the field of personalized medicine. Moreover, the biobank participants in the Finnish Red Cross Blood Service (FRCBS) Biobank have expressed high willingness to receive information relevant to their health. In this study we screened the FRCBS Biobank genome data, N = 43,868, for HFE C282Y (+/+) genotype. Clinically verified results were returned to 82 biobank participants (0.19% of the total cohort). In addition, we conducted a survey on their experience on receiving genetic risk information from a biobank. We demonstrate a high occurrence of blood donors not being aware of their genetic risk, a relatively high penetrance of the HFE C282Y (+/+) and a clear acceptance of receiving genetic risk information from the biobank by the participants. We show how genetic information stored in a biobank can be used in a precisely defined context, such as blood donation. Further comprehensive studies are needed to fully understand the possibilities biobanks could offer in personalized medicine.
A case study of a novel homozygous EDAR splice site variant in hypohidrotic ectodermal dysplasia with tooth agenesis: molecular dynamics insights.
Nejati P, Khosravi T, Lorestani S … +1 more , Oladnabi M
BMC Med Genomics · 2025 Dec · PMID 41408253 · Full text
Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that can caused by mutations in the EDAR gene, which encodes the Ectodysplasin A receptor, leading to defective ectodermal structure development. This study i...
Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that can caused by mutations in the EDAR gene, which encodes the Ectodysplasin A receptor, leading to defective ectodermal structure development. This study investigates the molecular impact of a novel homozygous c.730 + 1G > T splice site variant in the EDAR gene, identified in a consanguineous Iranian family with HED. The 10-year-old proband presented with a classic, severe HED phenotype, including anhidrosis (impaired sweating) leading to recurrent hyperthermia, sparse hair, dry skin, and severe oligodontia with only three teeth present. Co-occurring thyroid dysfunction was also noted. To elucidate the variant’s predicted structural and functional consequences (likely exon 8 skipping), Molecular Dynamics (MD) simulations were performed over 50 ns, focusing on the EDAR protein’s conformational dynamics. The simulations revealed that the predicted variant-induced structural alteration leads to a more compact and rigid EDAR structure, significantly reducing its conformational flexibility. This structural change likely disrupts critical receptor interactions and downstream signaling, which are key factors in HED pathogenesis. These findings highlight the power of combining detailed clinical phenotyping with MD simulations in uncovering the precise molecular mechanisms underlying EDAR dysfunction in HED, expanding the mutational spectrum of the gene and supporting precise genetic diagnosis for improved clinical management.
Whole exome sequencing in pediatric hyperammonemia: significant diagnostic yield and identification of three novel variants.
Hajati R, Hashemian F, Salehpour S … +1 more , Sayad A
BMC Med Genomics · 2025 Dec · PMID 41402828 · Full text
BACKGROUND: Hyperammonemia, not a disorder, but an outcome of a disorder marked by elevated ammonia levels in the blood, is a serious medical condition that makes accurate diagnosis based on clinical and laboratory findi...
BACKGROUND: Hyperammonemia, not a disorder, but an outcome of a disorder marked by elevated ammonia levels in the blood, is a serious medical condition that makes accurate diagnosis based on clinical and laboratory findings challenging. In this scenario, employing advanced genetic tests like whole exome sequencing can provide crucial insights that help clinicians better manage the disease. Also, identifying disease-causing variants provides conditions for genetic counseling and subsequent preventive measures, including prenatal diagnosis. METHODS: This study was conducted at the Comprehensive Genetic Services Center (CGSC) of Shahid Beheshti University of Medical Sciences (SBMU), Iran, from 2020 to 2024, involving 20 pediatric patients with clinically suspected hyperammonemia due to inborn errors of metabolism (IEMs). All patients underwent biochemical testing, including plasma amino acid (PAA). Whole-exome sequencing (WES) was performed for molecular diagnosis, and identified variants were interpreted according to ACMG/AMP guidelines. The identified variants were confirmed by Sanger sequencing in all the probands. No additional in vitro functional assays were performed. RESULTS: Among the twelve genetically confirmed cases, pathogenic or likely pathogenic variants were identified in genes related to urea cycle disorders (CPS1, OTC, ASS1), organic acidemias (MMUT, PCCB, HMGCL), amino acid transport defects (SLC7A7), and mitochondrial disorders (PDHA1). Patients with CPS1 variants (P2 and P3) presented with hyperammonemia, seizures, and developmental delay, with distinct biochemical profiles reflecting different degrees of enzyme deficiency. The patient with MMUT variant (P10) showed marked metabolic acidosis, consistent with methylmalonic aciduria. Variants in OTC (P4, P5) and ASS1 (P6) were associated with urea cycle dysfunction with hyperammonemia, but the elevated plasma citrulline level was a significant biochemical finding in the patient (P6). Patients with HMGCL (P7), SLC7A7 (P8), and PCCB (P11) variants exhibited organic aciduria patterns compatible with their respective enzymatic defects. In addition, a hemizygous variant in PDHA1 (P12) was identified in a male patient with increased lactate and microcephaly. Detailed clinical, biochemical, and molecular features of all confirmed cases are summarized in Table 3. CONCLUSION: This study highlights the efficacy of whole exome sequencing in diagnosing genetically heterogeneous conditions like hyperammonemia, with implications for treatment optimization and genetic counseling. The identification of novel variants enhances understanding of the genetic landscape in populations with high rates of consanguinity. Future research should focus on expanding genetic databases and exploring the functional impacts of newly discovered variants.
Genomic surveillance and phylo-evolutionary analysis of SARS-CoV-2 variants in Osun state, Nigeria during the second wave of COVID-19 pandemic.
Akinde SB, Oyedara OO, Olumakinde TS … +18 more , Olaniyan OP, Adeyemi FM, Bolarinwa RA, Adeagbo OY, Oluokun TE, Sule WF, Ojo OO, Iwalokun BA, Fajoyegbe ES, Oladipo EK, Oluwayelu DO, Wahab AA, Durosomo HA, Ajani TF, Adebunmi AA, Olayode O, Obire O, Olaitan JO
BMC Med Genomics · 2025 Dec · PMID 41390807 · Full text
BACKGROUND: SARS-CoV-2 genome sequencing, genomic characterization, and global data sharing are recommended to facilitate countermeasures against COVID-19. This study involved whole genome sequencing and phylo-evolutiona...
BACKGROUND: SARS-CoV-2 genome sequencing, genomic characterization, and global data sharing are recommended to facilitate countermeasures against COVID-19. This study involved whole genome sequencing and phylo-evolutionay analysis of SARS-CoV-2 variants circulating in Osun State, Nigeria between January and June, 2021. METHODS: In the present retrospective, molecular epidemiologic study, a total of 60 nasopharyngeal samples from RT-qPCR-positive COVID-19 patients originating from eight study locations were analyzed. This was done using RNA extraction application of the McKinsey Global Institute’s (MGI) DNBSEQ-G50RS high-throughput genome Sequencing Technology and Bioinformatics Analysis Pipeline. Quantitative data were analyzed with descriptive and inferential statistics. RESULTS: Forty-five SARS-CoV-2 (45/60) whole genome sequences (WGSs) were successfully analyzed with participants being mostly male adults (64.4%) and a median age of 44 years. Five PANGO lineages including: B (35.6%), B.1.525 (31.1%), B.1.1.7 (28.9%), B.1 (2.2%), and L.3 (2.2%) were identified, with Eta VOI (14/45) and Alpha VOC (13/45) as the dominant variants. A total of 29/45 of these genomes exhibited amino acid (aa) substitutions in the viral spike (S) protein, totaling 275 substitutions. Six of these genome sequences carried key mutations, including H69del, V70del, Y144del, D614G, N501Y, A570D, P681H, T716I, and Q677H. These mutations are known to influence SARS-CoV-2 transmissibility, virulence, and potential resistance to neutralization by vaccine-induced antibodies/convalescent sera. Phylo-evolutionary analysis revealed three distinct clusters, 16 sequences from Lineage B clustered closely with the reference Wuhan-Hu-1 strain (NC_045512.2). Notably, 19 of our WGSs showed genomic relatedness to SARS-CoV-2 strains from other regions of Nigeria, as well as, from West/other African countries, including Egypt, Senegal, Morocco and South Africa. The single L.3 lineage reported clustered with strains from Nigeria and Benin. CONCLUSIONS: These evidences suggest inbound or outbound transmission of the dominant Eta and Alpha variants. The study highlights the dominance of Eta VOIs and Alpha VOCs during the second COVID-19 wave in Osun State, Nigeria, suggesting potential inbound and outbound spread of the virus between other states in Nigeria and other African countries. The general absence of severe illness (except for four participants with shortness of breath) among study participants may indicate a protective effect of post-exposure immune response; however, underreporting of severe cases cannot be ruled out as a potential contributing factor.
Constructing anoikis-related signatures in glioma and identifying PLAU as a new prognostic biomarker.
Tong H, Zhang A, Tan R … +7 more , Tan W, Shi Y, Zhu S, Zhang Z, Qiao D, Liu L, Zhao Z
BMC Med Genomics · 2025 Dec · PMID 41390410 · Full text
BACKGROUND: Glioma, the most common aggressive tumor found in the central nervous system, is linked to a poor prognosis. Anoikis is a form of cell death that arises from the detachment of cells. Disruption of the anoikis...
BACKGROUND: Glioma, the most common aggressive tumor found in the central nervous system, is linked to a poor prognosis. Anoikis is a form of cell death that arises from the detachment of cells. Disruption of the anoikis pathway can facilitate the survival and dispersal of cancer cells from the primary tumor site, thus playing a critical role in the spread and advancement of cancer. The process of Epithelial-to-mesenchymal transition (EMT) is crucial in the progression and spread of cancer, where epithelial cells undergo a loss of polarity and adhesion, transitioning into mesenchymal cells with heightened capability for invasion and metastasis. However, there is a dearth of research examining the mechanism of anoikis and its correlation with the EMT process in glioma. METHODS: In our study, data was extracted from 1317 samples of glioma for comparative examination. Through the utilization of 28 genes associated with resistance to cell detachment, we aimed to distinguish various categories of glioma patients by evaluating the immune environment and pathways of enrichment within the two subgroups. By implementing diverse statistical methodologies such as COX regression analysis and the least absolute shrinkage and selection operator regression, we developed a risk scoring system to categorize glioma patients into cohorts of high and low risk. The clinical features, infiltration of immune cells, and responsiveness to drugs were thoroughly investigated for both categories, highlighting distinctions across various domains. Moreover, our investigation encompassed in vitro trials to assess the function and expression of the pivotal gene, PLAU. RESULTS: The differences in prognoses, immune status, and drug sensitivities between high-risk and low-risk groups highlight the need for personalized treatment approaches in glioma patients. By integrating risk scores with clinicopathological characteristics, a nomogram was created to better predict patient outcomes and guide treatment decisions. The nomogram demonstrated its usefulness through decision curve analysis, showing potential benefits for enhancing clinical strategies in glioma management. In cell experiments, targeting Plasminogen activator urokinase (PLAU)led to a notable decrease in the growth, spread, and movement abilities of T98G and U251 cell lines, as well as blocking the epithelial-mesenchymal transition process. CONCLUSION: The study we conducted establishes the groundwork for comprehending the function of anoikis genes in glioma, and recognizes PLAU as a potential biomarker for glioma.
A pathway-informed mutual exclusivity framework to detect genetic interactions in pediatric cancer.
Spinou A, Gremmen R, Drost J … +1 more , Kemmeren P
BMC Med Genomics · 2025 Dec · PMID 41388546 · Full text
BACKGROUND: The exponential increase of sequenced cancer genomes has enabled the in-silico study of genetic interactions in tumors across many cancer types—particularly synthetic lethality, where two gene alterations lea...
BACKGROUND: The exponential increase of sequenced cancer genomes has enabled the in-silico study of genetic interactions in tumors across many cancer types—particularly synthetic lethality, where two gene alterations lead to cell death—and identify new candidate therapeutic targets. This rise is primarily present in adult cancer, while in-silico investigation of genetic interactions remains challenging in pediatric cancer especially in tumors of low incidence. Consequently, this underscores the need for specialized approaches to advance our understanding of genetic interactions in pediatric oncology. METHODS: Here, we present the pathway-informed genetic interaction framework (PIGI) that employs mutual exclusivity and co-occurrence testing and leverages biological pathways to infer candidate genetic interactions. Pathways facilitate the detection of hidden biology by grouping genes affected by single nucleotide variants or small indels in functional units, as well as alleviate key confounders of these analyses: pathway epistasis and cancer subtypes—thereby highlighting genes of greater interest. RESULTS: PIGI detected candidate genetic interactions by assessing pathway mutual exclusivity and co-occurrence in two primary pediatric cancer datasets, DKFZ and TARGET. PIGI detected, from high significance pathway relationships, 35 mutually exclusive and 2 co-occurring mutated gene pairs. The already known mutually exclusive gene pair of TP53-DROSHA is detected in the much smaller collection of the DKFZ Wilms tumors. Over half of the identified gene pairs represent new discoveries that have not been previously described in the literature. Four of them could be promising candidates for synthetic lethal genetic interactions. CONCLUSION: These findings highlight the benefits of genetic interactions inference by exploring a different aspect of pediatric cancer data through pathways and propose new gene pairs for follow-up synthetic lethality experimentation.
Sex differences in progressive multiple sclerosis brain gene expression in oligodendrocytes and OPCs.
LaBarre BA, King D, Ploumakis A … +4 more , Pinzon AM, Guttmann CRG, Patsopoulos N, Chitnis T
BMC Med Genomics · 2025 Dec · PMID 41388417 · Full text
Multiple sclerosis is a neurological autoimmune disease with sex-imbalanced incidence; in the USA, the disease is more likely to affect females at a ratio of 3:1. In addition, males are more likely to have a more severe...
Multiple sclerosis is a neurological autoimmune disease with sex-imbalanced incidence; in the USA, the disease is more likely to affect females at a ratio of 3:1. In addition, males are more likely to have a more severe disease course at time of diagnosis. Questions about both causes and downstream effects of this disparity remain. We aim to investigate gene expression differences at a cellular level while considering sex to discover fine-scale sex disparities. These investigations could provide new avenues for treatment targeting, or treatment planning based on sex.Public single-nuclei RNA-sequencing data from three publications of progressive MS including control brains were analysed using the Seurat R package. Differential gene and pathway expression was looked at both within a specific data set which has sub-lesion level sample dissection and across all studies to provide a broader lens. This allowed for the consideration of cell types and spatial positioning in relation to the interrogated lesion in some of the calculations.Our analysis showed expression changes in the female MS oligodendrocytes and oligodendrocyte progenitor cells compared to healthy controls, which were not observed in the corresponding male affected cells. Differentially up-regulated genes in females include increased HLA-A in the oligodendrocytes, and increased clusterin in the oligodendrocyte progenitor cells. There are also several mitochondrial genes in both the oligodendrocytes and oligodendrocyte progenitors which are up-regulated in females, including several directly involved in electron transport and which have previously been associated with neurodegenerative diseases.These results point to altered states in oligodendrocyte progenitors and oligodendrocytes that in combination with known physiological dissimilarities between sexes may denote different programming in males and females in response to the onset of demyelinating lesions. The potential for increased debris clearance mediated by clusterin and availability of oligodendrocyte progenitors in females may indicate an environment more primed for repair, potentially including remyelination. This could contribute to the disparity in etiology in females versus males.
RANK hypomethylation is associated with primary osteoporosis in elderly men in Xinjiang: a case-control study.
Maimaitiwusiman Z, Shang J, Xiang H … +3 more , Bai X, Halan B, Wang H
BMC Med Genomics · 2025 Dec · PMID 41372879 · Full text
BACKGROUND: RANK is a candidate gene for osteoporosis based on both functional and genetic mechanisms. This study investigated the association between RANK methylation and osteoporosis among community-dwelling elderly pe...
BACKGROUND: RANK is a candidate gene for osteoporosis based on both functional and genetic mechanisms. This study investigated the association between RANK methylation and osteoporosis among community-dwelling elderly people in Xinjiang, China. METHODS: This case-control study was based on an epidemiological investigation. Initially, methylated cytosine-rich cytosine phosphate-guanine sites (CpGs) were identified within the RANK promoter region using a screening cohort. Subsequently, selected CpGs were detected via bisulfite sequencing in the primary cohort comprising 90 elderly men (47 with osteoporosis and 43 without). Finally, the correlations between osteoporosis and the methylation rates of the identified CpGs were assessed. RESULTS: Age and prevalence of diabetes differed significantly between individuals with and without osteoporosis (P = 0.025 and P = 0.005, respectively), while other factors showed no statistically significant differences between the case and control groups (P > 0.05). The RANK methylation rate was significantly higher in the control group than in the osteoporosis group (P < 0.001). Furthermore, after covariance analysis to adjust for age, smoking, drinking, and diabetes, a significantly higher RANK methylation rate was observed in control individuals versus those with osteoporosis among elderly men from Xinjiang (P = 0.001). Multivariate logistic regression analysis, adjusted for confounding factors (age, smoking, alcohol consumption, and diabetes), further demonstrated that RANK hypomethylation was significantly associated with osteoporosis (odds ratio = 0.310, 95% confidence interval: 0.886–0.976). CONCLUSIONS: RANK hypomethylation shows a significant association with osteoporosis in elderly male residents in Xinjiang communities. These results support that RANK hypomethylation may play a role in the pathogenesis of osteoporosis.
Genotypic and haplotype analysis of SOCS3 gene polymorphisms (rs4969169, rs12953258, rs1061489) in association with clinicopathological factors in breast cancer.
Alipeddi RR, Padala C, Puranam K … +5 more , Ulaganathan K, Neeharika RD, Sampanmudumby P, Chinta SK, Hanumanth SR
BMC Med Genomics · 2025 Dec · PMID 41372779 · Full text
BACKGROUND: Breast cancer (BC) is the most common malignancy diagnosed among women worldwide. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a critical role in regula...
BACKGROUND: Breast cancer (BC) is the most common malignancy diagnosed among women worldwide. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a critical role in regulating cellular differentiation, maturation, proliferation, and apoptosis across various cell types involved in cancer initiation and progression. The suppressor of cytokine signaling 3 (SOCS3) acts as a key negative regulator of the JAK/STAT pathway. Therefore, investigating the role of single nucleotide polymorphisms (SNPs) in the SOCS3 gene is essential to better understand their contribution to the pathogenesis of breast cancer. METHODS: This case-control study included 300 female patients with breast cancer and 300 healthy female volunteers as controls. Ethical approval was obtained from the Institutional Ethics Committee prior to the commencement of study and was in compliance with the Helsinki Declaration. Written informed consent was obtained from all participants. Three SOCS3 SNPs-rs4969169 (C > T), rs12953258 (C > A), and rs1061489 (G > A)-were genotyped using Polymerase chain reaction-Restriction fragment length Polymorphism and Amplification refractory mutation system-PCR methods. Genotypic distributions, allele frequencies, and haplotype associations were analyzed, with statistical significance set at p < 0.05. RESULTS: The TT genotype and T allele of rs4969169 (C > T) conferred 4.29-fold and 2.16-fold increased risk, respectively, for breast cancer. Similarly, the CA genotype and A allele of rs12953258 (C > A) were associated with 1.95-fold and 2.02-fold increased risk, while the GA genotype and A allele of rs1061489 (G > A) conferred 4.58-fold and 3.87-fold increased risk, respectively. Haplotype analysis revealed significant associations with advanced disease stage, lymph node involvement, lobular carcinoma, and negative receptor status for ER, PR, and HER2/neu. The T-C-G, C-A-G, C-C-A, and T-C-A haplotypes conferred 2.18-, 2.64-, 3.65-, and 13.66-fold increased risk, respectively, for breast cancer development. CONCLUSION: Therefore, our study results suggest the significance of genotypic and haplotype analysis of SOCS3 gene polymorphisms and its impact on progression and risk prediction of breast cancer.
Hair follicle gene expression profiling in the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS).
Buschur KL, Martorella M, Garcia-Flores R … +18 more , Smith BM, Ziosi M, Barjaktarevic I, Bleecker ER, Christenson SA, Comellas AP, Criner GJ, Dransfield MT, Hansel NN, Kaner RJ, Krishnan JA, Meyers DA, Oelsner EC, Ortega VE, Paine R, Woodruff PG, Barr RG, Lappalainen T
BMC Med Genomics · 2025 Dec · PMID 41366429 · Full text
BACKGROUND: Transcriptomic analysis is common in large cohort studies but is generally restricted to cells in blood, which limits inferences about organs of interest, and direct organ sampling is mostly infeasible in lar...
BACKGROUND: Transcriptomic analysis is common in large cohort studies but is generally restricted to cells in blood, which limits inferences about organs of interest, and direct organ sampling is mostly infeasible in large cohorts. New techniques for RNA-seq from noninvasive biosamples may provide the opportunity to profile transcriptomes of additional tissues for more organ-relevant insights at scale. We investigated the feasibility and utility of hair follicle gene expression profiling in a multi-center study of chronic obstructive pulmonary disease (COPD). METHODS: Bulk RNA-seq was performed on hair follicles collected in the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS), a multi-center longitudinal study of COPD (n = 97). The resulting hair follicle gene expression data were characterized and compared both to gene expression in whole blood and bronchial epithelium previously measured in SPIROMICS and to Genotype-Tissue Expression (GTEx) project tissue gene expression by principal component analysis and single-sample gene enrichment analysis, used to estimate hair follicle cell type proportions, and tested for association with disease-relevant lung phenotypes. eQTL discovery was also performed and colocalization with a genome-wide association study for lung function was tested. RESULTS: Hair follicles reliably produced transcriptomic data of sufficient quality and number for cell type composition, which revealed mostly epithelial and fibroblast cells. Comparison to other tissues previously profiled in SPIROMICS and GTEx project demonstrated transcriptomes from hair follicles were much more similar to those from lung parenchyma than blood. Combining these data with rich clinical, imaging, and genomic profiling in SPIROMICS, we found that they provided an attractive approach for discovery of associations with complex lung phenotypes, particularly of the airways. Finally, we investigated hair follicle genetic architecture through expression quantitative trait locus (eQTL) discovery and demonstrated better colocalization with lung-related genetic associations than blood. CONCLUSION: Here, we demonstrated that RNA-seq applied to hair follicle transcriptomic profiling can be scaled up successfully in a multi-center study to yield inferences not available from blood transcriptomics.
Systematic annotation and analysis of susceptibility genes associated with vaccine adverse events.
Song Q, Su J, Pan C … +4 more , Zhang X, Yang B, He Y, Xie J
BMC Med Genomics · 2025 Dec · PMID 41361427 · Full text
Susceptibility genes, including single-nucleotide polymorphisms (SNPs) in the DNA sequences, genetically predispose certain individuals to developing adverse events (AEs) following vaccination. Such AEs are often undetec...
Susceptibility genes, including single-nucleotide polymorphisms (SNPs) in the DNA sequences, genetically predispose certain individuals to developing adverse events (AEs) following vaccination. Such AEs are often undetected in initial clinical safety trials during vaccine licensing evaluations. Therefore, a comprehensive understanding of susceptibility genes is crucial for vaccine development, safety monitoring, and precision immunization. VaegenDB is a web-based centralized database and analysis system designed for managing, storing, and analyzing susceptibility genes associated with vaccine AEs. Basic information on these genes and supporting evidence are curated from peer-reviewed literature, while more detailed gene, AE, and vaccine data are automatically extracted from existing databases such as RefSeq and VIOLIN using in-house scripts. Currently, VaegenDB contains information on 160 susceptibility genes linked to 151 AEs and 86 vaccines. The system offers a user-friendly web interface that enables interactive querying and visualization of susceptibility genes. Bioinformatics analyses using VaegenDB reveal that a single susceptibility gene may harbor multiple genetic variations, one vaccine can be associated with several AEs, and a single AE may be influenced by multiple genes or SNPs. In addition, KEGG and GO enrichment analyses were employed to identify gene signatures-including functional annotations, mutation types, and expression patterns-associated with adverse reactions. The construction of this database and subsequent bioinformatics analyses help clarify enriched gene profiles and underlying mechanisms of vaccine-related AEs, thereby supporting rational vaccine design and advances in precision medicine.
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