BMC Medical Genomics[JOURNAL]
Sun
200 papers
Role of gut microbiota metabolites against vein graft restenosis: insights from network pharmacology, molecular docking and molecular dynamic simulation.
Li Z, Liu X, Bai Y … +2 more , Bai Y, Guo Z
BMC Med Genomics · 2025 Dec · PMID 41361311 · Full text
BACKGROUND: Gut microbiota metabolites are increasingly recognized for their role in modulating chronic disease progression. However, their potential impact on vein graft restenosis (VGR) remains unexplored. This study a...
BACKGROUND: Gut microbiota metabolites are increasingly recognized for their role in modulating chronic disease progression. However, their potential impact on vein graft restenosis (VGR) remains unexplored. This study aimed to elucidate the mechanisms by which gut microbiota and its metabolites attenuate VGR using an integrated approach of network pharmacology, molecular docking, and molecular dynamics (MD) simulations. METHODS: Gut microbiota, metabolites, and human gut targets were obtained from the gutMGene database. Metabolite targets were predicted using SwissTargetPrediction and Similarity Ensemble Approach, while disease targets were collected from GeneCards, Online Mendelian Inheritance in Man (OMIM), and DrugBank. Overlapping targets were used to construct both a protein-protein interaction (PPI) network and a gut microbiota–metabolites–targets–VGR (GM-M-T-V) network to identify key microbiota, core metabolites, and hub targets. Enrichment analysis investigated associated biological processes, cellular components, molecular functions, and signaling pathways. Drug-likeness and toxicity were evaluated with SwissADME and ADMETlab 2.0. Molecular docking and MD simulations assessed the binding affinity and dynamic characteristics of target-metabolite complexes. RESULTS: Integrated data from relevant databases identified 260 gut microbiota, 251 metabolites, 404 metabolite targets, 238 human gut targets, and 741 VGR-related targets. Among these, 16 overlapping targets were identified for further analysis. Enrichment analysis highlighted significant involvement of the relaxin signaling pathway, while PPI topology analysis pinpointed AKT1, NFKB1, EGFR, PTGS2, and PPARG as hub targets. Quercetin was prioritized as the core metabolite based on its top network connectivity, favorable drug-likeness prediction, and manageable in silico-predicted hepatotoxicity/genotoxicity risks in light of its absent clinical toxicity. Molecular docking revealed that quercetin bound to four hub targets (AKT1, NFKB1, EGFR, PPARG) with affinities (ranging from−6.0 to−8.9 kcal/mol) comparable or superior to positive controls. MD simulations further suggested favorable structural stability and binding affinity of the EGFR–quercetin complex. CONCLUSION: This integrative study elucidates the role of gut microbiota metabolites against VGR, identifying the microbial metabolite quercetin as a promising multi-target therapeutic agent primarily via the relaxin signaling pathway, which provides a mechanistic groundwork for a novel potential treatment strategy.
The rs34416841 polymorphism in the Alu element of the circSirt1 flanking intron is associated with an increased risk of myocardial infarction.
Zhou YL, Yang WC, Liao ZF … +7 more , Zheng SR, Qu YF, Li H, Mo HL, Xie YT, Wu ZG, Xiong XD
BMC Med Genomics · 2025 Dec · PMID 41353146 · Full text
BACKGROUND: circSirt1 can ameliorate neointimal hyperplasia and provide protection against atherosclerosis. Single nucleotide polymorphisms (SNPs) in circRNA flanking introns, particularly within Alu elements, may alter...
BACKGROUND: circSirt1 can ameliorate neointimal hyperplasia and provide protection against atherosclerosis. Single nucleotide polymorphisms (SNPs) in circRNA flanking introns, particularly within Alu elements, may alter back-splicing and influence circRNA formation efficiency. To investigate the association between polymorphisms in the circSirt1 flanking introns and susceptibility to myocardial infarction (MI), we performed a case-control study. METHODS: This study included 541 coronary artery disease (CAD) cases and 278 controls. Four SNPs (including rs33957861, rs2273773, rs145758730, and rs34416841 in circSirt1 gene) genotyping was conducted utilizing the polymerase chain reaction-ligation detection reaction (PCR-LDR) technique. The associations of these SNPs with the susceptibility were analyzed using multivariate logistic regression, and the haplotype analysis was performed using SHEsis software. RESULTS: The data showed the C allele of rs34416841 was significantly associated with an increased risk of MI (adjusted OR = 1.65, 95% CI = 1.07–2.56, P = 0.024). Consistent trends were observed in co-dominant (OR = 1.70, 95% CI = 1.04–2.77, P = 0.034) and dominant models (OR = 1.73, 95% CI = 1.07–2.79, P = 0.025). Notably, the C allele of rs34416841 specifically increased progression risk from stable CAD to MI (OR = 1.62, 95%CI:1.09–2.42, P = 0.018). Stratified analyses demonstrated stronger associations among younger individuals (≤ 60 years), males, smokers, non-drinkers and hypertension subjects. Consistent with these results, the C-T-C-G haplotype containing rs34416841C allele was also associated with increased MI risk (OR = 1.43, 95% CI = 1.03-2.00, P = 0.035). However, no statistically significant association was observed between the rs34416841 polymorphism and CAD risk across all tested genetic models. CONCLUSION: The rs34416841 polymorphism, located within an Alu element in the flanking intron of circSirt1, demonstrates significant associations with both MI susceptibility and CAD progression in the Han Chinese population.
Prenatal therapies: a Points to Consider framework for responsible innovation.
Meslin EM, Kant C, Mazzuri S … +1 more , Knoppers BM
BMC Med Genomics · 2025 Dec · PMID 41345937 · Full text
Prenatal therapies represent an emerging frontier in healthcare, enabling medical intervention at the fetal stage to address severe congenital conditions before irreversible harm occurs. As these transformative intervent...
Prenatal therapies represent an emerging frontier in healthcare, enabling medical intervention at the fetal stage to address severe congenital conditions before irreversible harm occurs. As these transformative interventions transition from bench to bedside, significant ethical, legal, and governance challenges arise, particularly concerning maternal-fetal risk-benefit dynamics, informed consent, and regulatory oversight. Recognizing the need for structured and adaptive ethical guidance, we propose a “Points to Consider” (P2C) Framework, developed through a multidisciplinary initiative involving experts in drug development, bioethics norms, human rights, and governance, based on a review of international scientific, regulatory, and ethical literature. The P2C integrates those considerations into nine thematic points addressing: maternal and fetal well-being; risk-benefit assessment, responsible research and clinical care, emerging technology, public engagement, funding sustainability, public health integration, lifecycle governance, and international collaboration. The P2C is designed to support the entire research-to-clinic continuum, fostering multidisciplinary global dialogue. By anchoring prenatal therapeutic innovations within international human rights norms, bioethics standards, and anticipatory governance practices, the P2C aims to ensure that future interventions are safe, ethically robust, and socially aligned. This initiative lays the groundwork for responsibly navigating the complex ethical landscape of prenatal medicine, with implications for policy, clinical practice, and global health equity.
Evaluating variants of uncertain significance in adult zebrafish via prime editing: a proof of concept with a COL1A2 variant.
Vanhooydonck M, Debaenst S, Vanbelleghem E … +6 more , De Saffel H, Syx D, Sips P, Coucke PJ, Willaert A, Callewaert B
BMC Med Genomics · 2025 Dec · PMID 41331565 · Full text
Genomic variants of uncertain significance (VUS) impede clinical decision-making. In this study, we employ a knock-in strategy in zebrafish to evaluate the COL1A2 c.2123G>A VUS, identified in a 78-year-old female with at...
Genomic variants of uncertain significance (VUS) impede clinical decision-making. In this study, we employ a knock-in strategy in zebrafish to evaluate the COL1A2 c.2123G>A VUS, identified in a 78-year-old female with atypical femoral fractures. Using prime editing, we generated different col1a2 zebrafish lines respectively harboring the VUS, a known pathogenic variant, and a known benign variant. Comprehensive skeletal phenotyping revealed no significant abnormalities in zebrafish harboring the VUS. In contrast, zebrafish with the pathogenic variant showed an increased eye diameter, scoliosis, vertebral fusions, vertebral compressions, fractures, and increased mineralization of the notochord and intervertebral ligament compared to wild type controls. Our findings represent the first demonstration that COL1A2 variant modeling via prime editing in zebrafish not only aids in functional validation, but also holds promise for uncovering the underlying pathogenic mechanisms. This approach can be applied to investigate VUS in other genes as well.
Identification of hub genes contributing to acute eczema using transcriptome sequencing and machine-learning approaches.
Zhao Y, Wang W, Li X … +2 more , Ye X, Han X
BMC Med Genomics · 2025 Dec · PMID 41327289 · Full text
BACKGROUND: Acute eczema (AE) is a multifactorial inflammatory skin disease with complex immune dysregulation. The identification of key pathogenic genes may provide novel biomarkers and therapeutic targets. METHODS: An...
BACKGROUND: Acute eczema (AE) is a multifactorial inflammatory skin disease with complex immune dysregulation. The identification of key pathogenic genes may provide novel biomarkers and therapeutic targets. METHODS: An AE rat model was induced using DNCB. Transcriptome sequencing was performed on skin lesions, and differentially expressed genes (DEGs) were identified via DESeq2. Weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network construction, functional enrichment, and "Friends" analysis were applied to screen hub genes. Multiple machine learning algorithms, including LASSO, support vector machine (SVM), and random forest (RF), were integrated for candidate selection. Quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry were used for validation. RESULTS: A total of 1717 DEGs (1190 upregulated, 527 downregulated) were identified. WGCNA and PPI analysis yielded 36 hub genes enriched in immune and inflammatory pathways, particularly Th1/Th2/Th17 differentiation, JAK-STAT, and PI3K-Akt signaling. Cross-validation by machine learning highlighted Icam1 as a top candidate. Experimental assays confirmed significant upregulation of ICAM-1 at mRNA and protein levels in AE lesions compared with controls. CONCLUSION: Icam1 is a key gene potentially driving inflammatory infiltration in AE and may serve as a diagnostic target. This integrative bioinformatics-experimental approach provides a robust framework for discovering pathogenic genes in inflammatory skin diseases.
Limited value of Nanopore adaptive sampling in a long-read metagenomic profiling workflow of clinical sputum samples.
Xu W, Top J, Viveen MC … +7 more , Slyzkyi A, Hermans N, van Erp S, Eiloz D, Anthony R, Kremer K, Schürch AC
BMC Med Genomics · 2025 Dec · PMID 41327286 · Full text
BACKGROUND: Oxford Nanopore adaptive sampling (NAS) is a method by which the long-read sequencing flowcell accepts or rejects DNA molecules that are actively being sequenced based on their initial ~ 500 bp sequences, sel...
BACKGROUND: Oxford Nanopore adaptive sampling (NAS) is a method by which the long-read sequencing flowcell accepts or rejects DNA molecules that are actively being sequenced based on their initial ~ 500 bp sequences, selectively increasing target data output. NAS promises up to 5-10 × enrichment of target sequencing yield without additional sample preparation, but this optimal performance is dependent on ideal sample parameters which may be difficult to achieve under many real-world use-cases. We evaluated the use of NAS for profiling clinical sputum metagenomes. METHODS: We sequenced DNA extracted from clinical sputa and spike-in controls of a mock community of bacterial respiratory pathogens, using the current R10.4.1 MinION flowcell chemistry. RESULTS: We achieved at best 3.1 × enrichment of bacterial sequence output with NAS due to the shorter read lengths (~ 2.5 kb) from the PCR amplification necessary to compensate for low DNA extraction yields. More critically, we encountered rapid pore loss during our runs that reduced total sequencing yield by an estimated 80%. We were unable to mitigate the pore loss despite extensive attempts to reduce contaminant carry-over, and we could not determine its cause but ruled out NAS and pore underloading as contributing factors. CONCLUSIONS: We conclude that the utility of NAS is often limited by the characteristics of the metagenomic sample studied, and that the factors contributing to pore loss need to be resolved before ONT sequencing can be reliably applied to long-read metagenomics.
Prenatally diagnosed chromosome 1p36 deletions: a retrospective case series, literature review, and genotype-phenotype correlations.
Liu N, Liu Z, Yi S … +2 more , Li M, Cai H
BMC Med Genomics · 2025 Dec · PMID 41327254 · Full text
BACKGROUND: Chromosome 1p36 deletion syndrome is the most common terminal autosomal deletion disorder. While postnatal features are well-defined, prenatal characterization remains less comprehensive. This study aims to d...
BACKGROUND: Chromosome 1p36 deletion syndrome is the most common terminal autosomal deletion disorder. While postnatal features are well-defined, prenatal characterization remains less comprehensive. This study aims to delineate the prenatal sonographic and genetic spectrum of this syndrome and explore genotype-phenotype correlations. METHODS: A retrospective analysis was conducted on 21 consecutive prenatally diagnosed cases of 1p36 deletion (2017–2025) from a single tertiary center. Data on maternal demographics, ultrasound findings, genetic results, inheritance patterns, and pregnancy outcomes were collected. A pooled analysis included 10 isolated cases (with complete ultrasound data) from our cohort and 33 previously reported cases. RESULTS: The cohort demonstrated a strong female predominance (71.4%, 15/21). Fifteen (71.4%) involved isolated 1p36 deletions, while six (28.6%) exhibited additional chromosomal aberrations. Pooled analysis of 43 prenatally diagnosed isolated cases (10 current and 33 published) revealed brain anomalies to be the most common prenatal feature (58.1%, 25/43), with ventriculomegaly (37.2%, 16/43), corpus callosum hypoplasia (9.3%, 4/43), and choroid plexus cysts (9.3%, 4/43) being the most frequent subtypes. Cardiac defects were observed in 39.5% (17/43) of cases, predominantly atrial/ventricular septal defects (ASD/VSD, 23.3%, 10/43) and Ebstein anomaly (11.6%, 5/43). Other frequently observed features included increased nuchal translucency (16.3%, 7/43) and single umbilical artery (14%, 6/43). Parental genetic analysis demonstrated de novo deletions in 80.0% (12/15) of cases, while 20.0% (3/15) were inherited from phenotypically normal parents. CONCLUSIONS: Congenital brain anomalies (particularly ventriculomegaly) and cardiac defects are hallmark prenatal features of isolated 1p36 deletion syndrome. Our findings underscore the role of key genes (RERE, SPEN, PRDM16, MMP23B) in shaping the phenotype and highlight the importance of parental genetic testing in counseling, given the potential for inherited variants with variable expressivity.
PICALM polymorphisms are associated with susceptibility to parkinson's disease in the Northern Chinese Han population: a case-control study.
Yu R, Li Y, Cao Y … +4 more , Kong Z, Zhou Y, Hou B, Xie A
BMC Med Genomics · 2025 Nov · PMID 41310592 · Full text
BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease. The phosphatidylinositol binding clathrin assembly protein (PICALM) gene has been implicated in neurodegenerative diseases. Howeve...
BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease. The phosphatidylinositol binding clathrin assembly protein (PICALM) gene has been implicated in neurodegenerative diseases. However, molecular genetic investigations into the role of the PICALM gene in PD within Chinese population are still lacking. AIM: We aim to determine whether two single nucleotide polymorphisms rs642949 and rs510566, in the PICALM gene are associated with the risk and clinical features of PD. METHODS: A total of 400 individuals with PD and 477 healthy controls were recruited. Genotyping of the PICALM gene loci (rs510566 and rs642949) was performed using TaqMan-based polymerase chain reaction-restriction fragment length polymorphism using DNA samples. RESULTS: For rs642949, the GA genotype conferred a significantly reduced risk of PD under additive model (P = 0.030, OR = 0.687, 95% CI: 0.506-0.931). Additionally, in male patients, the AA genotype was associated with a lower risk of PD compared to females (P = 0.008, OR = 0.355, 95% CI: 0.173-0.730; P = 0.044, OR = 0.721, 95% CI: 0.544-0.954). For rs510566, no significant differences were found in genotype frequencies, allele frequencies, or in any subgroup analysis (P > 0.05). CONCLUSIONS: The rs642949 might be associated with susceptibility to PD. In contrast, no such association was found for the rs510566. Further fundamental research is warranted to investigate the PICALM gene in PD.
Deciphering copy number variations and gene implications in an Egyptian cohort with autism spectrum disorders.
Mohamed AM, Eid OM, Amr KS … +8 more , Mahrous R, Hemimi M, Elsaeid A, Erian PSF, Gharib S, Hussein SH, El-Massieh PMA, Meguid NA
BMC Med Genomics · 2025 Nov · PMID 41299679 · Full text
BACKGROUND: Genetic factors are major contributors to autism spectrum disorders (ASD), with copy number variations (CNVs) playing a significant role. Our objective was to identify and assess CNVs and their associated gen...
BACKGROUND: Genetic factors are major contributors to autism spectrum disorders (ASD), with copy number variations (CNVs) playing a significant role. Our objective was to identify and assess CNVs and their associated gene-level impacts in Egyptian ASD patients. METHODS: Our cohort comprised 40 non-syndromic ASD children, ranging in age from one year and nine months to 12 years. We conducted karyotyping, multiple ligation-dependent probe amplification (MLPA), Methylation-Specific MLPA (MS-MLPA), and chromosomal microarray (CMA) analyses for all patients. Additionally, quantitative real-time PCR (qPCR) analyses were performed on selected patients and their parents. RESULTS: We identified pathogenic or likely pathogenic CNVs in seven patients (17.5%), variants of uncertain significance (VUS) in 10 patients (25%), and classified other variants as benign. Pathogenic or likely pathogenic CNVs affected chromosomes 16p11.2 (two patients), 15q11q13 (three patients), 22q11.2 (one patient), and 7q11.23 (one patient). Many of the affected genes are associated with neuronal functions. Patients with CNVs exhibited increases in three parameters on the Children's Autism Rating Scale (CARS): restrictive and repetitive behavior, adaptation to changes, and responses to taste, smell, and touch. According to the Autism Diagnostic Interview-Revised (ADI-R), patients with pathogenic or likely pathogenic CNVs had an increased third parameter for restricted, repetitive, and stereotyped patterns of behavior. Patients with pathogenic or likely pathogenic CNVs demonstrated some clinical manifestations involving microcephaly (two patients), macrocephaly (one patient), and abnormal electroencephalogram (EEG) with generalized epileptic focus (two patients). qRT-PCR was performed for some parents, and the CNVs were found to be de novo. CONCLUSIONS: CNV detection via CMA proved invaluable and is considered a primary tool in ASD diagnosis. Distinguishing between inherited and de novo CNVs is crucial for accurate genetic counseling. Most genes involved in the detection of pathological or likely pathogenic CNVs are linked to neuronal functions, and these CNVs impact specific parameters in CARS and ADI-R assessments. Future efforts should prioritize a more comprehensive understanding of the genetic underpinnings of ASD, enabling the adoption of personalized treatment strategies.
Advanced machine learning techniques for coronary artery disease risk prediction in early middle-aged adults.
Ntritsos G, Ornan E, Feldhay E … +2 more , Chernin G, Evangelou E
BMC Med Genomics · 2025 Nov · PMID 41299655 · Full text
BACKGROUND: Coronary artery disease (CAD) is the leading cause of death globally, with early risk prediction being vital for timely intervention. In this study we utilized advanced machine learning techniques, incorporat...
BACKGROUND: Coronary artery disease (CAD) is the leading cause of death globally, with early risk prediction being vital for timely intervention. In this study we utilized advanced machine learning techniques, incorporating clinical, lifestyle, and Genetic factors with the aim to enhance the 10-year risk prediction of CAD in early middle-aged adults (40–55 years). METHODS: For developing the machine learning models, we used data from the UK Biobank, a large cohort of over 500,000 participants. Among participants aged 40 to 55, we identified 3,012 CAD cases and 155,176 controls, without any prior CAD diagnosis. More than 700 clinical and lifestyle variables were evaluated, alongside a polygenic risk score (PRS) derived from more than 560,000 genetic variants. Forward feature selection was performed, followed by the application of a stacking ensemble model combining Random Forest and Deep Learning Neural Networks as base learners with a Logistic Regression model serving as a meta-learner. The model’s performance for the 10-years prediction of CAD risk was evaluated using Area Under the Receiver Operating Characteristic Curve (AUC) and calibrated against the ACC/AHA guidelines. RESULTS: Forward feature selection identified 22 CAD risk factors, including the PRS. The final model yielded an AUC of 0.81 in the training dataset and 0.80 in the testing dataset. At the 7.5% risk threshold, the model demonstrated higher sensitivity (0.511 vs. 0.346) and comparable specificity (0.863 vs. 0.866) compared to the ACC ASCVD model. The Net Reclassification Index (NRI) improved by 13.79%, emphasizing the model’s accuracy and alignment. CONCLUSIONS: Our findings highlight the potential of combining Genetic information with clinical and lifestyle factors through machine learning to improve CAD risk prediction in early middle-aged adults. The use of a stacking ensemble approach enabled modeling of complex relationships, yielding superior performance over standard risk models. This framework supports more precise and actionable 10-year risk stratification, reinforcing the value of PRSs when combined with traditional factors. Future research should validate these methods across diverse populations and clinical environments.
Transcriptomic profiling of DYT-TOR1A patients-derived iPSC reveals dysregulation in extracellular matrix, lipid metabolism, and Chr22q11.23.
Setó-Salvia N, Houlden H, Warner TT
BMC Med Genomics · 2025 Nov · PMID 41299643 · Full text
BACKGROUND: DYT-TOR1A is an early-onset generalised movement disorder characterised by involuntary muscle contractions, leading to abnormal postures and repetitive movements. The trinucleotide GAG in-frame deletion (ΔGAG...
BACKGROUND: DYT-TOR1A is an early-onset generalised movement disorder characterised by involuntary muscle contractions, leading to abnormal postures and repetitive movements. The trinucleotide GAG in-frame deletion (ΔGAG) in the TOR1A gene is the most common Mendelian form of dystonia. The TOR1A gene encodes for TorsinA protein, involved in several molecular functions, including chaperone activity, protein quality control, synaptic vesicle recycling, vesicular trafficking, protein folding, homeostasis of the nuclear envelope integrity, and lipid metabolism. There is increasing evidence that DYT-TOR1A dystonia is a neurodevelopmental disorder, beginning in the period where structural and functional abnormalities manifest early in physiological maturation. Recent publications have highlighted the importance of the extracellular matrix and lipid metabolism in dystonia, processes important to cellular neurodevelopment. In this study we aimed to elucidate the gene expression profiles of mutant DYT-TOR1A patient-derived iPSCs to identify key pathways and differentially expressed proteins involved in the early stages of neurodevelopment. RESULTS: Of the 39,065 genes analysed, 1,322 were found to be significantly dysregulated (p < 0.05). For the purposes of this study, we focus on the 36 most significantly dysregulated genes (q < 0.05) and discuss their biological relevance. We identified 28 upregulated and 8 downregulated genes in human DYT-TOR1A patient-derived induced pluripotent stem cells (iPSCs). Most of the encoded proteins constitute fundamental components of extracellular matrix and lipid metabolism, suggesting impairments related to the microenvironment for cell growth, and cell differentiation, membrane fluidity, receptor trafficking, as well as neurodevelopment. In addition, we identified changes in the expression of genes localised in the nucleus, suggesting dysregulation in transcription factors involved in development, particularly in the forebrain and hippocampus. Interestingly, a high proportion of dysregulated genes are localised on Chromosome 22q11.23, a locus already identified as key in dystonia. CONCLUSIONS: Our study in iPSC-derived from DYT-TOR1A patients shows a transcriptomic profile, which validates previous candidate genes highlighted in other animal models of dystonia. We believe that our results will help elucidate early mechanisms in neurodevelopment of DYT-TOR1A dystonia.
Genetic crossroads of cardiovascular disease and its comorbidities: toward holistic therapeutic strategies.
Mishra BH, Mishra PP
BMC Med Genomics · 2025 Nov · PMID 41299637 · Full text
BACKGROUND: With increasing life expectancy, the prevalence of cardiovascular disease (CVD) accompanied by comorbidities is rising, presenting a growing challenge for healthcare systems. Understanding shared genetic fact...
BACKGROUND: With increasing life expectancy, the prevalence of cardiovascular disease (CVD) accompanied by comorbidities is rising, presenting a growing challenge for healthcare systems. Understanding shared genetic factors underlying CVD and its comorbid conditions may facilitate the development of more effective strategies for prevention and treatment. METHODS: In this study, we investigated genetic correlations between CVD and common comorbidities using genome-wide association study (GWAS) summary statistics from the FinnGen R12 release, comprising data from 500,000 Finnish individuals. Following standard quality control procedures, we examined 19 disease endpoints using linkage disequilibrium score regression (LDSC) to estimate heritability and pairwise genetic correlations. Disease traits with significant heritability (z-score ≥ 4) and Bonferroni-corrected significant correlations (adjusted p < 0.05) were selected for genomic structural equation modeling (Genomic SEM) to construct a latent genomic factor (LGF), representing shared genetic liability. RESULTS: Out of the 19 diseases, four CVDs (transient ischemic attack, atrial fibrillation, myocardial infarction and heart failure) and seven comorbidities (type 2 diabetes, asthma, obesity, depression, chronic obstructive pulmonary disease, gingivitis and hypertension) showed statistically significant genetic correlations. A multivariate GWAS of the LGF identified 141 novel associated loci across 29 independent SNPs. These loci overlapped with 16 protein-coding genes, including NPC1, TMEM106B, PTPN22, MAP2K5 and MSRA, implicating them in the shared pathogenesis of CVD and its comorbidities. CONCLUSIONS: These findings underscore a shared genetic architecture between CVD and its comorbidities. We provide genetic evidence supporting the re-evaluation of these gene targets in the context of integrated, holistic and multi-disease treatment strategies.
Long-read sequencing identifies a novel de novo inversion in SMARCC2 in a pediatric patient with Coffin-siris syndrome 8: a case report.
Ibrahim AA, Aamer W, Aliyev E … +8 more , Al-Maraghi A, Elhag SF, Abdi M, Syed N, Palaniswamy S, Akil ASA, Kamal M, Fakhro KA
BMC Med Genomics · 2025 Nov · PMID 41291750 · Full text
BACKGROUND: Coffin-Siris Syndrome 8 (CSS8; MIM# 618362) is a rare neurodevelopmental disorder caused by heterozygous variants in the SMARCC2 gene. Patients with CSS8 present with variable phenotypic presentations, with s...
BACKGROUND: Coffin-Siris Syndrome 8 (CSS8; MIM# 618362) is a rare neurodevelopmental disorder caused by heterozygous variants in the SMARCC2 gene. Patients with CSS8 present with variable phenotypic presentations, with speech abnormalities, behavioral issues, hypotonia, and dysmorphic features being the most common. Here, we report a novel de novo inversion involving SMARCC2, identified through long-read whole-genome sequencing, which highlights its added diagnostic value in uncovering complex structural variants. CASE PRESENTATION: The patient is a 12-year-old male of Arab descent, born to healthy, non-consanguineous parents. He presented with speech difficulties and behavioral issues, including autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD). Long-read sequencing identified a 233 kb inversion on chromosome 12, with breakpoint 1 disrupting SMARCC2 between exons 16 and 17. This inversion was confirmed by Sanger sequencing. Disruption of SMARCC2 is predicted to cause loss of function, resulting in haploinsufficiency. CONCLUSIONS: This is the first report of a structural variant in a patient with CSS8. This finding expands our genetic understanding of CSS8 and demonstrates the diagnostic utility of long-read sequencing in uncovering clinically relevant structural variants that may be missed by conventional methods.
Genetic spectrum of congenital cataract with optional ocular and multisystem abnormalities.
Zhang H, Li F, Liu Z … +7 more , Chang P, Wang D, Zhao Y, Li S, Ding X, Zhang R, Zhao YE
BMC Med Genomics · 2025 Nov · PMID 41291698 · Full text
PURPOSE: To identify disease-causing gene variants in 114 probands with congenital cataract (CC), either isolated or accompanied by additional ocular abnormalities and multisystem disorders. METHODS: A total of 114 proba...
PURPOSE: To identify disease-causing gene variants in 114 probands with congenital cataract (CC), either isolated or accompanied by additional ocular abnormalities and multisystem disorders. METHODS: A total of 114 probands with CC who accept cataract surgery between 2021 and 2022 were enrolled. All probands and available family members underwent a comprehensive ophthalmologic examinations and received clinical diagnoses. Medical history and examination data were collected. Whole-exome sequencing (WES) was performed for all probands, and candidate variants were further validated by co-segregation analysis. RESULTS: Among 114 probands, 49 presented with isolated CC, and 11 exhibited CC combined with systemic abnormalities such as congenital heart disease (CHD), laryngeal cartilage hypoplasia and developmental delay, the remaining were associated with congenital ocular anomalies including iris hypoplasia, posterior capsular defect, microcornea, and microphthalmia. In total, 49 variants were identified across 19 genes, 23 of which were novel. The detection rate of variants by WES was substantially higher in inherited families (68.75%, 11/16) than in sporadic cases (38.78%, 38/98), with an overall detection rate of 42.98% (49/114). CONCLUSIONS: This study provided a comprehensive characterization of the diverse clinical phenotypes of CC in Chinese cohort and updates the mutational landscape of CC-associated genes. By employing WES, we expand the genetic spectrum and highlight additional genotype-phenotype correlations in CCs.
The role of ITGA3 expression in predicting liver metastasis in patients with epithelial ovarian cancer.
Zhu K, Cheng T, Wang Y
BMC Med Genomics · 2025 Nov · PMID 41286938 · Full text
OBJECTIVE: Integrin alpha-3 (ITGA3) has been implicated in tumor metastasis in various cancers, but its role in epithelial ovarian cancer (EOC)-associated liver metastasis (LM) remains unclear. This study aimed to invest...
OBJECTIVE: Integrin alpha-3 (ITGA3) has been implicated in tumor metastasis in various cancers, but its role in epithelial ovarian cancer (EOC)-associated liver metastasis (LM) remains unclear. This study aimed to investigate its role in LM in primary EOC patients. METHODS: It was a retrospective study with a sample size of n = 235 receiving surgical resection at Puren Hospital Affiliated to Wuhan University of Science and Technology between January 2020 and December 2021, including 98 LM (LM group) and 137 non-LM cases (N-LM group). ITGA3 expression was assessed by immunohistochemistry. ROC curves were used for predictive performance analysis, Kaplan-Meier curves for survival analysis, and Cox regression analysis for identification of risk factors. RESULTS: Markedly elevated ITGA3 expression in tumor tissues was found in the LM group (P < 0.001), which demonstrated strong predictive value for LM in EOC patients (area under the curve (AUC) = 0.881, sensitivity = 70.41%, specificity = 87.59%, P < 0.001), and strongly correlated with tumor size and postoperative residual lesions (both P < 0.05). Compared with the L-ITGA3 group, the H-ITGA3 group had a higher incidence of postoperative LM (P < 0.001) and showed a left-shifted curve in Kaplan-Meier analysis (P < 0.001). ITGA3 expression in tumor tissues (HR = 5.977), tumor grade (HR = 1.441), and postoperative residual lesions (HR = 1.697) were identified as independent risk factors for postoperative LM. CONCLUSIONS: ITGA3 expression in tumor tissue significantly aids in predicting LM in EOC patients and is independently and closely related to adverse clinicopathological outcomes.
First clinical report of a rare PDZD7 nonsense variant and recurrent mutations in Iranian families with autosomal recessive non-syndromic hearing loss.
Ghasemi H, Esmaeilzadeh E, Abghari FZ … +5 more , Mohseni M, Akbarpoor E, Khorram Khorshid HR, Bazazzadegan N, Najafipour R
BMC Med Genomics · 2025 Nov · PMID 41276803 · Full text
BACKGROUND: Hereditary hearing loss (HHL) is a genetically heterogeneous disorder, with autosomal recessive non-syndromic hearing loss (ARNSHL) comprising a significant proportion of cases globally. To investigate its ge...
BACKGROUND: Hereditary hearing loss (HHL) is a genetically heterogeneous disorder, with autosomal recessive non-syndromic hearing loss (ARNSHL) comprising a significant proportion of cases globally. To investigate its genetic basis, we performed whole-exome sequencing (WES) in four consanguineous Iranian families affected by ARNSHL. METHODS: WES was performed for the proband of each family using an Illumina platform. Secondary analysis was conducted with the DRAGEN Bio-IT Platform, and variant annotation was performed using wANNOVAR. Variants were prioritized based on inheritance patterns and bioinformatic predictions. Selected variants were validated by Sanger sequencing and assessed according to American College of Medical Genetics and Genomics / Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: Through this approach, we identified a previously reported missense variant in CDH23:c.5908G > A (p.Glu1970Lys), a nonsense variant in PDZD7:c.175 C > T (p.Arg59Ter) with no prior clinical report, and a recurrent nonsense variant in CDC14A:c.1126 C > T (p.Arg376Ter) in two families, providing further support as a founder mutation in Iran. CONCLUSION: These findings illustrate the potential diagnostic value of WES in ARNSHL and report, for the first time, a clinical association of the PDZD7 variant (c.175 C > T) with hearing loss. Pathogenic variants in CDH23 and CDC14A are consistent with their established involvement in HHL. Overall, this study provides additional insights into the genetic landscape and genotype–phenotype correlations in ARNSHL.
Performance testing for the sensitivity and resolution of low-pass WGS for small CNV detection.
Huang S, Li J, Liu D … +10 more , Zou Y, Hang T, Yuan H, Yang Y, Li H, Dong M, Qian Y, Sun Y, Huang C, Bai G
BMC Med Genomics · 2025 Nov · PMID 41272749 · Full text
BACKGROUND: Low-pass genome sequencing (LP GS) has been widely used for the detection of copy number variations (CNVs). As a key algorithmic parameter of LP GS, window selection may influence the performance of LP GS. Ho...
BACKGROUND: Low-pass genome sequencing (LP GS) has been widely used for the detection of copy number variations (CNVs). As a key algorithmic parameter of LP GS, window selection may influence the performance of LP GS. However, limited studies have investigated this parameter for the detection of small CNVs. METHODS: To evaluate of the impact of sliding window on true positive rate, additional interpretation workload and resolution, 40 simulated samples with 19 pre-defined CNVs of various read amounts were simulated. Fifty-seven clinical cases with previously ascertained CMA results (27 positive cases and 30 negative cases) were used to further evaluate the influence of sliding window for detection sensitivity and specificity. RESULTS: In general, the true positive rate increased with the increase of sequencing depth for simulated samples. The algorithm by sliding a 10-Kb window in 1-Kb increments showed higher true positive rate, especially for CNVs < = 30 Kb. For deletions of 30 Kb, the algorithm by sliding a 10-Kb window in 1-Kb increments showed a true positive rate of 100% for all read amounts, while the algorithm by sliding a 50-Kb window in 5-Kb increments had a detection sensitivity of 80.0% even with 100 M read amount. The results of overlap analysis showed that the algorithm by sliding a 10-Kb window in 1-Kb increments showed less variability for both deletions and duplications (especially for CNVs < = 30 Kb), indicating higher detection resolution. Further combining the potential introduction of the additional interpretation workload by 10-Kb window in 1-Kb increments, 50 M reads is recommended for detecting most small CNVs. For the 57 clinical cases, the algorithm by sliding a 50-Kb window in 5-Kb increments and the algorithm by sliding a 10-Kb window in 1-Kb increments showed detection sensitivity of 85.19% (23/27) and 96.30% (26/27), respectively. The algorithm by sliding a 10-Kb window in 1-Kb increments detected all the CNVs missed by sliding a 50-Kb window in 5-Kb increments except for one 25.8 Kb deletion. The specificity for both algorithms was calculated as 96.67% (29/30). CONCLUSION: Window selection, together with sequencing depth, could influence CNV detection sensitivity and resolution of LP GS for small CNVs. This study provided a set of evaluation methods and pathways based on simulated samples and clinical cases. For CNVs < = 30 kb, 10-Kb window in 1-Kb increments and >= 50 M reads were recommended for LP GS. It would be advisable for clinical labs conducting LP GS to determine the range of sensitivity and resolution for different sliding windows and sequencing depth for CNV detection.
Clinical use of whole-genome sequencing in children with developmental delay or intellectual disability.
Xu J, Xu Y, Su W … +3 more , Chen L, Wang Y, Li H
BMC Med Genomics · 2025 Nov · PMID 41272673 · Full text
BACKGROUND: Determining the underlying cause of developmental delay or intellectual disability (DD/ID) is challenging yet crucial. Establishing a genetic basis for cases of unexplained DD/ID is integral to informing clin...
BACKGROUND: Determining the underlying cause of developmental delay or intellectual disability (DD/ID) is challenging yet crucial. Establishing a genetic basis for cases of unexplained DD/ID is integral to informing clinical decisions and anticipating patient outcomes. In this report, we share our institutional insights derived from employing whole-genome sequencing (WGS) to investigate unexplained DD/ID in pediatric populations. METHODS: A retrospective study was conducted on 115 children aged 1 month to 16 years with unexplained DD/ID who underwent WGS. We analyzed demographic profiles and catalogued genetic variants identified, in conjunction with examining clinical variables potentially associated with diagnostic yield. RESULTS: WGS data from 115 pediatric patients identified a total of 33 pathogenic or likely pathogenic single nucleotide variants and small insertions/deletions, of which 22 were classified as diagnostic cases and 11 as carriers. In addition, 11 pathogenic or likely pathogenic copy number variations were detected. Clinical attributes such as gender, age at diagnosis, gestational maturity, birth weight, perinatal complications (anoxia, jaundice), comorbid symptoms, hereditary background, neuromuscular function (muscle tone and strength), presence of epilepsy, neuroimaging, and electroencephalography patterns did not show a significant association with WGS findings. Nonetheless, a noteworthy association emerged between earlier age at diagnosis and increased diagnostic yield via WGS. CONCLUSIONS: WGS serves as a powerful tool for uncovering genetic etiologies in children with unexplained DD/ID, with meaningful implications for clinical care, genetic counseling for families, and long-term management planning.
Long-range PCR and Nanopore sequencing for localisation and phasing variants: an end-to-end clinical application workflow.
Jamshidi J, Rowntree C, Fadaee S … +5 more , Zhang F, Zhu Y, Buckley M, Hart F, Roscioli T
BMC Med Genomics · 2025 Nov · PMID 41257875 · Full text
BACKGROUND: Next-Generation short-read sequencing has limited diagnostic utility in phasing distantly separated variants and analysing genomic regions with high homology. Determining the phase of variants from parental c...
BACKGROUND: Next-Generation short-read sequencing has limited diagnostic utility in phasing distantly separated variants and analysing genomic regions with high homology. Determining the phase of variants from parental chromosomes is critical for accurate identification of compound heterozygosity. Long-read sequencing technology is able to overcome these limitations through the analysis of long haplotypes of separated variants. This study has developed and validated a robust, end-to-end workflow for phasing and localising variants using long-range PCR (LR-PCR) and targeted Nanopore sequencing for clinical implementation. METHODS: NA24385 (HG002) reference DNA was used for all tests. Four PCR kits were tested to optimise LR-PCR for targets between 1 and 20 kb. Amplicons were barcoded and sequenced on Flongle flow cells, with up to eight amplicons on each flow cell. An in-house bioinformatic pipeline was developed to analyse the amplicons. This pipeline is capable of detecting chimeric reads (a known PCR artefact), and incorporating Clair3 for variant calling, and WhatsHap and HapCUT2 for phasing. RESULTS: The UltraRun LongRange PCR Kit performed with a 90% success rate for DNA amplification up to 22 kb. All 15 tested heterozygous Single Nucleotide Variant (SNV) pairs, and 10 small InDels, with inter-variant distances from 5.8 to 21.4 kb, were phased with 100% concordance to known phase. Furthermore, SNV calling within six low-mappability genes demonstrated precision and sensitivity of 1 against benchmark data. The median proportion of chimeric reads was maintained at 2.80% (range 1.79-16.12%) under optimised conditions. CONCLUSIONS: This study establishes a reliable and affordable clinical diagnostic workflow for accurate phasing of variants separated by up to ~ 20 kb and for variant localisation in genomic regions not able to be sequenced by short-read sequencing. This integrated approach enables implementation in diagnostic settings to resolve complex genetic findings and improve variant interpretation. The bioinformatic pipeline and documentation are available at https://github.com/j-jamshidi/ONT_amp_phase .
Early alternative splicing signatures and RBP networks in MASLD progression to cirrhosis.
Chen L, Ma W, Hu Y … +3 more , Qin Y, Zhao S, Yang J
BMC Med Genomics · 2025 Nov · PMID 41257843 · Full text
Non-alcoholic fatty liver disease (MASLD) affects approximately 32.4% of adults globally, progressing from simple steatosis to non-alcoholic steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma (HCC). Alternat...
Non-alcoholic fatty liver disease (MASLD) affects approximately 32.4% of adults globally, progressing from simple steatosis to non-alcoholic steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma (HCC). Alternative splicing (AS) is crucial for gene expression regulation, and its dysregulation is linked to disease progression. To identify early molecular signatures indicative of cirrhosis in MASLD, we analyzed RNA sequencing data from liver tissues of healthy controls (n = 10), MASLD patients (n = 9), and cirrhosis patients (n = 10) obtained from the SRA database (accession ERP146053). Utilizing SUVA for splicing event detection and k-means clustering, we examined dynamic changes in alternative splicing events and constructed regulatory networks of RNA-binding proteins (RBPs). Integration with immunological profiles enabled us to explore the interplay between splicing variants and immune responses during disease progression. We identified 671 differential alternative splicing events. Clustering revealed dynamic splicing patterns across disease stages, with two key patterns associated with DNA damage response (DDR) and epithelial-mesenchymal transition (EMT) processes, showing early progressive alterations correlating with disease severity. Twelve immune-related splicing events were significantly associated with changes in immune cell populations, highlighting their role in immune regulation during Liver disease progression. Additionally, 11 RBPs, including CELF5 and PCBP1, showed expression changes that correlate with splicing events associated with MASLD progression. Identifying early alternative splicing signatures and understanding RBP networks enhance our ability to predict disease progression and present potential therapeutic targets for early intervention.
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