BMC Medical Genomics[JOURNAL]
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200 papers
Genetic architecture of patients with autism spectrum disorder - data analysis based on the literature review.
Ręka G, Wojciechowska K, Lejman M
BMC Med Genomics · 2026 Jul · PMID 42401939 · Full text
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition including incorrect functioning in communication, social interaction, and repetitive behavior. Global prevalence is estimated as 1-2%, with a p...
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition including incorrect functioning in communication, social interaction, and repetitive behavior. Global prevalence is estimated as 1-2%, with a predominance of men. Different pre- and perinatal, environmental, immunological, neurobiological, genetic, and epigenetic factors are involved in the etiology of ASD. The study aims to analyze genetic abnormalities in patients with ASD according to data from the current literature. MATERIALS AND METHODS: Studies available in the PubMed and Google Scholar databases were chosen through a literature search. Only papers published from 2020, available as full-text publications in English, with studies conducted on humans, original papers, or meta-analyses were included. RESULTS AND DISCUSSION: The following types of genetic variation were identified: copy number variants, larger insertions, inversions, uniparental disomies, tandem repeat expansions, common single nucleotide polymorphisms, single nucleotide variants, short insertions/deletions, and mitochondrial variants. Epigenetic factors, like histone modifications, deoxyribonucleic acid (DNA) methylation, and micro ribonucleic acid might play an important role in ASD predisposition. Genes identified in the review were mainly involved in neurodevelopment, synaptic formation, neuronal migration, neurotransmission, glial proliferation, ubiquitination, chromatin remodeling, or transcription. ASD is described as a component of the phenotype in fragile X syndrome, tuberous sclerosis complex, neurofibromatosis type 1, Angelman, Phelan-McDermid, Smith-Lemli-Opitz syndromes, and chromosome trisomies. Current guidelines for genetic diagnosis of ASD recommend performing directed genetic studies in the first line (like multiplex ligation-dependent probe amplification - MLPA, analysis of FMR1 gene), in case of a negative result, chromosomal microarray as a routine method, then next-generation sequencing (NGS) panel testing, WES (whole exome sequencing), or even WGS (whole genome sequencing) as the last test. CONCLUSIONS: Wider access to modern diagnostic methods has increased the number of ASD patients in whom the genetic etiology of the disorder has been uncovered. Knowledge of the genetic background would be applicable in the diagnosis, prevention, prognosis, and individualized treatment.
Elective genomic sequencing for adults in research, clinical and commercial contexts.
Linderman MD, Adelson SM, Berro TM … +25 more , Anderson JL, Crawford SD, Cunningham TJ, Esplin ED, Ewing-Crawford AT, Nielsen DE, Pereira S, Schmidlen T, Andrighetti H, Bleyl SB, Church GM, Haverfield EV, Hegde M, Konstantinos LN, Kruszka P, Leonard D, May T, McGinniss M, Pandya V, Schadt EE, Greshake Tzovaras B, Zettler B, McGuire AL, Green RC, PeopleSeq Study Team
BMC Med Genomics · 2026 Jul · PMID 42400015 · Full text
PURPOSE: Elective genomic sequencing (EGS) returns monogenic disease findings in multiple genes, including potentially novel variants, and may also provide participants with carrier status, pharmacogenomic and other heal...
PURPOSE: Elective genomic sequencing (EGS) returns monogenic disease findings in multiple genes, including potentially novel variants, and may also provide participants with carrier status, pharmacogenomic and other health-related information. The PeopleSeq Study assessed participants' motivations for and concerns about EGS and the associated clinical and psychosocial outcomes across diverse EGS providers. METHODS: We administered a shared questionnaire to participants who chose to undergo EGS via 18 academic, clinical, or commercial EGS platforms. RESULTS: We enrolled 1575 participants, of whom 1147 (72.8%) completed a questionnaire after receiving their EGS results. A majority (60.3%) of the participants who completed a post-result questionnaire self-reported receiving results they assessed as important, including negative findings, and 75.9% reported a form of health-related utility. Among a subset (19.4%) who shared their EGS reports, 16.6% (37 of n = 223) received a monogenic finding and self-reported results deemed "important" were consistent with EGS reports. Most participants (74.1%) discussed their results with their family, but fewer discussed their results with a healthcare provider other than the site team (41.7%) or had one or more medical visits as a direct result of their EGS testing (23.1%). Participants expressed diverse motivations for EGS, with 91.4% expressing interest in their personal disease risk and 54% who expressed quasi-indication-based motivations related to family medical history. Individuals motivated by family history reported important results at a significantly higher rate. CONCLUSIONS: Early adopters of EGS are motivated by general interest in their health as well as quasi-indication-based considerations such as family history. A majority of participants learned results they considered medically important, but a much smaller segment engaged healthcare providers with their results.
Targeting acetylcholine: a novel strategy for treating lung adenocarcinoma.
Li S, Song Y, Wang H … +6 more , Ma J, Bai J, Xie X, Guo B, Wei Z, Yao Y
BMC Med Genomics · 2026 Jul · PMID 42399905 · Full text
BACKGROUND: Lung cancer remains one of the deadliest cancers, both in terms of the incidence and mortality rates. Although a combination therapy comprising immune checkpoint inhibitors and chemotherapy has become the sta...
BACKGROUND: Lung cancer remains one of the deadliest cancers, both in terms of the incidence and mortality rates. Although a combination therapy comprising immune checkpoint inhibitors and chemotherapy has become the standard therapy for driver gene-negative lung adenocarcinoma, its efficacy is yet to be further improved. Additionally, new treatment methods still need to be developed. Acetylcholinesterase (AChE) has emerged as a potential therapeutic target in various cancers. However, its role in lung adenocarcinoma remains poorly understood. OBJECTIVE: This study aims to investigate the role of AChE in the progression of lung adenocarcinoma and to design and synthesize small-molecule compounds targeting AChE for exploring their potential as novel therapeutic agents. METHODS: AChE is significantly overexpressed in lung adenocarcinoma. Therefore, we synthesized two novel AChE inhibitors and characterized them by nuclear magnetic resonance and high-resolution mass spectrometry. Subsequently, two inhibitors were added to lung adenocarcinoma A549 and H1975 cells to detect changes in their biological behaviors such as cell proliferation, apoptosis, cell cycle, and colony-formation ability. Simultaneously, a mouse transplant tumor model was constructed and an AChE inhibitor was injected intraperitoneally to observe changes in the volume and weight of the mouse transplant tumor. RESULT: Our AChE inhibitors showed significant cytotoxicity against A549 and H1975 cells. They can effectively inhibit cell proliferation, induce apoptosis, prevent cell cycle progression, and reduce colony-formation ability. The mouse transplant tumor model confirmed that they can inhibit cell proliferation. The tumor volume and weight were significantly reduced in the intraperitoneal injection inhibitor group. Notably, the inhibitor did not cause pathological damage to normal organs. CONCLUSION: Our novel AChE inhibitors can potentially be used to treat lung adenocarcinoma and to develop a promising new direction for future lung adenocarcinoma treatments.
Role of the PTPN22 C1858T (R263Q) variant in tuberculosis susceptibility: genetic and functional evidence from a South Asian cohort.
Ain FU, Shahzad F, Jahan S … +4 more , Javed K, Tahir R, Javed H, Siddiqua R
BMC Med Genomics · 2026 Jul · PMID 42399866 · Full text
BACKGROUND: The PTPN22 gene encodes Lyp, a phosphatase involved in downregulating T-cell receptor signaling and modulating immune homeostasis. Although PTPN22 polymorphisms rs2476601 (R620W) and rs33996649 (R263Q) are as...
BACKGROUND: The PTPN22 gene encodes Lyp, a phosphatase involved in downregulating T-cell receptor signaling and modulating immune homeostasis. Although PTPN22 polymorphisms rs2476601 (R620W) and rs33996649 (R263Q) are associated with autoimmune diseases, their role in infectious diseases such as tuberculosis susceptibility remains unclear. OBJECTIVE: To evaluate the association of PTPN22 polymorphisms with TB susceptibility and assess their functional relevance through gene expression profiling in a South Asian cohort. METHODOLOGY: PTPN22 polymorphisms and expression in 111 TB patients and 85 controls were analyzed by ARMS-PCR and RT-qPCR, with association and predictive analyses performed using logistic regression, ROC, LD (Haploview), and SPSS v26. RESULTS: A significant association was observed between the rs33996649 C/T genotype and increased TB susceptibility (p < 0.008; OR = 5.87), while no significant association was found for rs2476601. Logistic regression indicating a stronger contribution to TB risk for rs33996649 (1.1279) compared to rs2476601 (0.2276). ROC curve analysis yielded an area under the curve (AUC) of 0.63, suggesting good predictive power for the combined genetic model. Linkage disequilibrium analysis demonstrated low correlation between the SNPs (D' ≈ 0.40, r2 ≈ 0), indicating independent inheritance. PTPN22 expression was modestly upregulated in TB patients (mean fold change = 1.2 vs. 1.0 in controls), though the difference was not statistically significant (p > 0.05), possibly reflecting compensatory immune regulation in variant carriers. CONCLUSION: The PTPN22 rs33996649 (R263Q) variant shows a significant independent association with TB susceptibility, highlighting its role as a genetic risk factor and potential target for immunogenetic research.
Improved prognostic survival models for pediatric medulloblastoma using high dimensional gene expression data.
Amona EB, Sumy MSA, Jones T … +6 more , Wang S, Mistry AM, Raj A, Donninger H, Yaddanapudi K, Kong M
BMC Med Genomics · 2026 Jul · PMID 42387537 · Full text
Genetic, epigenetic, and transcriptomic analyses have stratified medulloblastoma (MB) into four canonical subgroups of Wingless Type (WNT), Sonic Hedgehog (SHH), and Group 3 and Group 4, with distinct patient profiles an...
Genetic, epigenetic, and transcriptomic analyses have stratified medulloblastoma (MB) into four canonical subgroups of Wingless Type (WNT), Sonic Hedgehog (SHH), and Group 3 and Group 4, with distinct patient profiles and prognoses. Recent classification strategies have also considered combining Group 3 and Group 4 tumors into a Non-WNT/Non-SHH subgroup to account for biological overlap and heterogeneity. Using high-dimensional gene expression data from 487 pediatric and young adult patients and over twenty-one thousand transcripts, this study explores which genes can improve prognostic accuracy for survival while accounting for molecular stratification, histological subtype, key oncogenic drivers (MYC and MYCN amplification), and established clinical covariates, including age group (< 3 vs. 3-21 years) and metastatic status. We then develop a multi-stage framework for identifying prognostic genes and evaluating modern survival modeling strategies. In the first stage, gene screening was performed using Benjamini-Hochberg adjusted Cox regression across false discovery rate (FDR) thresholds from 1% to 6%, with the number of retained genes increasing from 15 at 1% to 146 at 6% FDR. In the second stage, multiple survival models were evaluated, including LASSO, Elastic Net, Ridge regression, SCAD, MCP, PCA-Cox, and Random Survival Forests, using ten-fold cross-validation with the Integrated Brier Score as the primary calibration metric and the concordance index as a secondary discrimination measure. Although Ridge regression achieved the lowest prediction error at higher FDR thresholds, it did not perform variable selection and retained large gene sets, limiting interpretability. In contrast, the 6% FDR Elastic Net model provided an optimal balance between predictive accuracy and model sparsity while reducing the gene set from 146 to 49 genes, yielding an interpretable final multivariable model. Gene-level effects from the final Elastic Net-penalized Cox model revealed a clear prognostic gradient. Genes associated with poorer survival included FKBP4, CSNK2A2, GPC4, GATA3, NPY, LYPD1, CLCA4, and BNC2, which have been implicated in tumor progression, signaling pathways, and immune-related processes, whereas genes associated with improved survival included ZNF774, COX10, FBLIM1, and UNC13C, reflecting roles in cellular regulation and protective biological processes. These findings demonstrate that combining FDR-based screening with Elastic Net-penalized Cox modeling yields a robust, parsimonious, and biologically meaningful prognostic framework for medulloblastoma, achieving strong predictive performance while maintaining interpretability in high-dimensional genomic settings.
Identification of a novel pathogenic variant in MYLK in an Iranian family with non-syndromic familial aortic aneurysm and dissection by whole-exome sequencing and literature review.
Jafari H, Salehi M, Behjati M … +2 more , Jazi MH, Garshasbi M
BMC Med Genomics · 2026 Jun · PMID 42365314 · Full text
BACKGROUND: Non-syndromic familial thoracic aortic aneurysm and dissection (ns-FTAAD) is an inherited disease that follows an autosomal dominant pattern; however, pinpointing the responsible genes is often complex. The M...
BACKGROUND: Non-syndromic familial thoracic aortic aneurysm and dissection (ns-FTAAD) is an inherited disease that follows an autosomal dominant pattern; however, pinpointing the responsible genes is often complex. The MYLK gene has been identified as one implicated in TAAD, which necessitates careful and specialized clinical oversight. Systematically gathering evidence on the disease-causing potential of rare genetic variants through detailed family studies is crucial for developing more effective treatment protocols for individuals with this life-threatening hereditary condition. This study reports the identification of a novel pathogenic variant causing ns-FTAAD and provides a comprehensive review of all associated TAAD variants. METHODS: We report an Iranian family with ns-FTAAD associated with a novel MYLK germline variant. We evaluated all relevant clinical and genetic information. Whole-exome sequencing (WES) was used for variant detection, and Sanger sequencing was performed for validation. A literature search for all TAAD types was conducted on PubMed. The extracted data included the total number of patients studied, the subset with MYLK variants, specific nucleotide and protein changes, patient demographics, pathological features, and clinical symptoms. RESULTS: Exome sequencing led to the identification of a novel variant, NM_053025.4:c.2208_2230dup (p.Ile744Argfs*9), that led to a premature stop codon and nonsense-mediated decay. Five people were variant carriers and three people were non-carriers. A total of 1,440 patients clinically diagnosed with TAAD were recruited in these studies, among whom 59 were carriers of an MYLK variant. Among the 34 variants collected, the distribution was as follows: missense (58.82%), frameshift (14.71%), splicing (5.88%), CNVs (5.88%), and other (14.71%). CONCLUSION: Our study expands the mutational landscape of MYLK-related ns-FTAAD with a novel pathogenic variant. The aggregation of all reported cases highlights that while missense variants predominate, loss-of-function mechanisms like frameshift variants are a significant cause of disease. These findings are crucial for risk assessment, familial screening, and the clinical management of affected families.
Genomic determinants of fluoroquinolone resistance in Escherichia coli in Nigeria: dominance of QRDR mutations and limited contribution of PMQR in a cross-sectional study.
Medugu N, Aworh MK, Abdulraheem K … +3 more , Hull DM, Harden L, Thakur S
BMC Med Genomics · 2026 Jun · PMID 42321812 · Full text
BACKGROUND: Fluoroquinolone-resistant Escherichia coli is a major global clinical threat, particularly in low- and middle-income countries like Nigeria. However, the full genomic landscape, including the relative contrib...
BACKGROUND: Fluoroquinolone-resistant Escherichia coli is a major global clinical threat, particularly in low- and middle-income countries like Nigeria. However, the full genomic landscape, including the relative contributions of chromosomal mutations, plasmid-mediated resistance, and the role of high-risk clones, remains poorly characterized in this setting. This study aimed to define the genomic mechanisms, clonal distribution, and genotype-phenotype relationships of fluoroquinolone resistance in clinical E. coli isolates from Nigeria. METHODS: A cross-sectional study of 107 clinical E. coli isolates was conducted. Phenotypic susceptibility to ciprofloxacin and nalidixic acid was determined using VITEK 2 and broth microdilution. Whole-genome sequencing was performed, and analysis included detection of quinolone resistance determining region (QRDR) mutations (gyrA, parC, parE) and plasmid-mediated quinolone resistance (PMQR) genes, multilocus sequence typing (MLST), and phylogenetic analysis. Statistical associations were evaluated using chi-squared tests or Fisher's exact tests. RESULTS: Ciprofloxacin non-susceptibility was high at 86.0%. Resistance was primarily driven by a conserved chromosomal mutation profile; the combination of gyrA S83L, gyrA D87N, and parC S80I was present in 85 isolates and was associated with ciprofloxacin non-susceptibility in all affected isolates in this cohort. Isolates with only gyrA mutations were resistant to nalidixic acid but susceptible to ciprofloxacin, consistent with a stepwise resistance pathway. In this cohort, the triple QRDR signature (gyrA S83L + gyrA D87N/Y + parC S80I) was a perfect positive predictor of ciprofloxacin non-susceptibility (85/85; 100%). The ST131 lineage dominated, accounting for 21.5% of isolates and universally carrying the complete triple QRDR profile; notably, no ST131 isolate carried a PMQR determinant. Plasmid-mediated quinolone resistance (PMQR) genes were detected in 15.0% of isolates but were not independently associated with ciprofloxacin non-susceptibility in this cohort in the absence of concomitant QRDR mutations. Efflux pump genes were ubiquitous and non-predictive. Notably, six isolates, all from urine, were non-susceptible (R/I) despite lacking all known QRDR and PMQR determinants, pointing to uncharacterized mechanisms. In a multivariable logistic regression model that included ST131 status, PMQR carriage, and parE mutation status, ST131 was associated with ciprofloxacin non-susceptibility (adjusted OR 5.96, 95% CI 1.21-29.4, p = 0.028), whereas PMQR carriage was not (adjusted OR 0.94, 95% CI 0.18-4.85, p = 0.94). The triple QRDR signature was not included in this model because it perfectly predicted ciprofloxacin non-susceptibility in this cohort. Resistance patterns varied by clinical source, with the highest burden in bloodstream and wound infections. This stepwise hierarchy from first-step gyrA mutations to the classic triple QRDR profile is summarised in the graphical abstract, Fig. 1. CONCLUSIONS: Fluoroquinolone resistance in Nigerian clinical E. coli is predominantly driven by chromosomal QRDR mutations within successful clones like ST131. PMQR genes and efflux pumps appeared to play a supplementary role rather than being independent drivers of ciprofloxacin resistance in this cohort. These data support prioritising key QRDR mutations in genomic reporting and local stewardship decisions, while the QRDR-negative resistant urine isolates require further investigation.
Crosstalk mediators implicated in the Stevens-Johnson Syndrome through gene regulatory network analysis.
Watanabe M, Ueta M, Nishigaki H … +5 more , Mizushima K, Naito Y, Kinoshita S, Sotozono C, Takayama J
BMC Med Genomics · 2026 Jun · PMID 42316229 · Full text
Stevens-Johnson syndrome (SJS) is a rare and severe mucocutaneous disorder often triggered by medications or infections. Our previous research identified that four key genes, Ikzf1, Ptger3, Mavs, and Tlr3 are involved in...
Stevens-Johnson syndrome (SJS) is a rare and severe mucocutaneous disorder often triggered by medications or infections. Our previous research identified that four key genes, Ikzf1, Ptger3, Mavs, and Tlr3 are involved in SJS susceptibility and the conjunctival epithelial innate immune response, demonstrating their role in regulating interferon-stimulated genes. However, the interplay among these regulatory factors remains unclear. This study aimed to elucidate the crosstalk mechanisms between the pathways regulated by these four genes in conjunctival epithelial cells. We constructed a comprehensive gene regulatory network using transcriptomic data from murine conjunctival epithelial cells under 16 distinct conditions, including polyI:C stimulation across wild-type, knockout, and transgenic backgrounds for the key genes. A targeted network analysis systematically identified numerous candidate genes mediating the crosstalk between the regulatory pathways initiated by Ikzf1, Ptger3, Mavs, and Tlr3. The identified candidates suggest the involvement of diverse signaling pathways previously unlinked to SJS pathology. Our findings suggest that the pathogenesis of SJS may arise not from the dysfunction of isolated genes but from the disruption of a balance maintained by intricate pathway crosstalk.
Familial lymphoma and genetic predisposition: an updated review.
Braun L, Graffeo R, Kapilan K … +3 more , Mandhair HK, Rabaglio M, Novak U
BMC Med Genomics · 2026 Jun · PMID 42316213 · Full text
BACKGROUND: Several factors contribute to the development of malignant lymphomas including environmental exposures, bacterial and viral infections, as well as familial and genetic factors. MAIN BODY: Numerous somatic var...
BACKGROUND: Several factors contribute to the development of malignant lymphomas including environmental exposures, bacterial and viral infections, as well as familial and genetic factors. MAIN BODY: Numerous somatic variants are involved in lymphomagenesis, and an increasing number of germline variants predisposing patients to lymphoid neoplasm have been identified. Although most lymphomas arise sporadically, epidemiological studies have linked a familial history of lymphomas and other hematological tumors with an increased lymphoma risk. Although rare, familial clustering of malignant lymphoma is well documented, and the constellations suggest inherited risk factors. Recent technological advancements have improved our ability to identify genetic factors associated with lymphoma that overall lead to a better understanding of genetic susceptibility for these entities. In this context, we here provide a comprehensive perspective on lymphoma risk factors to support improved lymphoma risk assessment and testing. A dedicated clinical management could influence future advances in lymphoma therapies and might also prevent severe toxicity and secondary malignancies. However, to date, only few susceptibility genes for malignant lymphomas have been identified. Highly penetrant mutations in known genes cannot account for most of the excess in a polygenic and heterogenic disease such as cancer. High-throughput sequencing identifies pathogenic variants that may constitute most low-penetrance alleles. However, their detection requires many well-characterized cases and controls. In this review, we therefore also include a short discussion on a Swiss cohort where we prospectively collect and samples for genetic data from individuals with a family history of lymphoma. We are convinced that such an approach is more informative and feasible than a population-based project with unselected cases and aim to better inform both genetic counsellors and oncologists. CONCLUSION: Inherited genetic factors contribute to lymphoma risk in a subset of patients. Improved identification of susceptibility variants, particularly through family-based studies, may enhance risk assessment and inform personalized clinical management.
Discovery and validation of a prognostic SPP1/PLAU signature in HPV-negative oropharyngeal squamous cell carcinoma.
Jin G, Yang H, Du J … +10 more , Shang L, Shen N, Miao L, Liu S, Yang Z, Wang X, Wei R, Ma W, Chen Y, Wang C
BMC Med Genomics · 2026 Jun · PMID 42304187 · Full text
BACKGROUND: This study aimed to identify and validate robust prognostic biomarkers for oropharyngeal squamous cell carcinoma (OPSCC), with a specific focus on the high-risk HPV-negative subtype. METHODS: Integrated bioin...
BACKGROUND: This study aimed to identify and validate robust prognostic biomarkers for oropharyngeal squamous cell carcinoma (OPSCC), with a specific focus on the high-risk HPV-negative subtype. METHODS: Integrated bioinformatics analysis was performed on transcriptomic data from four GEO datasets (n = 418 samples). Differentially expressed genes (DEGs) were identified, and a protein-protein interaction (PPI) network was constructed for the most dysregulated genes. Key modules were analyzed via survival analysis and multivariate Cox regression. The top candidate genes were validated at the protein level using immunohistochemistry (IHC) in an independent cohort of 304 OPSCC patients. RESULTS: A 33-gene module related to extracellular matrix organization showed significant prognostic association. It stratified patients into high- and low-risk groups with markedly different overall survival (HR = 2.71, p < 0.001). From this module, SPP1 and PLAU were identified as independent prognostic factors through multi-step screening. Both genes were significantly overexpressed in tumors (approximately 20-fold and 10-fold, respectively, p < 0.001), with high expression strongly correlated with advanced tumor stage (p < 0.01) and, notably, the HPV-negative subtype (p < 0.001). In survival analysis, high expression of either SPP1 or PLAU was associated with poorer overall survival (SPP1: p < 0.001; PLAU: p < 0.001) and progression-free survival (p < 0.001). IHC validation confirmed high protein expression in 69.7% (SPP1) and 54.8% (PLAU) of cancer tissues. A prognostic nomogram integrating the SPP1/PLAU signature with clinical variables was constructed with strong predictive accuracy (C-index = 0.75). CONCLUSION: The SPP1/PLAU dual-gene signature is a robust and independent prognostic biomarker for OPSCC, with particular clinical utility for stratifying high-risk HPV-negative patients.
Genetic diversity of the Plasmodium falciparum msp2 gene in children from the Eastern Democratic Republic of Congo: a comparative study of clinical and subclinical infections.
Nasibu MM, Mulakwa LM, Chirimwami SM … +5 more , Amisi CB, Ahadi JB, Zakitoka RK, Bulabula ANH, Bulabula A
BMC Med Genomics · 2026 Jun · PMID 42288863 · Full text
BACKGROUND: Plasmodium falciparum is the main cause of malaria-related illness and death in sub-Saharan Africa. Despite control efforts, asymptomatic carriers, particularly children, continue to sustain transmission. Imp...
BACKGROUND: Plasmodium falciparum is the main cause of malaria-related illness and death in sub-Saharan Africa. Despite control efforts, asymptomatic carriers, particularly children, continue to sustain transmission. Improving surveillance requires a better understanding of the genetic diversity and parasite burden of symptomatic versus asymptomatic infections. OBJECTIVE: To compare Plasmodium falciparum genotypic profiles and msp2 gene copy numbers in symptomatic and asymptomatic children in Kindu, and assess associations with clinical status. METHODS: Children aged 6 months to 12 years were recruited from health centres and schools. DNA extracted from dried blood spots (Chelex 100) was analysed by nested PCR to identify msp2 allelic families (FC27, 3D7, multiplicity of infection) and by quantitative PCR to estimate copy number. Statistical tests compared groups and predictors of symptomatic infection. RESULTS: Of the 522 children included, those in the symptomatic group were younger than those in the asymptomatic group (mean age: 5.77 vs. 7.25 years; p < 0.001) and were more frequently male (70%). P. falciparum prevalence was higher among symptomatic children (69.8%). The FC27 allele family and polyclonal infections (higher multiplicity of infection) were strongly associated with symptomatic malaria (aOR = 6.50 and 24.58, respectively; p < 0.01). Gene copy number was higher in symptomatic and polyclonal infections, but was not independently associated with clinical status after multivariable adjustment (aOR = 0.98; p = 0.134). Parasite positivity remained a strong independent predictor of symptomatic disease (aOR = 3.83; p < 0.001). CONCLUSION: Symptomatic malaria in children is more closely associated with parasite genotype diversity than density. This emphasises the importance of control strategies for molecular surveillance.
Loss of CASQ2 promotes vascular smooth muscle cell phenotypic switching in aortic dissection uncovered by integrated single-cell transcriptomics.
Chen K, Wang M, Zhang Z … +6 more , Chen Y, Zhu H, Yang T, Xia Y, Guo M, Li J
BMC Med Genomics · 2026 Jun · PMID 42288847 · Full text
BACKGROUND: Aortic dissection (AD) is a life-threatening cardiovascular disease with limited effective therapeutic options. Phenotypic switching of aortic vascular smooth muscle cells (VSMCs) from a contractile to a path...
BACKGROUND: Aortic dissection (AD) is a life-threatening cardiovascular disease with limited effective therapeutic options. Phenotypic switching of aortic vascular smooth muscle cells (VSMCs) from a contractile to a pathological state is a critical driver of AD progression. However, the molecular regulators governing this transition remain incompletely understood. This study aimed to identify a critical regulator of VSMC phenotypic switching in AD and to investigate its underlying mechanisms and translational relevance. METHODS: Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing datasets obtained from the Gene Expression Omnibus (GEO) database were integrated for analysis. To enhance robustness and reduce dataset-specific bias, weighted gene co-expression network analysis (WGCNA) was performed in both aortic aneurysm (AA) and AD cohorts to identify gene modules associated with VSMC function. Overlapping VSMC-related modules were intersected to define candidate genes. Key regulators were further prioritized in AD datasets using LASSO regression and validated by single-cell RNA sequencing (scRNA-seq) pseudotime trajectory analysis to delineate dynamic gene expression during VSMC phenotypic switching. Functional validation was conducted in an angiotensin II (Ang II)-induced experimental AD mouse model with AAV9-mediated CASQ2 overexpression, as well as in primary VSMCs isolated from the abdominal aorta of mice and treated with Ang II in vitro. Aortic morphology, medial calcification, VSMC phenotypic markers, intracellular Ca homeostasis, and endoplasmic reticulum (ER) stress signaling were systematically evaluated. RESULTS: WGCNA identified a conserved gene module comprising 64 genes associated with VSMC phenotypic transition. Integrative LASSO and scRNA-seq analyses prioritized CASQ2 as a key gene with reduced expression in AD VSMCs. Pseudotime analysis revealed progressive downregulation of CASQ2 during osteochondrogenic phenotypic switching. In AngII-induced experimental AD mice, CASQ2 expression was decreased in the aortic media and accompanied by enhanced medial calcification. In vivo, Ang II infusion markedly reduced aortic CASQ2 expression and induced medial dilation and calcification, accompanied by increased mortality. AAV9-mediated CASQ2 overexpression significantly improved survival, attenuated aneurysmal enlargement, reduced vascular calcification and partially restored contractile marker expression. In vitro, Ang II stimulation decreased CASQ2 levels in primary VSMCs, promoted osteochondrogenic marker expression, and induced intracellular Ca²⁺ overload. CASQ2 overexpression restored calcium-release complex components, suppressed cytosolic Ca²⁺ elevation, and markedly reduced ER stress activation. CONCLUSIONS: CASQ2 may represent a VSMC-enriched functional regulator involved in AD-associated phenotypic switching through calcium homeostasis and ER stress. These findings suggest that CASQ2 represents a potential therapeutic target in AD. Further studies are needed to determine its disease specificity and translational relevance.
Kyphoscoliotic Ehlers-Danlos syndrome due to a novel homozygous PLOD1 variant: severe vascular involvement and molecular diagnosis.
Yu Y, Zeng Y, Liu Y … +7 more , Liu Y, Shi Q, Zhu H, Wen J, Liang D, Li Z, Wu L
BMC Med Genomics · 2026 Jun · PMID 42277864 · Full text
BACKGROUND: Kyphoscoliotic Ehlers-Danlos syndrome (kEDS, OMIM: #225400) is a rare subtype of Ehlers-Danlos syndrome characterized by joint hypermobility and spinal deformity, with occasional vascular complications. The r...
BACKGROUND: Kyphoscoliotic Ehlers-Danlos syndrome (kEDS, OMIM: #225400) is a rare subtype of Ehlers-Danlos syndrome characterized by joint hypermobility and spinal deformity, with occasional vascular complications. The rarity of vascular phenotypes in kEDS often leads to low clinical suspicion, contributing to delayed diagnosis and poor outcomes. CASE PRESENTATION: We report a 13-year-old boy who presented with joint laxity, scoliosis, blue sclerae, and pectus excavatum, and who ultimately succumbed to aortic rupture. Initial whole-exome sequencing (WES) and copy number variation (CNV) analysis failed to identify a causative variant, and genes associated with Marfan syndrome were excluded by WES and multiplex ligation-dependent probe amplification (MLPA). Upon re-analysis of the WES data, however, a homozygous deletion spanning exons 15-16 of PLOD1 was detected and subsequently confirmed by quantitative PCR. CONCLUSIONS: This case demonstrates that small exon deletions in PLOD1 may not be reliably detected by routine WES/CNV pipelines, leading to diagnostic delay, and underscores the underrecognized vascular risk in kEDS. Clinicians should maintain vigilance for vascular complications in patients with kEDS and consider re-analysis strategies to ensure timely diagnosis and appropriate genetic counseling.
Associations of genetic variants in TCF7L2, MC4R, AGT and ACE genes with cardiometabolic diseases in Black South Africans.
Ngwa NE, de Buys K, Matshazi DM … +7 more , Levitt NS, Lombard C, Davison GM, Matsha TE, Kengne AP, Hemmings SMJ, Peer N
BMC Med Genomics · 2026 Jun · PMID 42271435 · Full text
BACKGROUND: Our study investigated the association between transcription factor 7-like 2 (TCF7L2-rs7903146), angiotensin convertase enzyme (ACE-rs4646994), angiotensinogen (AGT-rs699), angiotensin II type 1 receptor (AGT...
BACKGROUND: Our study investigated the association between transcription factor 7-like 2 (TCF7L2-rs7903146), angiotensin convertase enzyme (ACE-rs4646994), angiotensinogen (AGT-rs699), angiotensin II type 1 receptor (AGT1R-rs5186), fat mass and obesity-associated (FTO-rs17817499) and melanocortin 4 receptor (MC4R-rs17782313, rs12970134 and rs229616) single nucleotide polymorphisms (SNPs) with type 2 diabetes (T2D), obesity and hypertension in a Black South African population. METHODS: This cross-sectional study involved 560 Black South Africans aged 25 to 74 years. Participant demographic and lifestyle characteristics were self-reported; anthropometry and blood pressures (BP) measured; oral glucose tolerance tests used to diagnose T2D; and SNPs genotyped by polymerase chain reaction. The Benjamini-Hochberg method was used to control for multiple hypothesis testing, using a significance threshold of 0.12. RESULTS: Using the median test, systolic BP was significantly higher in carriers of the G/G genotype of rs229616 within the MC4R gene compared to carriers of the G/A genotype (p = 0.006, p-FDR = 0.030). In the same gene, logistic regression analysis showed that carriers of the minor C/C genotype of the rs17782313 SNP had a significantly higher risk of hypertension (OR = 1.37, p = 0.023, p-FDR = 0.115) in the unadjusted model. However, the significance was attenuated after adjusting for age, gender and BMI (OR = 1.32, p = 0.084, p-FDR = 0.140). Moreover, carriers of the minor T/T genotype of the TCF7L2 rs7903146 SNP had a lower risk of T2D in the crude model (OR = 0.66, p = 0.043, p-FDR = 0.108) and after adjustment for age, gender and BMI (OR = 0.63, p = 0.041, p-FDR = 0.108). These findings remained significant after correction for multiple comparisons. CONCLUSION: TCF7L2-rs7903146 (C/C genotype) and MC4R-17,782,313 (C/C genotype) SNPs are potential genetic risk factors for T2D and hypertension, respectively, in the Black South African population. Replicating these findings and exploring the role played by these genetic variants in downstream molecular pathways could aid in risk stratification and facilitate personalized approaches to healthcare delivery.
Angiotensin-Converting Enzyme 1 (ACE1) gene polymorphisms in pediatric patients with COVID-19: impact on disease severity and outcomes.
Mahmoudi S, Hosseinpour Sadeghi R, Pourakbari B … +2 more , Teymuri M, Mamishi S
BMC Med Genomics · 2026 Jun · PMID 42260544 · Full text
BACKGROUND: Angiotensin-converting enzyme 1 (ACE1) gene polymorphisms have been suggested to influence susceptibility to and severity of coronavirus disease 2019 (COVID-19) through dysregulation of the renin-angiotensin...
BACKGROUND: Angiotensin-converting enzyme 1 (ACE1) gene polymorphisms have been suggested to influence susceptibility to and severity of coronavirus disease 2019 (COVID-19) through dysregulation of the renin-angiotensin system. Despite considerable research on COVID-19, the influence of genetic factors, particularly polymorphisms in the ACE gene, on disease severity in pediatric populations remains inadequately understood. Therefore, the present study aimed to investigate the association of ACE1 insertion/deletion (I/D) polymorphism and ACE1 variants rs4341 and rs4343 with clinical manifestations, laboratory findings, and disease severity in hospitalized children with COVID-19. METHODS: This study included 100 hospitalized pediatric patients with confirmed COVID-19 infection. Demographic characteristics, including age and sex, clinical manifestations, comorbidities, disease severity, laboratory findings, ICU hospitalization, and mortality outcomes were recorded. Genotyping of the ACE1 I/D polymorphism was performed using PCR-based methods, while rs4341 (C/G) and rs4343 (A/G) polymorphisms were analyzed using PCR-restriction fragment length polymorphism (PCR-RFLP) assays. RESULTS: Among the 100 enrolled patients, 76% had mild/moderate disease and 24% had severe disease. The ACE1 D/D genotype was identified in 76% of patients, whereas the ACE1 I/I genotype was detected in only 3% of cases. In the analysis of the rs4341 polymorphism, among 77 successfully genotyped patients, the C/C genotype was predominant and identified in 56 out of 77 (73.7%) individuals, while the C/G genotype was observed in 20 out of 77 (26.3%) patients. Severe disease was observed in 34 out of 56 (61%) individuals carrying the rs4341 C/C genotype compared with 8 out of 20 (40%) individuals with the C/G genotype; however, the difference was not statistically significant (P = 0.12). Patients carrying the rs4343 A/A genotype exhibited significantly higher white blood cell counts [8.2 (5.7-11.9) ×10⁹ cells/L vs. 5.5 (4.2-7.8) ×10⁹ cells/L, P = 0.008], platelet counts [269 (220.2-332) ×10⁹ cells/L vs. 206 (161.5-300) ×10⁹ cells/L, P = 0.041], and lactate dehydrogenase levels [555.5 (494.8-601.7) U/L vs. 461 (403-593.7) U/L, P = 0.011] compared with rs4343 A/G carriers. CONCLUSION: In conclusion, although the ACE1 D/D genotype was highly prevalent among pediatric COVID-19 patients, it was not significantly associated with disease severity or ICU hospitalization. Similarly, no significant associations were identified between rs4341 or rs4343 polymorphisms and overall clinical outcomes. However, rs4343 variants were associated with differences in laboratory parameters, including WBC count, platelet count, and LDH levels, suggesting a possible role in host inflammatory responses during SARS-CoV-2 infection. These findings should be interpreted cautiously due to the relatively small sample size and lack of a healthy control group.
Correction: apolipoprotein D downregulation in OSCC: multi-database validation and clinical significance.
Wang S, Zhao J, Bai R … +4 more , Ou J, Tang C, Hang J, Nong X
BMC Med Genomics · 2026 Jun · PMID 42260520 · Full text
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A founder variant in TANGO2 p.(Leu148Trp) in ten Palestinian families: clinical characterization and haplotype analysis of TANGO2 deficiency disorder.
Canavati C, Ashhab M, Rabie G … +12 more , Hreimat L, Shatrit H, Kamal L, Zahdeh F, Dajani D, Atawneh O, Alsharha MA, Damseh N, Abu-Libdeh B, Dweikat I, Handal N, Kanaan M
BMC Med Genomics · 2026 Jun · PMID 42260493 · Full text
BACKGROUND: TANGO2 deficiency disorder (TDD) is a rare autosomal recessive condition characterized by recurrent metabolic crises, rhabdomyolysis, encephalopathy, seizures, intellectual disability, and life-threatening ca...
BACKGROUND: TANGO2 deficiency disorder (TDD) is a rare autosomal recessive condition characterized by recurrent metabolic crises, rhabdomyolysis, encephalopathy, seizures, intellectual disability, and life-threatening cardiac arrhythmias. METHODS: Here, we describe 16 affected individuals from 10 consanguineous Palestinian families harboring a shared homozygous missense variant in TANGO2 (NM_152906.7:c.443T > G; NP_690870.3:p.(Leu148Trp)). Exome sequencing identified the variant in three probands and targeted Sanger sequencing confirmed segregation in all remaining families. The variant is absent from population databases and is predicted to be deleterious by multiple in silico tools. Microsatellite marker analysis was performed using five short tandem repeat (STR) markers spanning the TANGO2 locus. RESULTS: Clinical presentation was heterogeneous, including developmental delay, recurrent encephalopathy, rhabdomyolysis, seizures, and cardiac involvement. Microsatellite marker analysis revealed a conserved ancestral haplotype flanking the TANGO2 locus in all genotyped affected individuals, supporting a founder effect in this population. Supportive management including coenzyme Q10 and B-complex vitamins (B-100) was commonly used; consistent with prior reports, some families described reduced frequency and/or severity of spells following supplementation. CONCLUSIONS: These findings provide strong clinical, genetic, and haplotype evidence supporting reclassification of the TANGO2 p.(Leu148Trp) variant as likely pathogenic and highlight the importance of early molecular diagnosis and targeted screening strategies in high-consanguinity populations.
The miR-4512/PDZK1IP1 axis in hepatocellular carcinoma: clinical significance, diagnostic value, and functional validation.
Chen X, Zhou G, Cen L … +2 more , Qin S, Dai M
BMC Med Genomics · 2026 Jun · PMID 42260473 · Full text
BACKGROUND: PDZK1IP1 is implicated in various cancers, but its role in hepatocellular carcinoma (HCC) remains unclear. AIM: To investigate the expression, clinical significance, and biological function of the miR-4512/PD...
BACKGROUND: PDZK1IP1 is implicated in various cancers, but its role in hepatocellular carcinoma (HCC) remains unclear. AIM: To investigate the expression, clinical significance, and biological function of the miR-4512/PDZK1IP1 axis in HCC. METHODS: Serum samples from 56 HCC patients, 57 cirrhosis patients, and 68 healthy controls were analyzed by qRT-PCR. Diagnostic and prognostic values were assessed by ROC curves and Kaplan-Meier/Cox regression analyses, respectively. The regulatory relationship was validated by dual-luciferase assay. Functional roles and downstream mechanisms were examined via cellular assays and Western blotting. RESULTS: Serum miR-4512 was significantly downregulated while PDZK1IP1 was upregulated in HCC patients, showing a negative correlation. Both markers served as independent prognostic factors for overall survival and disease-free survival. A triple diagnostic combination (miR-4512 + PDZK1IP1 + AFP) achieved an outstanding AUC of 0.988. Dual-luciferase assay confirmed miR-4512 directly targeted the 3'UTR of PDZK1IP1. Functionally, miR-4512 overexpression or PDZK1IP1 silencing suppressed HCC cell proliferation, migration, and invasion. Mechanistically, Western blot revealed that miR-4512 suppressed the Akt/mTOR signaling pathway and glycolysis, which was robustly reversed by PDZK1IP1 overexpression. CONCLUSION: The miR-4512/PDZK1IP1 axis regulates HCC progression via the Akt/mTOR and glycolysis pathways. Both molecules demonstrate significant potential as robust diagnostic and prognostic biomarkers for HCC.
Characterizing SMN1 hybrid and deletion alleles using large-scale SNP array-based SMA carrier screening.
Vidal-Folch N, Stout C, Winters J … +3 more , Oglesbee D, Hasadsri L, Cook SL
BMC Med Genomics · 2026 Jun · PMID 42251298 · Full text
BACKGROUND: Most spinal muscular atrophy (SMA) carrier screening assays quantify SMN1 exon 7 copy number, providing limited information about the prevalence or structure of SMN1-SMN2 hybrid alleles generated through gene...
BACKGROUND: Most spinal muscular atrophy (SMA) carrier screening assays quantify SMN1 exon 7 copy number, providing limited information about the prevalence or structure of SMN1-SMN2 hybrid alleles generated through gene conversion. As long-read sequencing (LRS) studies begin to resolve these alleles at high resolution, typically in modest cohorts, large population-scale data remain essential for defining the broader allele-frequency context in which such structural signatures occur. METHODS: We evaluated SMN1 exon 7 and exon 8 copy number in 18,015 individuals undergoing expanded carrier screening using a SNP-based array. Carriers were classified by deletion pattern, and representative cases underwent droplet digital PCR (ddPCR) to distinguish contiguous deletions from gene-conversion-derived hybrid alleles based on coordinated SMN1/SMN2 exon and intron copy number profiles. RESULTS: Among 457 carriers (2.5%), exon 7-only deletions accounted for ~ 53%, while exon 7 + 8 deletions comprised ~ 47%. ddPCR showed that exon 7-only deletions predominantly represented SMN1-SMN2 hybrid alleles, whereas exon 7 + 8 deletions reflected contiguous loss of both exons. Isolated exon 8 deletions were rare (~ 0.05%) and likewise exhibited hybrid architecture. This distribution contrasts with earlier population studies reporting a predominance of exon 7 + 8 deletions and indicates that hybrid alleles constitute a substantial proportion of SMN1 deletion alleles in the general population. CONCLUSIONS: While hybrid resolution is not required for routine SMA carrier detection, the unexpectedly high prevalence of hybrid alleles highlights an important category of SMN1 structural variation that merits deeper investigation. These population-scale data provide a framework to guide and contextualize future LRS-based analyses aimed at resolving SMN1 gene-conversion tracts, allele structures, and potential modifier variants relevant to SMA pathogenesis and therapeutic response. Together, these findings support a more comprehensive understanding of SMN1 allele diversity as genomic technologies advance toward high-resolution characterization of the SMN locus. TRIAL REGISTRATION: Clinical trial number: not applicable.
Sporadic cone-rod dystrophy caused by a heterozygous RAB28 p.Ser23Phe pathogenic variant and a de novo 4p16.1p15.33 deletion.
Park J, Jang W, Ahn Y … +1 more , Lee HJ
BMC Med Genomics · 2026 Jun · PMID 42231409 · Full text
BACKGROUND: Cone-rod dystrophy (CRD) is an inherited retinal dystrophy characterized by decreased visual acuity, color vision defects, and progressive loss of peripheral vision. RAB28-associated CRD is genetically homoge...
BACKGROUND: Cone-rod dystrophy (CRD) is an inherited retinal dystrophy characterized by decreased visual acuity, color vision defects, and progressive loss of peripheral vision. RAB28-associated CRD is genetically homogeneous and results from pathogenic variants in the RAB28 gene, which is essential for photoreceptor function. CASE PRESENTATION: Fundus examinations, optical coherence tomography, color vision tests, and full-field electroretinography (ERG) were performed in the proband. Genetic analysis, including clinical exome sequencing (CES), Sanger sequencing and chromosomal microarray (CMA), was conducted to determine the genetic cause in the proband. The patient exhibited significantly reduced visual acuity, severe color vision impairment, macular atrophy, and thinning of the photoreceptor layers. Full-field ERG revealed severely diminished cone responses, while rod responses were mildly reduced. Genetic analysis identified that the heterozygous RAB28 c.68 C > T/p.(Ser23Phe) pathogenic variant was inherited exclusively from the father. Additionally, a 3.4 Mb deletion on chromosome 4p16.1p15.33 was detected only in the proband. Four genes associated with Mendelian diseases, including CLNK (OMIM *611434), HS3ST1 (*603244), NKX3-2 (*602183), and RAB28 (*612994), are located within this deletion region. CONCLUSIONS: This case illustrates a rare combination of a heterozygous RAB28 c.68 C > T/p.(Ser23Phe) pathogenic variant and a de novo 4p16.1p15.33 deletion, which is associated with AR CRD. Although extremely rare, bi-allelic RAB28 pathogenic variants can result from one inherited allele and a de novo deletion in the other.
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