Front Genet [JOURNAL]
Sun
200 papers
Ischemic stroke as an initial manifestation of Loeys-Dietz syndrome type 3 caused by the recurrent p.Arg287Trp variant in : a case report with familial context.
Chen CX, Zhou YY, Hong ZQ … +1 more , Hong QL
Front Genet · 2026 · PMID 42266410 · Full text
BACKGROUND: Loeys-Dietz syndrome type 3 (LDS3) is a rare autosomal dominant connective tissue disorder caused by pathogenic variants in While characteristic features include aortic aneurysm, hypertelorism, and bifid uvu...
BACKGROUND: Loeys-Dietz syndrome type 3 (LDS3) is a rare autosomal dominant connective tissue disorder caused by pathogenic variants in While characteristic features include aortic aneurysm, hypertelorism, and bifid uvula, ischemic stroke as the presenting symptom has been rarely reported. CASE PRESENTATION: We report a 32-year-old Chinese woman who presented with acute ischemic stroke involving the right occipital lobe and thalamus. Comprehensive vascular imaging revealed multiple arterial abnormalities, including aberrant right subclavian artery with aneurysmal dilatation, right vertebral artery aneurysmal dilatation with multisegmental stenosis, left vertebral artery multifocal segmental severe stenosis, and tortuous intracranial vessels Whole-exome sequencing identified a heterozygous pathogenic variant NM_005902.4:c.859C>T (p.Arg287Trp) in . Family history was significant for aortic dissection in her father. CONCLUSION: This case expands the phenotypic spectrum of LDS3, emphasizing that ischemic stroke may be an underrecognized initial presentation. Early genetic screening in young stroke patients with unusual vascular features may facilitate timely diagnosis and enable appropriate preventive interventions.
Characterization of circular RNAs in mammary tissue from Holstein cows at perinatal period and dry period.
Liang Y, Gu S, Zhang Z … +5 more , Wang Y, Li M, Karrow NA, Hua J, Mao Y
Front Genet · 2026 · PMID 42266409 · Full text
INTRODUCTION: Perinatal and dry periods are important physiological stages for cows to recover after calving and improve lactation performance. Exploring the expression characteristics of circRNAs as a molecular hotspot...
INTRODUCTION: Perinatal and dry periods are important physiological stages for cows to recover after calving and improve lactation performance. Exploring the expression characteristics of circRNAs as a molecular hotspot during the perinatal and dry periods of dairy cows is of great significance. METHODS: This study identified and compared circular RNAs (circRNAs) in the mammary tissue of three cows between the perinatal and dry periods. After analysis, we identified 10,388 circRNAs, ranging from 48 bp to 99,406 bp. RESULTS: Chromosome 1 had the most circRNAs, containing 597 circRNAs. Furthermore, 91.97% of the circRNAs belonged to sense-overlapping circRNA. CircRNAs contain different number of exons, ranging from 1 to 47 and most of the cirsRNAs harbored 1 to four exons. Compared with dry period, 132 circRNAs with significantly different expressions were identified in the perinatal period, 99 of which were upregulated and 33 downregulated. Enrichment analysis revealed the enrichment of circRNAs in the proliferation and differentiation of cells, such as regulation of chondrocyte differentiation and integral component of plasma membrane, phosphatidylinositol 3-kinase binding. The significantly enriched pathways further indicate that circRNAs play important roles in immunity and infection, such as cell adhesion molecules (CAMs), herpes simplex infection, and Kaposi's sarcoma-associated herpesvirus infection. DISCUSSION: This study revealed the expression profile and characteristics of circRNAs in the perinatal and dry period of Holstein cows, thus providing rich information for studying circRNAs functions and mechanisms underlying perinatal and dry period diseases, suggesting a new avenue to investigate the regulatory mechanisms of dairy cow genetic breeding.
Case Report: a novel homozygous frameshift variant causing severe neutral lipid storage disease with myopathy (NLSDM) in a Moroccan patient.
Faedo E, Araujo Chumacero MM, Missaglia S … +13 more , Lunati-Rozie A, Severa G, Onnée M, Das B, Martegani E, Lafage N, El Bejjani L, Barka I, Gobin-Limballe S, Badaoui B, Lefaucheur JP, Tavian D, Malfatti E
Front Genet · 2026 · PMID 42266408 · Full text
Neutral lipid storage disease with myopathy (NLSDM) is an ultra-rare autosomal recessive lipid metabolism disorder caused by variants, leading to defective adipose triglyceride lipase (ATGL) function and pathological tr...
Neutral lipid storage disease with myopathy (NLSDM) is an ultra-rare autosomal recessive lipid metabolism disorder caused by variants, leading to defective adipose triglyceride lipase (ATGL) function and pathological triglyceride accumulation in multiple tissues. Fewer than 150 cases have been reported worldwide, and the clinical spectrum remains incompletely defined. A 57-year-old Moroccan man presented with diabetes, hearing loss, cataracts, hypertrophic cardiomyopathy, and asymmetric weakness. Whole-body muscle MRI revealed severe fatty infiltration of the supraspinatus muscles in the upper limbs and asymmetric right biceps femoris and left lateral gastrocnemius muscle with a patchy pattern in the lower limbs. A deltoid muscle biopsy revealed vacuoles filled with lipids. Peripheral blood smear analysis showed Jordans' anomaly. Next-generation sequencing disclosed the novel homozygous c.1043del, p.Phe348SerfsTer18 frameshift variant predicted to disrupt the adipose triglyceride lipase (ATGL) patatin domain. Bioinformatics protein modeling predicted disruption of the patatin domain and global structural instability, likely abolishing enzymatic activity. Western blotting performed on patient-derived muscle tissue revealed a truncated ATGL protein, functionally validating the truncating effect of this novel variant. This case broadens the phenotypic and molecular understanding of NLSDM.
Multimodal evidence for the association between muscle mass and NAFLD: insights from hospital-based data, NHANES and mendelian randomization.
Xie W, Li S, Han S
Front Genet · 2026 · PMID 42266407 · Full text
BACKGROUND: Sarcopenia has been suggested as a potential risk factor for non-alcoholic fatty liver disease (NAFLD), but the causal relationship remains unclear. METHODS: We conducted a multimodal study combining hospital...
BACKGROUND: Sarcopenia has been suggested as a potential risk factor for non-alcoholic fatty liver disease (NAFLD), but the causal relationship remains unclear. METHODS: We conducted a multimodal study combining hospital-based data, population survey, and Mendelian randomization (MR). A total of 2,384 patients with acute appendicitis (2016-2025) were analyzed using appendicular skeletal muscle mass index (ASMI) as a sarcopenia marker and CT-defined NAFLD as outcome. Logistic regression and SIMEX correction were applied. The association was validated in 21,696 NHANES participants (1999-2018) using the United States Fatty Liver Index (USFLI) and double-SIMEX correction. Finally, two-sample and multivariable MR were performed using GWAS summary data. RESULTS: Higher muscle mass was consistently associated with a lower NAFLD risk in hospital-based (OR = 0.16, 95% CI 0.03-0.82, P = 0.03) and NHANES populations (OR = 0.02, 95% CI 0.01-0.04, P < 0.001). MR analyses suggested a potential causal inverse relationship (OR = 0.91, 95% CI 0.84-0.99, P = 0.01), independent of BMI, cholesterol, and triglycerides (OR = 0.82, 95% CI 0.72-0.94, P = 0.003). CONCLUSION: This multimodal evidence suggested low muscle mass as a causal risk factor for NAFLD. Interventions that maintain or increase muscle mass may reduce NAFLD risk.
Eight-year follow-up of phenotypic progression in a Chinese XLRP pedigree with a novel gene mutation.
Sun H, Shi J, Yang S … +5 more , Tian H, Yang X, Xie G, Wei Y, Wang J
Front Genet · 2026 · PMID 42261552 · Full text
BACKGROUND: This study characterizes a Chinese X-linked retinitis pigmentosa (XLRP) pedigree harboring a pathogenic variant of the gene and presents the findings from 8-years follow-up with the aim of exploring the geno...
BACKGROUND: This study characterizes a Chinese X-linked retinitis pigmentosa (XLRP) pedigree harboring a pathogenic variant of the gene and presents the findings from 8-years follow-up with the aim of exploring the genotypic and phenotypic spectra. METHODS: We collected data from a Chinese pedigree comprising 23 individuals, including six affected males and five female carriers; all individuals underwent molecular analyses and comprehensive ophthalmic evaluations. RESULTS: We identified a novel c.392G>A (p.C131Y) mutation of the gene The baseline clinical evaluations of four affected males in the average age range of 1-8 years showed visual impairment; the mean visual acuity had a logMAR value of 0.5235 (range: 0.301-0.698) with an average spherical equivalent of -4.15D (range: -3.125D to -6.25D). The funduscopic observations were consistent with typical X-linked retinoschisis presentations, including pigmentary abnormalities, tessellated changes, and yellowish-white punctate exudations. We also detected disorganization of the outer retinal layer and decline of the electroretinography (ERG) amplitudes. Meanwhile, the five heterozygous carriers showed a wide range of phenotypic variability accompanied by mild or moderate visual changes. Intriguingly, asymmetric changes of the fundus were also detected in the retina of one of the carriers. During the 8-year follow-up period, the visual acuity remained unchanged or even improved slightly. Although early-onset myopia was more common in children, there was a slightly increasing trend in annual progression; moreover, while the retinal structure did not differ statistically significantly, the ERG changes indicated a steadily decreasing trend. CONCLUSION: The findings of this study provide insights into the pathogenicity of related XLRP, expand the spectrum of disease mutations, and enrich knowledge regarding the clinical phenotypes while highlighting the progressive nature and phenotypic variability.
Identification and molecular functional analysis of genes associated with addiction using integrated genetic web-based programs and databases.
Hossain WA, Butler MG
Front Genet · 2026 · PMID 42256342 · Full text
BACKGROUND: Addiction is a chronic, relapsing neuropsychiatric disorder despite adverse consequences. Addiction involves neurobiological changes in the reward, motivation, and memory systems, particularly affecting the d...
BACKGROUND: Addiction is a chronic, relapsing neuropsychiatric disorder despite adverse consequences. Addiction involves neurobiological changes in the reward, motivation, and memory systems, particularly affecting the dopaminergic pathways due to a complex interaction between inherited traits and life experiences. METHODS: To explore the role of genes in addictive behavior, we compiled a list of 332 clinically relevant genes from literature sources and searched GeneAnalytics, STRING web-based programs, and integrated genetic and protein databases for interactions and molecular profiles of genes in tissues and cells, diseases, pathways, biological processes, cellular components, functions, phenotypes, and compounds. RESULTS: We identified 332 genes associated with addictive behavior and predominantly expressed in the brain associated with schizophrenia, nervous system disorders, and cancer. Nine of the top 10 related pathways showed GPCR protein interaction and signaling involving the , , , and genes. The gene was recognized in eight of the top 10 high-scoring phenotypes involving the neurotransmitters dopamine and glutamate. We chose to study as the most identified gene when searching web-based programs and integrated genetic and protein databases. This gene encodes protein kinases that are required for protein phosphorylation, fundamental for most cellular functions, stabilization, regulation of targeted proteins including cell cycle control and signal transduction, neuron formation, and neurological function including the hippocampus. We identified the important PI3/AKT/mTOR signaling pathway that integrates extracellular growth signals, promotes proliferation, and inhibits apoptosis, which is important for brain function. These genes also overlap with other genes associated with ATPase activity, metabolism, and chaperone protein functions that play a role in addiction. In addition, we identified 29 genes that are shared with alcoholism/alcohol use disorder and overlap with interactive molecular functions and processes between alcoholism and addiction. CONCLUSION: Our study identified 332 addiction genes from literature sources and used integrated genetic approaches with two searchable web-based programs to provide insights into the complex molecular and genetic architecture of addiction. We identified cell cycle control factors, extracellular growth, signal transduction, and metabolism. The pathways involved selective protein phosphorylation and transduction of proteins as well as neurotrophic factors with mechanisms impacting nervous system development, plasticity and function when disturbed, leading to addictive behavior. Several genes associated with addiction overlapped with those associated with alcohol use disorder.
Exploratory transcriptomic analysis suggests candidate genes associated with loss of response to ustekinumab in Crohn's disease.
Lin J, Xie T, Zhong J … +4 more , Tu Y, Xiao C, Huang X, Wang Y
Front Genet · 2026 · PMID 42256341 · Full text
BACKGROUND: Despite the favorable safety and efficacy of ustekinumab in clinical practice for Crohn's disease, a subset of Crohn's disease patients still experience loss of response to this treatment. This study was thus...
BACKGROUND: Despite the favorable safety and efficacy of ustekinumab in clinical practice for Crohn's disease, a subset of Crohn's disease patients still experience loss of response to this treatment. This study was thus conducted to investigate the differential gene expression underlying ustekinumab loss of response in Crohn's disease patients. METHODS: This prospective study, grouped by response to ustekinumab, collected peripheral blood mononuclear cells from refractory moderate-to-severe adult Crohn's disease patients (8 vs. 9) who were admitted to the Second Affiliated Hospital of Guangzhou Medical University and received initial ustekinumab treatment between January 2024 and June 2025 for RNA sequencing. For exploratory pathway analysis, differentially expressed genes identified by DESeq2 using exploratory thresholds (|FC| > 1.5, < 0.05) were subjected to GO and KEGG enrichment, WGCNA, and PPI network analyses. Additionally, another 16 patients were included for the preliminary validation of candidate genes by qPCR. Furthermore, we conducted a clinical influence factor analysis on 81 patients who had already received medication. RESULTS: RNA sequencing identified 510 differentially expressed genes between ustekinumab responders and non-responders. Trait association analysis showed that the cyan module was the module most strongly associated with both ustekinumab non-response and stricturing behavior, consistent with the independent influence of stricturing behavior identified in the retrospective clinical study. This module was enriched in platelet activation, neutrophil extracellular trap formation, and focal adhesion (KEGG), as well as coagulation and platelet aggregation (GO). Among the 10 candidate genes selected for validation, FFAR2, ITGA2B, SOCS3, and KCNJ15 exhibited statistically significant differential expression. CONCLUSION: Our findings suggest that loss of response may be potentially associated with pro-inflammatory pathways independent of the drug's action pathways, as well as a "pro-fibrotic immune microenvironment" linked to intestinal strictures. Additionally, preliminary validation indicated that FFAR2, ITGA2B, SOCS3, and KCNJ15 may provide new perspectives for candidate differentially expressed genes associated with ustekinumab loss of response.
Episignature leads to diagnosis and reclassification of DYRK1A variant in a child with syndromic neurodevelopmental disorder: a case report.
Al-Younis I, Basque L, Crapoulet N … +8 more , Dyack S, Del Caño-Ochoa F, Ramón-Maiques S, MacKay SB, Rzasa J, Sadikovic B, McConkey H, Ben Amor M
Front Genet · 2026 · PMID 42256340 · Full text
BACKGROUND: Neurodevelopmental disorders (NDDs) are genetically heterogeneous, and standard genomic testing frequently yields variants of uncertain significance (VUS) or misses cryptic structural variants. Episignature a...
BACKGROUND: Neurodevelopmental disorders (NDDs) are genetically heterogeneous, and standard genomic testing frequently yields variants of uncertain significance (VUS) or misses cryptic structural variants. Episignature analysis, which detects disorder specific genome-wide DNA methylation patterns, has emerged as a functional tool to resolve diagnostic uncertainty. CASE PRESENTATION: We report a 7-year-old female with global developmental delay, autism spectrum disorder, epilepsy, microcephaly, and a distinctive facial gestalt. Initial trio whole-exome sequencing identified inconclusive VUSs in and . A therapeutic trial of uridine for the -related variants provided only transient benefit. Genome-wide DNA methylation analysis via EpiSign revealed a positive result for the episignature for Intellectual Developmental Disorder, Autosomal Dominant 7 (MRD7), associated with DYRK1A haploinsufficiency. Guided by this result, trio whole-genome sequencing identified a heterozygous deletion involving exon 5 of . The exact breakpoints were chr21:38,852,074-38,856,009 (GRCh37/hg19) and chr21:39,044,532-39,048,467 (GRCh38/hg38). This variant was reclassified from VUS to likely pathogenic based on concordant episignatures findings, clinical phenotype, and occurrence. CONCLUSION: This case highlights the utility of episignature analysis to help diagnose NDD patients, guide further molecular diagnostic testing, and as a functional assay to aid variant reclassification. Integration of epigenomic profiling with standard of care testing can shorten the diagnostic odyssey, prevent unnecessary interventions, and directly inform clinical management in patients with unresolved NDDs.
Case report: Whole-exome sequencing reveals a novel variant in a patient with epilepsy presenting with fever.
Guo W, Song D, Cheng K … +7 more , Wang C, Wang Y, Yang X, Lin Y, Jiang X, Liu X, Lan L
Front Genet · 2026 · PMID 42245406 · Full text
Epilepsy is a prevalent neurological disorder characterized by recurrent seizures and significant impacts on quality of life. This case report describes a 2-year-old male patient presenting with epilepsy associated with...
Epilepsy is a prevalent neurological disorder characterized by recurrent seizures and significant impacts on quality of life. This case report describes a 2-year-old male patient presenting with epilepsy associated with fever, in whom whole-exome sequencing (WES) revealed a novel variant in the gene, resulting in the amino acid substitution p.Leu187His. This variant is classified as likely pathogenic and is situated within a key functional domain of the BK channel, a crucial regulator of neuronal excitability. In silico analyses suggest that the substitution alters the local hydrophobicity and may disrupt the channel's function, potentially contributing to the patient's seizure activity. Additionally, the identification of this genetic variant underscores the importance of genetic factors in epilepsy, particularly in cases of drug-resistant epilepsy (DRE) or those with unclear etiology. The findings highlight the utility of WES in diagnosing genetically mediated epilepsy and the need for further research to establish comprehensive genotype-phenotype correlations, ultimately guiding personalized treatment strategies for affected individuals.
Case Report: Two siblings with a novel homozygous SLC18A2 variant causing parkinsonism-dystonia-2: a case series from Saudi Arabia.
Almutair M, Hakami W
Front Genet · 2026 · PMID 42245405 · Full text
BACKGROUND: Monoamine neurotransmitter disorders are rare, early-onset neurological conditions that frequently mimic cerebral palsy or epileptic encephalopathies, resulting in diagnostic delay. Parkinsonism-dystonia-2 (P...
BACKGROUND: Monoamine neurotransmitter disorders are rare, early-onset neurological conditions that frequently mimic cerebral palsy or epileptic encephalopathies, resulting in diagnostic delay. Parkinsonism-dystonia-2 (PKDYS2), caused by biallelic variants in , encodes vesicular monoamine transporter 2 (VMAT2), which is essential for dopamine and serotonin vesicular storage and release. The disorder is characterized by global developmental delay, parkinsonism, dystonia, and autonomic dysfunction. METHODS: This retrospective case report describes two siblings from a consanguineous family diagnosed with PKDYS2. Clinical, neuroimaging, and genetic data were collected from medical records, with longitudinal follow-up to assess disease progression and treatment response. Whole-exome sequencing (WES) was performed, and variants were analyzed using standard bioinformatics pipelines. A homozygous splice-site variant in (c.1122 + 2T>C) was identified, classified as likely pathogenic according to ACMG/ClinGen criteria, and confirmed by Sanger sequencing with parental segregation. RESULTS: Both siblings presented in early infancy with hypotonia, developmental delay, dystonia, and oculogyric crises, with normal neuroimaging. WES identified a homozygous splice-site variant (c.1122 + 2T>C) in both patients. Pramipexole resulted in partial improvement in one patient but was poorly tolerated in the other. Alternative therapies, including clonidine and trihexyphenidyl, provided limited symptomatic benefit. Both patients demonstrated severe and persistent neurodevelopmental impairment at follow-up. CONCLUSION: This case report identifies a previously unreported splice-site variant (c.1122 + 2T>C) in two siblings with a severe neurodevelopmental phenotype characterized by hypotonia, dystonia, autonomic dysfunction, and parkinsonian features. These findings highlight the key role of genetic testing in establishing the diagnosis, avoiding ineffective treatments, and guiding management. Early genetic evaluation should be considered in children with early-onset movement disorders.
Correction: SPDL1 overexpression is associated with the 18F-FDG PET/CT metabolic parameters, prognosis, and progression of esophageal cancer.
Liu HS, Guo Q, Yang H … +6 more , Zeng M, Xu LQ, Zhang QX, Liu H, Guo JL, Zhang J
Front Genet · 2026 · PMID 42245404 · Full text
[This corrects the article DOI: 10.3389/fgene.2022.798020.].
[This corrects the article DOI: 10.3389/fgene.2022.798020.].
Causal association and molecular mechanisms of periodontal disease and muscle wasting and atrophy: Mendelian randomization and bioinformatics analysis.
Liu Y, Zhang W, Liu Y … +3 more , Bian Y, Liu X, Liu W
Front Genet · 2026 · PMID 42245403 · Full text
BACKGROUND: Periodontal disease, a chronic inflammatory disorder, is increasingly linked to systemic conditions. This study investigates its causal role in muscle wasting via chronic inflammation, aiming to inform integr...
BACKGROUND: Periodontal disease, a chronic inflammatory disorder, is increasingly linked to systemic conditions. This study investigates its causal role in muscle wasting via chronic inflammation, aiming to inform integrative therapeutic strategies. METHODS: Mendelian randomization (MR) analysis was applied to assess causality. Periodontal disease-related genes were obtained from the GEO dataset GSE223924, and muscle atrophy-related targets from GeneCards. Shared targets were analyzed via protein-protein interaction (PPI) networks, followed by functional enrichment (GO/KEGG) and immune infiltration analyses. Key molecular alterations were validated in clinical samples using qRT-PCR and Western blot. Potential therapeutics were identified through drug prediction and molecular docking. RESULTS: Periodontal disease promotes muscle atrophy through systemic inflammatory dysregulation. We identified 415 shared targets, with IL-6, IL-1β, and IL-10 emerging as core genes. These were enriched in the PI3K-Akt signaling pathway and correlated significantly with altered immune cell infiltration. Experimental validation confirmed dysregulation of these cytokines in patient tissues. Through drug prediction and molecular docking, exploratory potential candidate compounds were obtained. These are only the results of the preliminary virtual screening, including rofecoxib, TT-301 and nelfinavir. CONCLUSION: This study initially explored the potential positive causal relationship between periodontal disease and muscle atrophy. This relationship is mediated by chronic inflammation centered on IL-6, IL-1β, and IL-10 within the PI3K-Akt pathway. The findings provide a translational foundation for dual-targeting therapeutic strategies.
Integrated clinical and multi-omics analysis links composite inflammatory indices to macrophage-associated molecular programs in aortic dissection.
Zhang B, Zhang Y, Zheng R … +2 more , Zhang Y, Wang L
Front Genet · 2026 · PMID 42245402 · Full text
BACKGROUND: Aortic dissection (AD) is a life-threatening vascular disease characterized by high mortality and complex pathophysiology involving inflammation and vascular wall degeneration. Composite inflammatory indices...
BACKGROUND: Aortic dissection (AD) is a life-threatening vascular disease characterized by high mortality and complex pathophysiology involving inflammation and vascular wall degeneration. Composite inflammatory indices derived from routine blood tests have shown prognostic value in AD; however, their role in disease assessment and their integration with molecular mechanisms remain unclear. METHODS: A total of 288 participants (144 AD patients and 144 controls) were enrolled for clinical analysis. Six composite inflammatory indices (NLR, MLR, SIRI, SII, PHR, and AISI) were calculated and evaluated using logistic regression and restricted cubic spline (RCS) models. Generalized propensity score (GPS) weighting was applied to reduce confounding. Multi-omics analyses were conducted by integrating single-cell RNA sequencing (GSE213740), bulk transcriptomic data (GSE153434), and inflammation-related gene sets. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were performed to identify candidate genes. Machine learning algorithms (LASSO, random forest, and SVM-RFE) were used for feature selection. External validation (GSE52093) and RT-qPCR experiments were conducted to verify feature genes. RESULTS: All six inflammatory indices were significantly elevated in AD patients (all P < 0.001) and independently associated with AD. RCS analysis revealed distinct nonlinear patterns, with AISI and SII showing continuous dose-response relationships, whereas NLR, MLR, and SIRI exhibited threshold effects. Associations remained robust across subgroups and after GPS weighting, with improved covariate balance (correlation coefficients <0.1). Single-cell analysis identified macrophages as the most prominently altered cell population, with 1,063 differentially expressed genes indicating extensive transcriptional reprogramming. Bulk RNA-seq analysis identified 2,766 DEGs (1,331 upregulated and 1,435 downregulated), and WGCNA revealed a key module (2,551 genes) strongly associated with AD (r = 0.98). Integrative analysis yielded 25 candidate genes, from which four genes (HIF1A, ITGA5, PLAUR, and TLR2) were consistently selected by machine learning. External validation and RT-qPCR confirmed significant upregulation of HIF1A, ITGA5, and PLAUR in AD tissues. CONCLUSION: Composite inflammatory indices are strongly associated with AD risk, and inflammatory-associated genes, particularly HIF1A, ITGA5, and PLAUR, may serve as potential diagnostic biomarkers and mechanistic targets.
Editorial: Unraveling GI cancer heterogeneity through single-cell multi-omics approaches.
Jansen RJ, Bardini R, Grassi E
Front Genet · 2026 · PMID 42245401 · Full text
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The association between gene polymorphisms and the risk of cancer based on a meta-analysis.
Li S, Feng X, Chen A … +5 more , Gui J, Gu C, Guo C, Deng Y, Mi Y
Front Genet · 2026 · PMID 42245400 · Full text
BACKGROUND: CD40, a constituent of the tumor necrosis factor (TNF) receptor superfamily, exhibits variable expression across different cancer types. It plays a role in mediating tumor cell proliferation, apoptosis, and s...
BACKGROUND: CD40, a constituent of the tumor necrosis factor (TNF) receptor superfamily, exhibits variable expression across different cancer types. It plays a role in mediating tumor cell proliferation, apoptosis, and survival, as well as antitumor immune responses and the tumor microenvironment. Although some studies have suggested a potential association between gene polymorphisms and cancer risk, definitive conclusions remain elusive. METHODS: We conducted a comprehensive literature search across PubMed, Web of Science, Google Scholar, Embase, and relevant Chinese databases for studies published up to 3 February 2025. Our systematic analysis focused on elucidating the association between CD40 polymorphisms and cancer susceptibility, employing various comparative models and subgroup analyses. We analyzed the differential expression of CD40 between various tumor tissues and their corresponding normal tissues, as well as the impact of CD40 expression levels on the overall survival outcomes of cancer patients using the Gene Expression Profiling Interactive Analysis (GEPIA) database. Based on the NCBI database, we further investigated the distribution characteristics of the mutant allele for four single nucleotide polymorphisms (SNPs) in the gene across six major global populations. Additionally, we constructed a protein-protein interaction network for CD40 using the STRING database. RESULTS: By analyzing 10 high-quality studies (comprising 20 case-control studies), we illustrate that the specific gene polymorphism (rs1883832) has a significant impact on breast cancer susceptibility. However, no significant correlation was found between the other three CD40 polymorphisms (rs4810485, rs1800686, and rs3765459) and tumor susceptibility. CONCLUSION: Our study found a strong association between CD40 polymorphisms (rs1883832) and breast cancer risk. However, a limitation of this study is that it did not explore the potential application of CD40 in the early diagnosis of breast cancer, nor did it clarify its impact on patient prognosis or its feasibility as a biomarker. These critical issues will be key directions for future research.
Episignature-based modelled first-tier diagnostic approach in the Dutch Caribbean: advancing equal care through epigenetic classification.
van der Laan L, Luijckx A, Lo-A-Njoe S … +13 more , Ecury-Goossen GM, Falix FA, Faries S, Manshande ME, Philippi PAEAC, van der Plas EM, Veenhuis HD, Rafael-Croes L, Mannens MMAM, Sadikovic B, Henneman P, Alders M, van Haelst MM
Front Genet · 2026 · PMID 42238820 · Full text
INTRODUCTION: Access to advanced genetic testing in the Dutch Caribbean is limited due to financial and logistical constraints. As a result, many patients with rare disorders remain undiagnosed or receive uncertain resul...
INTRODUCTION: Access to advanced genetic testing in the Dutch Caribbean is limited due to financial and logistical constraints. As a result, many patients with rare disorders remain undiagnosed or receive uncertain results, leading to unequal genetic care. DNA methylation profiles, or episignatures, provide sensitive and specific biomarkers. The clinically validated EpiSign™ assay offers a cost-effective and rapid diagnostic approach. METHODS: In this study, we evaluated EpiSign™ as a modelled first-tier screening approach within a proposed diagnostic workflow in a resource-limited setting and assessed its diagnostic yield and clinical utility in 19 patients from the Dutch Caribbean. Peripheral blood DNA was analyzed using the EPIC array, and methylation profiles were classified via a support vector machine algorithm against the EpiSign™ Knowledge Database. All patients underwent ID-WES and/or CGH-array analysis as part of the diagnostic workup. Positive EpiSign™ findings were subsequently confirmed by these molecular analyses. RESULTS: EpiSign™ helped provide a clinical diagnosis for six cases, including Fragile X syndrome, Intellectual Developmental Disorder X-linked 93 (MRX93), ReNU syndrome, and Kleefstra syndrome 1, all confirmed by subsequent analyses. Several patients harbored variants of uncertain significance in genes not yet associated with known episignatures. DISCUSSION: These results demonstrate that EpiSign™ provides actionable diagnostic insights as a first-tier diagnostic tool, particularly when combined with genomic analyses in the absence of parental samples. Its dynamic database allows reanalysis as new episignatures are identified, increasing its potential clinical utility in resource-limited settings.
A scoping review of genetic studies of treatment-resistant schizophrenia.
Das U, Riel H, Enriquez MR … +5 more , Shirinbakhshmasoleh M, Rose A, Herrera M, Lu Y, Kowalec K
Front Genet · 2026 · PMID 42238819 · Full text
BACKGROUND: This scoping review synthesized the current evidence on the genetic architecture of treatment-resistant schizophrenia (TRS). TRS is typically characterized by an inadequate response to antipsychotic treatment...
BACKGROUND: This scoping review synthesized the current evidence on the genetic architecture of treatment-resistant schizophrenia (TRS). TRS is typically characterized by an inadequate response to antipsychotic treatment in individuals with schizophrenia. Approximately 30% of individuals with schizophrenia develop treatment resistance, which is associated with greater disability, poorer prognosis, and increased mortality compared to treatment-responsive schizophrenia. Numerous studies have explored various genetic aspects of TRS; therefore, a scoping review was needed to summarize findings and consistent patterns, clarify the current level of understanding, and highlight remaining knowledge gaps. METHODS: A systematic search was conducted in PubMed up to March 2025. This scoping review followed PRISMA-ScR guidelines. Studies were included if they reported on genetic factors of TRS and its related constructs (clozapine resistance). Data on treatment resistance, study design, population characteristics, and genetic findings were extracted and synthesized. RESULTS: A total of 102 studies were included. Definitions of TRS varied across studies, with most using proxies such as clozapine use, antipsychotic polypharmacy, or they used presence of symptoms despite antipsychotic treatment. Most studies compared TRS with treatment-responsive schizophrenia and predominately included participants of European genetic ancestry. Genetic findings spanned common variants (e.g., identified from genome-wide association studies or in cumulative measures such as polygenic risk scores [PRS]), rare variants, and copy number variants and functional genomics such as gene expression and epigenetic markers. Common variants dominated the literature but explained only a small proportion of TRS liability. Higher schizophrenia PRS, specific rare variants, and copy number variants were associated with TRS, while TRS-specific PRS remain in development. GWAS largely focused on schizophrenia broadly, with substantial genetic overlap between TRS and schizophrenia. Transcriptomic and epigenomic data provide additional but limited insights, often confounded by drug exposure. CONCLUSION: Heterogeneous TRS definitions and limited ancestry diversity constrain progress, and robust TRS-specific genetic markers remain scarce. Harmonized criteria and larger, diverse cohorts are needed. Integrating genetic, epigenetic, and clinical data could improve early risk identification and guide precision treatment strategies.
The association of the TLR3 SNP rs3775291 with schizophrenia is influenced by age.
Wang Y, Peng L, Liu Y … +4 more , Gao Z, Wang J, Zhang T, Wang Y
Front Genet · 2026 · PMID 42238818 · Full text
BACKGROUND: Toll-like receptor 3 (TLR3) plays an important role in the pathogenesis of schizophrenia and the single nucleotide polymorphism (SNP) rs3775291 is associated with central nervous system diseases. In this stu...
BACKGROUND: Toll-like receptor 3 (TLR3) plays an important role in the pathogenesis of schizophrenia and the single nucleotide polymorphism (SNP) rs3775291 is associated with central nervous system diseases. In this study, we analysed the association between rs3775291 and schizophrenia. METHODS: A case-control study was performed that included 394 patients with schizophrenia and 445 healthy controls. Peripheral venous blood was collected, whole-genome DNA was extracted, and rs3775291 polymorphisms were detected using PCR and direct sequencing. Differences in distribution of allele and genotype frequencies between the two groups were compared using co-dominant, dominant, and recessive genetic models. The effects of sex, age, and family history were also analysed. RESULTS: Allele and genotype frequencies of rs3775291 were not associated with schizophrenia overall, nor were they associated with schizophrenia in the different sex or family history groups (P > 0.05). However, in the < 40 years age group, co-dominant and dominant model analyses showed that the frequency of TC and CC genotypes in patients with schizophrenia was significantly higher than that in the control group (P < 0.05), and TC and CC genotypes were associated with susceptibility to schizophrenia. There was no significant difference among people older than 40 years. CONCLUSION: The effect of rs3775291 on schizophrenia was age-related, TC and CC genotypes were associated with susceptibility to schizophrenia in younger individuals, and the TT genotype had a protective effect regarding schizophrenia.
mRNALocator-imb: an imbalance-tolerant ensemble framework integrating random forest and transformer for mRNA subcellular localization prediction.
Hu J, Liu H, Wang L … +1 more , Wu H
Front Genet · 2026 · PMID 42238817 · Full text
The subcellular localization of mRNAs determines the spatial context of protein translation and plays a critical role in the precise regulation of protein function. However, existing computational approaches for predicti...
The subcellular localization of mRNAs determines the spatial context of protein translation and plays a critical role in the precise regulation of protein function. However, existing computational approaches for predicting eukaryotic mRNA localization are often limited by inadequate exploitation of sequence-derived information and suboptimal performance under highly imbalanced data distributions. To address these challenges, we propose mRNALocator-imb, an imbalance-aware ensemble framework for mRNA subcellular localization prediction. The proposed model integrates physicochemical property-based features with k-mer frequency vectors, and adopts a hybrid architecture that combines Random Forest and Transformer networks to capture both global sequence patterns and contextual dependencies. To explicitly mitigate class imbalance, Random Oversampling and Label-Distribution-Aware Margin (LDAM) loss are incorporated during Transformer training, while the Synthetic Minority Over-sampling Technique (SMOTE) is employed to rebalance the data for Random Forest learning. Extensive experiments demonstrate that mRNALocator-imb consistently outperforms conventional machine learning methods and state-of-the-art predictors, particularly in scenarios characterized by severe class imbalance. Overall, this study presents a robust and generalizable framework for sequence-based subcellular localization prediction, with broad applicability to other imbalanced learning problems in bioinformatics.
Editorial: Transcription factors as regulators of adaptive immunity.
Patiño LC, Zhang D
Front Genet · 2026 · PMID 42232521 · Full text
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