Front Genet [JOURNAL]
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200 papers
Transcriptomic analysis reveals FcγR-mediated phagocytosis as a key pathway for the anti-inflammatory action of polysaccharides in loach.
Zhao Y, Xu X, Fan R … +2 more , Dai L, Chen L
Front Genet · 2026 · PMID 42394950 · Full text
(Cobitidae) is a small economic fish, which is widely distributed in ponds, reservoirs, and lakes in China. Because of its tasty meat and plentiful nutritional value, it is known as "water ginseng." Saccharide is the mos...
(Cobitidae) is a small economic fish, which is widely distributed in ponds, reservoirs, and lakes in China. Because of its tasty meat and plentiful nutritional value, it is known as "water ginseng." Saccharide is the most active component in the dry rhizome of the Chinese herbal medicine , and the content of polysaccharide is the highest. It is reported that polysaccharides (PSPs) have a significant therapeutic effect on inflammation. Based on the known pharmacological effects of PSPs, we fed PSPs to the acute inflammatory model of loach induced by lipopolysaccharides and analyzed the transcriptomic changes of the loach liver by RNA sequencing. The results show that a total of 10,250 differentially expressed genes (DEGs) were obtained after PSP treatment, and 5,652 DEGs were upregulated. The GO and KEGG enrichment analyses indicated that the DEGs regulated by PSPs are mainly involved in carbohydrate metabolism and the organismal immune system. After verifying the reliability of the sequencing results by RT-qPCR, we found that FcγR-mediated phagocytosis may be a key pathway for the anti-inflammatory effect of PSPs. This study provides important information on the molecular mechanism of PSPs in the treatment of inflammation in .
A novel splice site variant underlying the A phenotype: immunogenetic basis and functional dissection.
Guan HL, Hou J, Gao JL … +4 more , Li J, Zhang XM, Chen X, Fu XM
Front Genet · 2026 · PMID 42394949 · Full text
BACKGROUND: Accurate ABO blood group typing is essential for transfusion safety. However, ABO subtypes resulting from genetic variation can complicate this process. In contrast to the extensively studied exonic variants...
BACKGROUND: Accurate ABO blood group typing is essential for transfusion safety. However, ABO subtypes resulting from genetic variation can complicate this process. In contrast to the extensively studied exonic variants in the gene, splice-site variants are rarely reported, and the mechanisms underlying their contribution to ABO subtypes remain poorly characterized. METHODS: Four unrelated, healthy blood donors exhibiting mixed-field agglutination with anti-A reagents were subjected to Sanger sequencing. Long-range PCR coupled with nanopore sequencing was further performed to resolve the phased haplotype across the entire locus. The impact of the identified variant on splicing was predicted and validated by an minigene assay; its effects on protein structure were assessed using bioinformatic tools. Short tandem repeat (STR) analysis was also conducted to exclude blood group chimerism. RESULTS: Four unrelated Chinese blood donors exhibiting mixed-field agglutination with anti-A reagents were identified. Sanger sequencing and nanopore sequencing revealed that all four probands harbored a novel c.239 + 6T>C variant in the allele, with short tandem repeat (STR) analysis ruling out chimerism as the cause of the mixed-field agglutination. analysis predicted activation of a cryptic splice site, leading to retention of a 55-bp intronic fragment in the mRNA transcript. Further, the minigene splicing assay validated this predicted aberrant splicing pattern and additionally revealed trace production of the normally spliced transcript. Secondary and three-dimensional structural modeling further predicted that the resulting aberrant transcript encodes a severely truncated and catalytically compromised glycosyltransferase A, providing a molecular basis for the observed A antigen expression defect. CONCLUSION: In conclusion, a novel ABO variant (c.239 + 6T>C) responsible for the A phenotype was identified, and the mechanism underlying this phenotype was elucidated. By elucidating how a splice site variant disrupts glycosyltransferase function and alters antigen expression, this study contributes to a deeper understanding of the immunogenetic basis of ABO variation, with implications for transfusion safety and personalized immunohematology.
Case Report: Identification of two novel variants in a patient with a ciliopathy resembling Alström syndrome.
Ran CQ, Yang M, Chen L … +1 more , Liu X
Front Genet · 2026 · PMID 42394948 · Full text
BACKGROUND: Alström syndrome (AS) is a rare autosomal recessive ciliopathy caused by biallelic pathogenic variants in the gene. The condition is characterized by a spectrum of clinical manifestations, including cone-rod...
BACKGROUND: Alström syndrome (AS) is a rare autosomal recessive ciliopathy caused by biallelic pathogenic variants in the gene. The condition is characterized by a spectrum of clinical manifestations, including cone-rod dystrophy, sensorineural hearing loss, metabolic disturbances, and progressive multiorgan involvement. Ciliopathies share considerable clinical overlap, and some cases present with features that resemble AS without meeting all diagnostic criteria. This study aims to identify the pathogenic variants in a Chinese patient with a ciliopathy resembling AS. CASE PRESENTATION: We report a 27-year-old Chinese female with a body mass index (BMI) of 28.4 kg/m. The patient initially presented with progressive hearing loss at age 2 years, followed by visual impairment beginning at age 8 years. At age 17 years, she developed progressive alopecia accompanied by scaly, patchy papules. By age 22 years, she was diagnosed with polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus (T2DM). Laboratory investigations revealed dyslipidemia and hyperinsulinemia. Abdominal ultrasonography demonstrated hepatic steatosis and medullary sponge kidney, while pelvic ultrasound indicated polycystic ovarian morphology. Echocardiography revealed ventricular septal thickening. Whole-exome sequencing (WES) identified that our patient was a compound heterozygote for two novel variants in the gene, comprising c.12114 + 1G>T and c.1856_1860dup (p.Ser621Leufs*23). Both variants were classified as likely pathogenic in accordance with the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Based on the clinical phenotype and molecular findings, a diagnosis of a ciliopathy resembling AS was made, although a definitive diagnosis of AS could not be confirmed due to incomplete ocular phenotyping. Disease management included metformin and pioglitazone for T2DM, continued use of hearing aids, and scheduled regular follow-up evaluations. CONCLUSION: This report describes two novel variants, expanding the known mutational spectrum of the gene. Genetic testing plays a supportive role in diagnosis and is valuable for familial screening and counseling, although a definitive diagnosis of AS would require complete ophthalmic phenotyping and functional validation.
Integrative analysis identifies Hspa5 as a key regulator of the ERS/UPR-immune axis in spinal cord injury.
He G, Yang A, Xia H
Front Genet · 2026 · PMID 42394947 · Full text
BACKGROUND: Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are critical in secondary spinal cord injury (SCI), but their systematic characterization and link to immune infiltration remain uncl...
BACKGROUND: Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are critical in secondary spinal cord injury (SCI), but their systematic characterization and link to immune infiltration remain unclear. This study aimed to identify key ERS/UPR-related genes and their association with the immune microenvironment to find robust biomarkers for SCI. METHODS: We analyzed bulk RNA-seq data (GSE151371) to identify differentially expressed genes (DEGs), followed by pathway enrichment analyses. Machine learning (SVM-RFE) and protein-protein interaction networks were used to screen for hub genes. The identified hub genes were validated using an independent cohort (GSE5296), single-cell sequencing data (GSE213240), and qRT-PCR in a murine SCI model. RESULTS: We identified 17 ERS-related and 27 UPR-related DEGs, primarily enriched in neuron death pathways. SCI samples showed elevated ERS/UPR phenotype scores that positively correlated with myeloid cell infiltration. PPI analysis pinpointed and as central hub genes. However, multi-level validation confirmed that while Hspa5 was consistently and significantly upregulated across all platforms, Dnajc3 did not show significant differential expression in single-cell sequencing and qRT-PCR validation, thereby limiting its credibility as a direct transcriptional biomarker. A diagnostic nomogram incorporating both genes achieved an AUC of 0.745. CONCLUSION: ERS/UPR activation is a critical component of the post-SCI transcriptomic response and is closely linked to immune remodeling. emerges as a robust and dominant hub gene, representing a promising therapeutic target for SCI.
Evaluation of genomic selection to improve survival of eastern oysters infected with .
Delomas TA, Proestou DA, Small JM
Front Genet · 2026 · PMID 42394946 · Full text
Dermo disease is a chronic disease of eastern oysters infected by the protozoan parasite . This disease often causes mortality on farms at the end of the grow-out cycle and has been identified by producers as a top conce...
Dermo disease is a chronic disease of eastern oysters infected by the protozoan parasite . This disease often causes mortality on farms at the end of the grow-out cycle and has been identified by producers as a top concern. We here assessed the potential for marker-assisted selection and genomic selection to improve survival to infection in a laboratory disease challenge. Three year classes of oysters from a family-based breeding program were challenged and genotyped with a 66k single nucleotide polymorphism (SNP) array. Six SNPs were identified through a genome-wide association study as significantly influencing survival, but none explained more than 4% of the total genetic variance for survival. This suggests that marker-assisted selection is not a viable option. Genomic selection was estimated to yield a 9% relative increase in accuracy compared to pedigree-based selection, and using a subset of 3,500 SNPs was found to give comparable accuracy to that with the full panel.
A rescue assay for genetic diagnosis of oculocutaneous albinism using melanocytic MNT1 knock-out cells.
Mercier E, Michaud V, Sequeira A … +2 more , Arveiler B, Javerzat S
Front Genet · 2026 · PMID 42394945 · Full text
The molecular diagnosis of albinism is hampered by a significant number of genetic variants of unknown significance (VUS) including a majority of missense and in-frame insertion deletion variants. This contributes to the...
The molecular diagnosis of albinism is hampered by a significant number of genetic variants of unknown significance (VUS) including a majority of missense and in-frame insertion deletion variants. This contributes to the high rate of unresolved genetic diagnosis for this disease. We designed a straightforward test of missense VUS in albinism genes based on functional rescue. As a proof of concept, the assay was set up for testing variants in the gene associated with oculocutaneous albinism type 1. The gene was knocked-out in the human melanogenic MNT1 cell line and the resulting unpigmented clones used as host cells for rescue experiments. Selected VUS and control sequences were run through the assay. Expression of tyrosinase was quantified by Western blot, melanin synthesis was evaluated by direct observation as well as absorbance monitoring. One VUS, p.Ser270Phe (S270F) can be classified as likely pathogenic as it fails to restore pigmentation, whereas rescue was achieved with D305E and A391T. The two most frequent missense VUS of , S192Y and R402Q, were also tested independently or in combination confirming the pathogenic effect of their association in . All in all, this new assay is a proof of concept and can be considered for testing variants in other albinism genes such as and .
Stepwise genetic testing strategy identified pathogenic variants in 10 Chinese duchenne muscular dystrophy patients.
Zhao D, Yang W, Yang K … +3 more , Wu D, Qi N, Liao S
Front Genet · 2026 · PMID 42394944 · Full text
BACKGROUND: Duchenne muscular dystrophy (DMD) results from pathogenic variants in the gene. Despite routine screening using Multiplex Ligation-dependent Probe Amplification (MLPA) and Whole-Exome Sequencing (WES), a sub...
BACKGROUND: Duchenne muscular dystrophy (DMD) results from pathogenic variants in the gene. Despite routine screening using Multiplex Ligation-dependent Probe Amplification (MLPA) and Whole-Exome Sequencing (WES), a subset of cases remains molecularly unexplained. This diagnostic gap is often attributed to the inherent limitations of these methods in detecting deep intronic variants or complex structural rearrangements. METHODS: We implemented a tiered molecular diagnostic workflow for 10 male patients with suspected DMD. Primary screening for copy number variations (CNVs) was performed via MLPA. Negative cases were sequentially analyzed using WES and Whole-Genome Sequencing (WGS). Pathogenicity was validated through splicing predictions, mRNA transcript analysis, and chromosomal breakpoint mapping. RESULTS: MLPA identified CNVs in six cases. WES resolved two additional patients, identifying a frameshift variant (c.7392delC) and a nonsense variant (c.4729C>T). In the remaining two cases, WGS identified a deep intronic variant (c.9225-287C>A) and a 9.4 Mb chromosomal inversion. Functional analysis of the c.9225-287C>A variant revealed the activation of a 58-nucleotide pseudoexon, resulting in a frameshift (p.H3076Vfs*15) and truncated dystrophin expression. For the 9.4 Mb inversion, WGS successfully mapped the breakpoints to DMD intron 7, enabling definitive carrier identification within the family. CONCLUSION: Our findings demonstrate that WGS is a robust tool for detecting pathogenic variations that evade standard MLPA and WES protocols, including deep intronic variants and large-scale inversions. This study emphasizes the clinical necessity of an integrated, tiered genomic approach to ensure accurate genetic counseling and facilitate access to precision therapies.
Short CAG repeat variation as a regulatory factor in health and disease.
Manjarrez JR
Front Genet · 2026 · PMID 42394943 · Full text
Short cytosine-adenine-guanine (CAG) trinucleotide repeats, which encode polyglutamine (polyQ) tracts, are prevalent features of genes enriched in transcriptional and regulatory functions, including the androgen receptor...
Short cytosine-adenine-guanine (CAG) trinucleotide repeats, which encode polyglutamine (polyQ) tracts, are prevalent features of genes enriched in transcriptional and regulatory functions, including the androgen receptor (AR) and huntingtin (HTT). While expanded CAG repeats are well established in neurodegenerative disease pathogenesis, the functional significance of short, non-pathogenic repeat lengths remains underappreciated. This review connects evidence demonstrating that short CAG/polyQ tracts act as dynamic modulators of protein conformation, transcriptional activity, and protein-protein interactions. Variation within physiological repeat ranges influences receptor sensitivity, cellular signaling, and phenotypic diversity. The AR serves as a central model, where shorter repeat lengths enhance transactivation and androgen responsiveness and are associated with increased prostate cancer risk, while longer non-expanded repeats are linked to reduced receptor activity and modest reproductive and metabolic effects. Mechanistically, repeat length and sequence composition jointly influence repeat stability, RNA structure, and downstream regulatory processes. Beyond AR, short CAG variation contributes to neuropsychiatric phenotypes and broader regulatory networks. Collectively, short CAG repeats function as quantitative regulators of gene activity, shaping disease susceptibility, physiological variation, and evolutionary adaptation.
Potential role of the mutation in pulmonary fibrosis in a gene-edited mouse model.
Ruan H, Wang H, Zhu C … +8 more , Li Z, ASu Y, Ji Z, Li Y, Gu L, Fu C, Yu H, Yue P
Front Genet · 2026 · PMID 42388730 · Full text
INTRODUCTION: TRPV4 is a non-selective cation channel of the TRPV family and plays a key role in fibrosis, but its pathological mechanisms in genetically susceptible individuals remain unclear. This study aimed to invest...
INTRODUCTION: TRPV4 is a non-selective cation channel of the TRPV family and plays a key role in fibrosis, but its pathological mechanisms in genetically susceptible individuals remain unclear. This study aimed to investigate the potential role of the c.1491+1G>A splice-site mutation in pulmonary fibrosis using a gene-edited mouse model. METHODS: The mutation was identified in a family with autosomal dominant familial digital arthropathy-brachydactyly (FDAB). A corresponding gene-edited mouse model was generated using CRISPR/Cas9 technology. Histopathological analysis, single-cell RNA sequencing (scRNA-seq), qPCR, Western blot, and immunofluorescence co-staining were employed to assess phenotypic, transcriptomic, and molecular changes in the lungs. RESULTS: The model mice exhibited skeletal abnormalities and multi-organ damage, with pronounced pulmonary fibrosis. In the lung tissues of homozygous mutant (-Hom) mice, wild-type expression was significantly reduced, accompanied by thickened alveolar septa, pulmonary congestion, and increased collagen deposition. scRNA-seq revealed a decrease in the proportions of alveolar macrophages and NK cells, while Clara cells, fibroblasts, mesothelial cells, and alveolar type II cells increased. The ALCAM-CD6 and MIF-CD74 signaling axes were significantly upregulated. qPCR confirmed the transcriptional upregulation of , , , and ; Western blot further validated the increased protein levels of ALCAM, CD6, and CD74; and immunofluorescence confirmed the enhanced co-localization of MIF and CD74 in lung tissue. CONCLUSION: The c.1491+1G>A mutation is associated with exacerbated pulmonary fibrosis, altered lung cellular composition, disrupted ALCAM-CD6 immune regulatory pathways and MIF signaling homeostasis, and enhanced pro-fibrotic cell communication. These findings provide novel molecular targets for the development of anti-fibrotic therapies targeting this pathway.
Utilization of whole exome sequencing to identify hereditary mutations in Palestinian families with hereditary cancers.
Qutob N, Hindiyeh M, Zahdeh F … +4 more , Alian A, Thawabteh R, Sallam H, Natsheh A
Front Genet · 2026 · PMID 42388729 · Full text
INTRODUCTION: Hereditary cancers arise from germline pathogenic variants that confer increased lifetime cancer risk. In Palestine, the genetic basis of hereditary cancer predisposition remains limited. The objective of t...
INTRODUCTION: Hereditary cancers arise from germline pathogenic variants that confer increased lifetime cancer risk. In Palestine, the genetic basis of hereditary cancer predisposition remains limited. The objective of this study is to investigate germline variants associated with hereditary cancer susceptibility in Palestinian families with strong cancer history. METHODS: Families with suspected hereditary breast cancer were recruited, and germline DNA extracted from peripheral blood was first analyzed using a BRCA1/2 panel. Whole-exome sequencing (WES) was subsequently performed in BRCA-negative probands to identify additional candidate hereditary variants. A total of 34 individuals from three unrelated families were included in the study, comprising 8 affected and 26 unaffected individuals. Segregation analysis and in silico functional assessment were conducted to evaluate variant pathogenicity. RESULTS: We identified a splice-site variant in RAD50 (c.2524+3A>G) in Family I, a truncating MSH4 variant (c.328C>T; p.R110X) and a missense STAT6 variant (c.1216C>G; p.L406V) in Family II, and a splice-region PRKAR1A variant (c.973+6T>C) in Family III. These variants are segregated with disease in the respective families and are predicted to affect protein function. CONCLUSION: Our findings highlight the importance of germline genomic analysis in characterizing hereditary cancer predisposition in underrepresented populations and provide preliminary data for future risk assessment and genetic counseling strategies in Palestine.
Research of N-acetyl-L-cysteine on CD40-CD40L pathway in pulmonary fibrosis induced by silicon dioxide.
Wang S, Wang L, Hu K … +4 more , Han J, Gan X, Lou Y, Li G
Front Genet · 2026 · PMID 42388728 · Full text
INTRODUCTION: To investigate the effect of N-acetyl-L-cysteine (NAC) on the CD40-CD40L signaling axis during the development of pulmonary fibrosis in silicosis. METHODS: Seventy-five patients treated in our department be...
INTRODUCTION: To investigate the effect of N-acetyl-L-cysteine (NAC) on the CD40-CD40L signaling axis during the development of pulmonary fibrosis in silicosis. METHODS: Seventy-five patients treated in our department between January 2018 and June 2023 were enrolled and allocated to five groups (n = 15 each): healthy control, silicosis, routine treatment, intervention-1, and intervention-2. Bronchoalveolar lavage fluid (BALF) was collected from all subjects. CD40L expression on T lymphocyte surfaces was measured by flow cytometry. BALF concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), interferon-γ (IFN-γ), and monocyte chemoattractant protein-1 (MCP-1) were quantified by ELISA. BALF samples from each group were co-cultured with the human fetal lung fibroblast cell line HFL-1; Collagen I expression was assessed by immunocytochemistry and α-smooth muscle actin (α-SMA) expression by Western blotting. RESULTS: T cells isolated from BALF of silicosis patients exhibited significantly higher surface CD40L expression than those from healthy controls. Both intervention groups showed marked reductions in T-cell CD40L expression compared with the untreated silicosis group, with the greatest decrease in intervention-2. BALF levels of IL-6, IL-8, IFN-γ, and MCP-1 were significantly elevated in silicosis patients versus controls. Compared with the silicosis group, the routine treatment, intervention-1, and intervention-2 groups demonstrated progressive reductions in these cytokines, most pronounced in intervention-2. HFL-1 cells cultured with silicosis BALF displayed significantly increased α-SMA and Collagen I expression relative to cells exposed to control BALF. BALF from the routine treatment group produced no significant change in HFL-1 α-SMA fluorescence versus the silicosis group, whereas BALF from intervention-1 and intervention-2 significantly reduced HFL-1 α-SMA and Collagen I expression, with intervention-2 yielding the largest effect. DISCUSSION: NAC downregulates T-cell surface CD40L expression and disrupts CD40-CD40L interactions, attenuating production of multiple proinflammatory cytokines, reducing collagen synthesis and deposition, and thereby delaying the progression of interstitial pulmonary fibrosis in silicosis.
Novel variants in LSS related hypotrichosis simplex 14.
Hua S, Fang B, Cheng Y … +4 more , Zhang X, Zhang Y, Qian Q, Zhang J
Front Genet · 2026 · PMID 42382131 · Full text
BACKGROUND: Hypotrichosis simplex (HS) is a rare form of hereditary alopecia caused by a variety of gene variants, with onset in childhood. Few studies regarding -related HS(HS 14) have been reported and genotype-phenoty...
BACKGROUND: Hypotrichosis simplex (HS) is a rare form of hereditary alopecia caused by a variety of gene variants, with onset in childhood. Few studies regarding -related HS(HS 14) have been reported and genotype-phenotype correlations in the gene are still not completely clear. METHODS: In this study, we tried to make a definite diagnosis in two Chinese pediatric patients clinically suspected of congenital hypotrichosis. Peripheral blood samples of these two patients and their parents were collected and whole-exome sequencing (WES) was performed to elucidate the genetic cause. WES revealed four different compound heterozygous variants in in two probands that confirmed a diagnosis HS 14, including two novel variants. AlphaFold two was performed to predict three-dimensional structures, and the PROVEAN analysis software was utilized to assess the functional changes of novel missense variant. RESULTS: Two previously reported variants,c.1054G>A; p.(Gly352Arg) and c.1303C>T; p.(Arg435Cys) were observed and two novel heterozygous variants,c.1594G>C; p.(Glu532Gln) and c.1010C>T; p.(Pro337Leu) were found in these 2 HS patients. CONCLUSION: In this study, we successfully identified variants in in two probands that confirmed a diagnosis of HS, including two novel variants. These findings expanded the variantal spectrum of -related HS 14. Moreover, teeth dysplasia could be an associated phenotype in patient with HS 14.
Network-based analysis identifies shared mechanisms between ischemic stroke and myocardial infarction and therapeutic ingredients of Buyang Huanwu Decoction.
Zhang S, Lin Y, Xiao W … +2 more , Chen W, Zhang S
Front Genet · 2026 · PMID 42382130 · Full text
INTRODUCTION: Ischemic stroke (IS) and myocardial infarction (MI) share overlapping etiology and pathology, highlighting the need for dual-effective therapies. Buyang Huanwu Decoction (BHD) has shown efficacy against bot...
INTRODUCTION: Ischemic stroke (IS) and myocardial infarction (MI) share overlapping etiology and pathology, highlighting the need for dual-effective therapies. Buyang Huanwu Decoction (BHD) has shown efficacy against both diseases individually, but its core ingredients and dual therapeutic mechanisms remain unclear. METHODS: Using network-based analysis, we identified shared targets and convergent pathways for IS and MI, prioritized BHD ingredients by network proximity, and performed functional enrichment analyses. Molecular docking validated interactions between the key target GSK-3β and core ingredients, and surface plasmon resonance (SPR) experimentally determined the binding affinity of the top-ranked ingredient, Myricanone, to GSK-3β. RESULTS: Thirteen shared core targets were identified, with the "Lipid and atherosclerosis" pathway as the principal common mechanism. Ten key BHD ingredients with predicted dual therapeutic effects were prioritized. Among the shared targets, emerged as a central node. Molecular docking showed stable binding of all core ingredients to GSK-3β, with Myricanone exhibiting the strongest affinity (-9 kcal/mol), which was confirmed by SPR (KD = 55.1 µM). CONCLUSION: These findings elucidate the shared mechanisms of BHD against IS and MI, supporting its potential as a multi-target phytotherapeutic strategy for ischemic cardio-cerebrovascular disorders.
GWAS analysis of a depression cohort defined by an EHR-phenotyping algorithm reveals the role of immune regulations in depression risk.
Xian S, Carrell D, Smoller JW … +3 more , Wei WQ, Jarvik GP, Crosslin DR
Front Genet · 2026 · PMID 42382129 · Full text
INTRODUCTION: Depression is a common psychiatric disorder and a leading cause of disability. Large-scale genomic studies have identified common variants associated with depression. However, researchers often rely on self...
INTRODUCTION: Depression is a common psychiatric disorder and a leading cause of disability. Large-scale genomic studies have identified common variants associated with depression. However, researchers often rely on self-reported phenotypes, domain expertise-defined rules, and simple diagnostic codes (ICD9, ICD10) to identify depression participants, which suffers from inconsistent cohort definition and limited sample sizes. Thus, there is a lack of validated, efficient EHR phenotyping algorithms that precisely recognize depression cases. METHODS: We implemented a validated EHR phenotyping algorithm to construct a cohort of individuals with depression (11,532 cases and 39,631 controls, total n = 51,163) and conducted a genome-wide association study (GWAS) using this cohort. We validated the EHR-derived depression cohort using LDSC regression, comparing genetic similarities between our cohort and existing large meta-analyses. Top-ranked SNPs were selected and annotated to investigate downstream biological pathways and potential mechanisms that interfere with depression susceptibility. RESULTS: Our study reproduced previously identified genetic associations () with depression susceptibility. We also identified novel SNPs within the HLA region and IGVH region, suggesting an association between immune function and depression phenotype. We also demonstrated the robustness of the phenotyping algorithm through genetic correlation analysis (LDSC), showing a highly genetic similarity (rg = 0.8317, = 1.7758e-11) between our cohort and large meta-analysis cohorts of major depressive disorder. CONCLUSION: Our results demonstrate a robust validation of the EHR-based depression phenotyping algorithm using genetic analysis while providing novel genetic associations between depression and immune functions.
Ferroptosis, lipid metabolism, and genetic regulation in postoperative rehabilitation of elderly hip fractures: from molecular mechanisms to clinical translation.
Xie X, Zhu Y, Lu X … +6 more , Guo Y, Xiao S, Li X, Lu H, Li G, Liu H
Front Genet · 2026 · PMID 42382128 · Full text
BACKGROUND: Elderly hip fracture represents a major global public health challenge, with postoperative rehabilitation involving complex molecular mechanisms and metabolic networks. Beyond osteoporotic fractures, patholog...
BACKGROUND: Elderly hip fracture represents a major global public health challenge, with postoperative rehabilitation involving complex molecular mechanisms and metabolic networks. Beyond osteoporotic fractures, pathological hip fractures caused by tumor bone metastasis constitute a non-negligible proportion in elderly patients, with molecular pathological mechanisms significantly different from osteoporotic fractures. Recent research has confirmed that ferroptosis (iron-dependent regulated cell death) and lipid metabolism dysregulation are key links in fracture healing and functional recovery, while genetic polymorphisms, epigenetic modifications, and tumor microenvironment modulate these processes through multiple pathways. Nursing assessment and intervention play an irreplaceable role in promoting functional recovery and preventing complications. OBJECTIVE: This review systematically elucidates the molecular mechanisms of ferroptosis and lipid metabolism in postoperative rehabilitation of elderly hip fractures (including tumor metastatic pathological fractures), explores the genetic and epigenetic regulatory networks, analyzes multidisciplinary nursing intervention strategies, and provides a theoretical basis for translating basic research into clinical application. METHODS: PubMed, Web of Science, Embase, and CNKI were searched to include basic and clinical research published from 2015 to 2025. Keywords included ferroptosis, lipid metabolism, hip fracture, tumor bone metastasis, pathological fracture, genetic regulation, nursing intervention, and muscle atrophy. RESULTS: Ferroptosis participates in secondary injury and inflammatory responses at fracture sites through lipid peroxidation, glutathione depletion, and iron overload. Lipid metabolism dysregulation, especially polyunsaturated fatty acid (PUFA) metabolic abnormalities, not only promotes ferroptosis but also affects bone remodeling and muscle metabolism. Tumor bone metastasis exacerbates ferroptosis after pathological fractures by disrupting local iron metabolism homeostasis, upregulating ACSL4 expression, and promoting oxidative stress. Genetic polymorphisms of key regulatory factors such as GPX4 and FSP1, and DNMT-mediated epigenetic silencing, are closely related to prognosis in elderly patients. Systematic nursing interventions including nutritional management, pain control, early mobilization, and psychological support improve functional outcomes by regulating the oxidative stress-inflammation axis. CONCLUSION: Ferroptosis, lipid metabolism, genetic regulation, and nursing interventions together constitute a complex regulatory network in postoperative rehabilitation of elderly hip fractures (including pathological fractures), providing multi-level clinical intervention targets. Future research should focus on establishing elderly- and tumor-specific fracture assessment systems, developing highly selective ferroptosis-regulating drugs, advancing clinical translation of multi-omics biomarkers, and building precision multidisciplinary rehabilitation programs integrating nursing care.
Single-cell and pseudobulk analyses reveal hidden mitochondrial expression imbalance in gastric cancer.
Chang L, Hou J, Li Y … +7 more , Liu S, Feng P, Li Y, Qiu C, Zheng P, Xue X, Mi Y
Front Genet · 2026 · PMID 42382127 · Full text
BACKGROUND: Mitochondrial function is essential for biology, particularly in cancer. However, cell-type-specific expression patterns of conserved mitochondrial genes in gastric cancer (GC) remain unclear. We herein raise...
BACKGROUND: Mitochondrial function is essential for biology, particularly in cancer. However, cell-type-specific expression patterns of conserved mitochondrial genes in gastric cancer (GC) remain unclear. We herein raised and tested a novel hypothesis of "mitochondrial conserved gene expression homeostasis imbalance" in GC cohorts with single-cell resolution. METHODS: This work analyzed an open-accessed scRNA-seq dataset (GSE206785, 24 GC patients, 48 samples) with Seurat and defined 43 clusters grouped into 15 cell subtypes. In parallel, Pseudobulk profiles were generated to simulate bulk RNA-seq. A mitochondrial conserved gene score was computed by Seurat AddModuleScore, GSVA, and AUCell. Mitochondria-related biomarkers were also screened, validated, and incorporated into a mitochondria-dependent prognostic model that was further evaluated. RESULTS: Without considering cell-type-specific expression patterns, Pseudobulk analysis showed no significant differences in mitochondrial conserved gene expression between GC and control samples. In contracst, single-cell analysis found a cell-type-specific imbalance, under which tumor-associated epithelial cells displayed relatively elevated mitochondrial conserved gene expression, while non-epithelial cells showed reduced. Notably, survival analyses identified gene and as robust prognostic biomarkers for early GC. CONCLUSION: Our findings support a mitochondrial conserved gene expression homeostasis imbalance in GC, which is characterized by compartment-specific mtGene expression imbalance. Also, and emerge as prognostic markers for therapies aimed at restoring mitochondrial homeostasis in GC.
Transcriptomic profiling and experimental validation of myeloid-cell-differentiation-related key genes in osteoarthritis.
Liu J, Zhang X, Xu H … +6 more , Fu X, Sheng D, Huang Y, Huang Y, Lv X, Lu W
Front Genet · 2026 · PMID 42382126 · Full text
OBJECTIVE: This study aims to leverage publicly available databases to systematically investigate the pathogenic mechanisms of osteoarthritis (OA), with particular focus on the role of myeloid cell differentiation (MCD)-...
OBJECTIVE: This study aims to leverage publicly available databases to systematically investigate the pathogenic mechanisms of osteoarthritis (OA), with particular focus on the role of myeloid cell differentiation (MCD)-related genes. Comprehensive multidimensional analyses were performed to elucidate the potential mechanisms through which these genes contribute to the pathophysiological processes of OA. The findings of this study are expected to provide a theoretical foundation for targeting MCD-related abnormalities in OA. METHODS: We systematically integrated data acquisition, differential expression analysis, intersection with MCD-associated gene sets, machine learning-based feature selection, and multidimensional bioinformatics analysis-including functional enrichment, immune infiltration profiling (using the CIBERSORT algorithm), and structure-guided molecular docking to elucidate the molecular links between MCD and OA pathogenesis. We subsequently performed a comprehensive suite of functionally complementary downstream analyses, including nomogram construction for clinical risk prediction, receiver operating characteristic (ROC) curve analysis to assess diagnostic performance, decision curve analysis (DCA) to evaluate clinical utility, and structure-based molecular docking to probe potential ligand-target interactions. RESULTS: We identified eight key genes (, , , , , , , and ) through systematic screening. Following expression level validation, , , and were found to exhibit consistent expression trends and statistically significant differences across two independent datasets. Using the immunological atlas (the CIBERSORT algorithm), we estimated the infiltration levels of 22 immune cell subtypes and found that immune cell infiltration was significantly associated with OA progression and molecular subtype. Furthermore, molecular docking simulations were performed between the three key genes and two candidate therapeutic compounds, which provided preliminary insights and potential clues for future clinical drug development targeting these molecular interactions. To investigate the mRNA expression levels of the key genes, we performed real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis. CONCLUSION: We integrated transcriptomic data with bioinformatics approaches and machine-learning techniques in this study to identify potential biomarkers associated with OA. We identified , , and as three key MCD-associated genes in OA; we further explored their biological functions and underlying regulatory mechanisms, which were supported by the experimental validation of the expression of the key genes.
Stereo-cell coupled with single-cell transcriptomics identifies a transitional metabolic state in maturing skeletal muscle myofibers.
Liang L, Gong Y, Chai C … +1 more , Hao S
Front Genet · 2026 · PMID 42382125 · Full text
Identification of skeletal muscle fiber types and metabolic reprogramming are crucial for postnatal muscle maturation, but high-resolution metabolism and spatial heterogeneity of muscle fibers in mid-maturation remain po...
Identification of skeletal muscle fiber types and metabolic reprogramming are crucial for postnatal muscle maturation, but high-resolution metabolism and spatial heterogeneity of muscle fibers in mid-maturation remain poorly understood. Our study performed single-cell RNA sequencing (scRNA-seq) and single-cell nuclear RNA sequencing (snRNA-seq) on five hind limb muscles from 5-week-old mice, combined with Stereo-cell at single muscle fiber resolution, to elucidate myofiber subtype maturation and its metabolic changes. Integrating scRNA-seq and snRNA-seq data, a comprehensive mouse skeletal muscle cell atlas was constructed, demonstrating the complementary advantages of the two techniques in capturing interstitial cells and multinucleated muscle fibers. Our analysis resolved a continuous maturational lineage from type I to IIB myonuclei (IIB_1-3). Notably, the IIB_3 myonuclei subtype exhibited a dual hypermetabolic phenotype, with increased oxidative phosphorylation (OXPHOS) and glycolytic activity, which differs from the purely glycolytic phenotype observed in adult mice. Stereo-cell further validated this transitional metabolic state and revealed spatial heterogeneity within individual IIB myofibers, with localized high-oxidation regions. Furthermore, we observed a mixed myofiber phenotype, with subtype-specific myosin heavy chain expression enriched at the myofiber terminals, indicating directional transformation of myofiber during maturation. In summary, this study reveals a previously undescribed transitional metabolic feature of IIB-type myofiber during postnatal muscle maturation and elucidates the spatial metabolic heterogeneity of myofiber, providing new insights into the regulatory mechanisms of skeletal muscle developmental plasticity and metabolic specialization.
Efficacy of long-acting growth hormone in Axenfeld-Rieger syndrome with a novel 3.824 Mb 4q25 deletion: a Case Report and systematic literature review.
Guan S, Wang J, Liu Z … +4 more , Qi Y, Sun X, Jiang K, Lin S
Front Genet · 2026 · PMID 42382124 · Full text
BACKGROUND: Axenfeld-Rieger syndrome (ARS) is a multisystem disorder primarily caused by mutations. While eye and dental anomalies are classic, the role of as a dosage-sensitive regulator of the human growth axis remai...
BACKGROUND: Axenfeld-Rieger syndrome (ARS) is a multisystem disorder primarily caused by mutations. While eye and dental anomalies are classic, the role of as a dosage-sensitive regulator of the human growth axis remains clinically under-recognized. We aim to elucidate the link between large-scale 4q25 microdeletions and severe growth hormone deficiency (GHD). METHODS: A 5.4-year-old boy with ocular segment dysgenesis and short stature underwent family-based whole-exome sequencing (WES). Standardized growth hormone (GH) stimulation tests and longitudinal growth dynamics analysis based on 44 precise clinical data points collected from birth to age 7.45 years were performed. A systematic literature review of 10 ARS cases with growth failure was conducted to propose a pathogenic model. RESULTS: WES identified a novel 3.824Mb heterozygous deletion at 4q25 (arr[GRCh38] 4q25(108,929,697-112,753,289)×1), encompassing critical genes including , , , , and . Our systematic review revealed a dosage-sensitive correlation between the microdeletion scale at the 4q25 region and the severity of growth axis impairment. The patient exhibited complete GHD (peak GH: 4.22 ng/mL) and a 1.5-year bone age delay. Following 20 months of PEG-rhGH therapy, the patient achieved a significant catch-up growth with a cumulative height gain of 16.5 cm, with his height standard deviation score (Ht-SDS) improving from -2.0 SD to within the normal range. Our mechanistic model suggests that haploinsufficiency disrupts the (Pit-1) transcriptional cascade, leading to pituitary hypoplasia. CONCLUSION: This study reports the one of the most extensive longitudinal follow-up of successful PEG-rhGH therapy in ARS to date. We propose that large 4q25 deletions represent a high-risk genotype for GHD. Mandatory growth monitoring and early endocrine screening are recommended for ARS patients with chromosomal deletions in this region to optimize developmental outcomes.
Age-associated clinical characteristics and mutation landscape in pediatric Wilson's disease: a study from southwest China.
Wu T, Zhang Y, Peng X … +7 more , Chang Y, Qin T, Zhu J, Tang Q, Tian J, Zhao R, Xu H
Front Genet · 2026 · PMID 42376281 · Full text
BACKGROUND: Wilson's disease (WD) is a rare autosomal recessive disorder of copper metabolism caused by pathogenic variants in . However, the regional mutational spectrum, genotype-phenotype correlations, and biochemical...
BACKGROUND: Wilson's disease (WD) is a rare autosomal recessive disorder of copper metabolism caused by pathogenic variants in . However, the regional mutational spectrum, genotype-phenotype correlations, and biochemical trajectories in pediatric populations from Southwest China remain incompletely defined. METHODS: In total, 170 pediatric patients with WD were enrolled. The clinical data, imaging findings, and biochemical parameters were obtained. Age-stratified analyses were also conducted. variants were analyzed in 81 patients using whole-gene sequencing. Genotype-phenotype associations were evaluated using logistic regression. RESULTS: Hepatic presentation was predominant (84.12%), with neurological and mixed phenotypes more common in older patients. The incidence of Kayser-Fleischer rings, hepatic steatosis, cirrhosis, and abnormal brain magnetic resonance imaging (MRI) findings increased with age at diagnosis (all p < 0.01). Protein-truncating variants were significantly associated with neurological involvement (odds ratio [OR] = 4.058, p = 0.01), and male sex was an independent predictor (OR = 5.342, p = 0.006). The p. Pro992Leu variant was associated with hepatic fibrosis and steatosis (both p = 0.001). Liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma-glutamyltransferase [GGT]) decreased with increasing age at onset, whereas total cholesterol and low-density lipoprotein [LDL] cholesterol levels increased. 76 variants were identified, with exon 8 being the primary hotspot. The most frequent alleles were c.2333G>T, c.2975C>T, and c.2310C>G. Co-occurrence analysis identified c.2975C>T as the central allele, with extensive allelic heterogeneity observed. CONCLUSION: This study aimed to investigate age-related differences in clinical and biochemical features at disease onset in pediatric WD, with complementary analyses of genetic variation. It delineates age of onset-dependent phenotypic progression and a highly heterogeneous mutational landscape in pediatric WD. Intronic variants and rare insertions further expand the mutation spectrum.
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