Front Genet [JOURNAL]
Sun
200 papers
Genetic analysis of three familial cases of pure terminal 19p13.3 duplication caused by maternal balanced translocation t(19;21) (p13.3;p12).
Chen JY, Cai MJ, Chen XL … +1 more , Ge YS
Front Genet · 2026 · PMID 42306095 · Full text
INTRODUCTION: This study presents a genetic analysis of three-generation family exhibiting terminal 19p13.3 duplication resulting from a maternal balanced translocation, t (19; 21) (p13.3; p12). Additionally, we reviewed...
INTRODUCTION: This study presents a genetic analysis of three-generation family exhibiting terminal 19p13.3 duplication resulting from a maternal balanced translocation, t (19; 21) (p13.3; p12). Additionally, we reviewed previously reported cases with similar aberrations. METHODS: Peripheral blood or amniotic fluid samples from six family members were comprehensively analyzed using G-banding, N-banding, fluorescence in situ hybridization (FISH), and copy number variation sequencing (CNV-seq). Furthermore, a genomic mapping analysis was performed on 23 cases of terminal 19p13.3 duplication, combining our findings with those from previously reported cases. RESULTS: The results demonstrated that the maternal balanced translocation resulted in three offspring inheriting the 19p13.3 terminal duplication. The proband presented with typical clinical features such as intrauterine growth restriction, microcephaly, intellectual disability, developmental delay, and facial abnormalities, in addition to precocious puberty, autism spectrum disorder (ASD) features, and a shortened lingual frenulum. The precocious puberty phenotype is postulated to be associated with the KISS1R gene within the duplicated region. Genomic mapping identified a minimal overlapping region (MOR) of approximately 313 kb (chr19:3,223,850-3,536,224), encompassing four OMIM genes (CELF5, NFIC, DOHH, FZR1) and two protein-coding genes (SMIM24, SMIM44). CONCLUSION: This study clarifies the genetic mechanism of pure terminal 19p13.3 duplication in offspring resulting from a parental balanced translocation involving D/G group chromosomes. It also defines a novel critical region based on case samples with 19p13.3 terminal duplication, providing new insights into the genotype-phenotype correlations associated with terminal pure 19p13.3 duplications.
Molecular characterization of a rare heterozygous variant in a Chinese family with moderate hypertriglyceridemia.
Liu H, Yuan X, Wang J … +6 more , Mao Y, Wang J, Wang D, Tian F, Yang Y, Xiang B
Front Genet · 2026 · PMID 42306094 · Full text
BACKGROUND: The development of hypertriglyceridemia (HTG) can be attributed to either a monogenic or a polygenic etiologic basis, and the understanding of this molecular basis is incomplete. APOA5 plays a critical role i...
BACKGROUND: The development of hypertriglyceridemia (HTG) can be attributed to either a monogenic or a polygenic etiologic basis, and the understanding of this molecular basis is incomplete. APOA5 plays a critical role in triglyceride (TG) metabolism, and APOA5 deficiency is a recognized cause of HTG. However, the effects of rare variants observed only in isolated cases are often difficult to establish conclusively. This study aims to find the genetic cause of moderate HTG in a Chinese family, and conduct preliminary verification. METHODS: Eight family members received biochemical testing, and genetic testing based on whole-exome sequencing (WES). Basic information including body mass index (BMI), medical history, prescription for TG management, and smoking and drinking habits was recorded. Comprehensive residue conservation analysis and computational simulation of protein structure stability were performed to measure the impact of the assumptive causal variant. RESULTS: A rare heterozygous variant (p.R223C) was identified. Specifically, six family members who carried the variant had substantially higher fasting plasma TG level than the admitted threshold (1.7 mmol/L) with the highest of 4.96 mmol/L, while a non-carrier in this family was normal in TG. The p. R223C variant was absent from ClinVar and gnomAD databases. Besides, predictions results supported the variant's potential deleteriousness. CONCLUSION: This study presents a familial case of moderate HTG associated with a rare variant, which is classified as Likely Pathogenic (LP) according to the ACMG/AMP guideline. The real effect of this variant requires further investigation via biochemical or cell-based studies.
Integrated metabolomic and transcriptomic analysis of anthocyanin accumulation mechanisms in maize kernels of different colors.
Jiang C, Shi H, Yan L … +8 more , Yin W, Li H, Lu H, Zhao H, Liu S, Wang S, Wei D, Huang Z
Front Genet · 2026 · PMID 42299342 · Full text
INTRODUCTION: Anthocyanins are important natural pigments and bioactive compounds in colored maize kernels. Although colored fresh-eating maize has attracted increasing attention because of its nutritional and functional...
INTRODUCTION: Anthocyanins are important natural pigments and bioactive compounds in colored maize kernels. Although colored fresh-eating maize has attracted increasing attention because of its nutritional and functional value, the molecular basis underlying anthocyanin accumulation in maize kernels with different colors remains incompletely understood. METHODS: In this study, four fresh-eating maize cultivars with contrasting kernel colors, including white (WN 2000), yellow (HN), multicolored (CN1), and black (HTN188), were used to investigate the mechanism of anthocyanin accumulation. Total anthocyanin content was measured across developmental stages, and integrated metabolomic and transcriptomic analyses were performed to identify anthocyanin-related metabolites, differentially expressed genes, and candidate regulatory factors associated with kernel pigmentation. RESULTS: Metabolomic profiling identified 49 anthocyanin-related metabolites/features, with marked enrichment of cyanidin-, peonidin-, and pelargonidin-related compounds in the black maize cultivar HTN188. Transcriptomic analysis identified 12,557 differentially expressed genes among the four cultivars, which were mainly enriched in phenylpropanoid biosynthesis, flavonoid biosynthesis, glutathione metabolism, fructose and mannose metabolism, and glyoxylate and dicarboxylate metabolism pathways. Several anthocyanin biosynthetic genes and regulatory transcription factor candidates were upregulated in anthocyanin-rich kernels, including DFR (Zm00001d011438), MYB (Zm00001d003052), bHLH (Zm00001d015990), and NAC (Zm00001d012508). In particular, the expression of DFR (Zm00001d011438) was strongly positively correlated with total anthocyanin content. Weighted gene co-expression network analysis further identified gene modules and candidate hub regulators associated with anthocyanin accumulation. DISCUSSION: These findings provide a comparative multi-omics perspective on anthocyanin accumulation in fresh-eating maize kernels of different colors. The results suggest that the high anthocyanin accumulation in black maize is associated with the coordinated enrichment of anthocyanin-related metabolites and the upregulation of key structural genes and transcription factors. This study provides candidate genes and regulatory information for future functional studies and anthocyanin-oriented breeding in fresh-eating maize.
Identification of novel variants in a suspected SCID patient and two couples undergoing carrier screening.
Peng Y, Sang YL, Zhu W … +8 more , Zhang N, Sun Y, Lin G, Lu GX, Tan YQ, Du J, Wang FY, He WB
Front Genet · 2026 · PMID 42299341 · Full text
BACKGROUND: Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. gene is a critical determinant of SCID, as JAK3-STAT pathway regulates development, proliferation, activat...
BACKGROUND: Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. gene is a critical determinant of SCID, as JAK3-STAT pathway regulates development, proliferation, activation, and differentiation of immune cells. This study aimed to identify the genetic cause of a family with a suspected SCID patient, and to perform carrier screening for two couples to assess the risk of conceiving offspring with birth defects. METHODS: Whole-Exome Sequencing was performed on five individuals from the three families. A series of functional experiments, including Western blotting and luciferase assays, were conducted to assess the pathogenicity of the identified variants. RESULTS: We identified seven variants, including five variants of uncertain significance (p.Arg402His, p.ILe688Phe, p.Leu129Phe, p.Met235Thr, p.Ala634Pro) and one pathogenic variant and one likely pathogenic variant (p.Gln1007Ter and p.Cys376Leufs*34). Among these, four variants (p.Gln1007Ter, p.Leu129Phe, p.Cys376Leufs*34 and p.Ala634Pro) were novel. functional experiments revealed that three of five variants of uncertain significance (VUSs) significantly reduced STAT5 phosphorylation and transcriptional activity, thereby reclassifying two variants (p.Arg402His and p.ILe688Phe) as likely pathogenic variants (LP) and one variant (p.Leu129Phe) as VUS with a Bayesian score of 3. In contrast, the remaining two variants (p.Ala634Pro and p.Met235Thr) did not affect JAK3 function, and were reclassified as VUS with a Bayesian score of 1 or 0. CONCLUSION: This study identified seven variants from three families, including four novel variants. Functional experiments revealed that two VUSs were reclassified as LP and one VUS were reclassified as VUS with a Bayesian score of 3. These findings highlight the importance of integrating genetic and functional analyses to enhance diagnostic accuracy, inform treatment strategies for patients, clarify of the risk for carrier-screening couples, improve genetic counseling, and guide reproductive interventions.
The impact of X chromosome inactivation on human health.
Gu J, Chen Q
Front Genet · 2026 · PMID 42294505 · Full text
X chromosome inactivation (XCI) is a crucial genetic regulatory mechanism in female cells, wherein one of the two X chromosomes is randomly silenced to balance gene expression between sexes. Despite the overall silencing...
X chromosome inactivation (XCI) is a crucial genetic regulatory mechanism in female cells, wherein one of the two X chromosomes is randomly silenced to balance gene expression between sexes. Despite the overall silencing, approximately 15%-30% of human genes escape XCI, leading to their biallelic expression in females. Many studies have highlighted the phenomenon of XCI skewing, where the inactivation is preferentially biased towards one X chromosome. XCI escape and XCI skewing are significantly associated with various health issues, including autoimmune disorders, neurodevelopmental disorders (NDDS), cardiovascular diseases (CVD) and cancer, etc. This review aims to provide a comprehensive overview of the mechanisms underlying XCI, its roles across different genders and disease states, and to explore the intricate relationship between XCI and human health. By emphasizing the significance of understanding XCI, this article seeks to shed light on potential therapeutic targets and avenues for further research in the field.
Epitranscriptomic regulation of endothelial plasticity under hemodynamic forces: insights from the KLF2/4-METTL3-H19 pathway.
Huang J, Yang Y
Front Genet · 2026 · PMID 42294504 · Full text
Hemodynamic shear stress is a fundamental biomechanical cue that shapes endothelial phenotypes and contributes to vascular diseases. Although flow-responsive transcription factors such as KLF2 and KLF4 are well recognize...
Hemodynamic shear stress is a fundamental biomechanical cue that shapes endothelial phenotypes and contributes to vascular diseases. Although flow-responsive transcription factors such as KLF2 and KLF4 are well recognized, how mechanical forces converge on epitranscriptomic mechanisms to regulate RNA fate remains incompletely understood. Emerging evidence identifies N-methyladenosine (mA) modification as a dynamic regulator of non-coding RNA stability and endothelial function, yet its integration into shear-dependent remodeling has not been systematically explored. This review synthesizes current evidence on the interplay between shear stress and the mA regulatory machinery and discusses how epitranscriptomic modulation of coding and non-coding RNAs may contribute to endothelial plasticity. Within this broader framework, the KLF2/4-METTL3-H19 pathway is presented as a representative mechanistic module illustrating how flow-responsive transcriptional programs may intersect with RNA methylation processes and reader-mediated transcript regulation. The potential implications of such interactions for endothelial-to-mesenchymal transition, barrier integrity, angiogenesis, and vascular diseases-including atherosclerosis, pulmonary arterial hypertension, and diabetic microangiopathy-are discussed. This integrated perspective highlights the emerging role of mechano-epitranscriptomic crosstalk in vascular biology and identifies directions for future investigation.
Low expression of hsa-miR-34c-5p in sperm is associated with unexplained recurrent miscarriage.
Tian H, Zhao XX
Front Genet · 2026 · PMID 42294503 · Full text
BACKGROUND: Recurrent miscarriage affects up to 1%-2% of reproductive-age couples, with nearly 50% of cases classified as unexplained recurrent miscarriage after comprehensive clinical workup. Current etiological researc...
BACKGROUND: Recurrent miscarriage affects up to 1%-2% of reproductive-age couples, with nearly 50% of cases classified as unexplained recurrent miscarriage after comprehensive clinical workup. Current etiological research focuses heavily on maternal factors, while the contribution of paternal factors-especially sperm-borne miRNAs, key epigenetic regulators of preimplantation embryonic development-remains understudied. This study aimed to profile differential sperm miRNA expression in partners of women with unexplained recurrent miscarriage, and explore its association with unexplained recurrent miscarriage. METHODS: We enrolled 22 partners of women with unexplained recurrent miscarriage (case group) and 19 healthy males undergoing routine preconception screening (control group) at the Affiliated Hospital of Inner Mongolia Medical University between July 2021 and February 2023. Sperm miRNAs were profiled via high-throughput sequencing, followed by RT-qPCR validation of 3 paternal miRNAs in embryos. GO and KEGG enrichment analyses were performed for target genes of key candidate hsa-miR-34c-5p. RESULTS: We identified 90 differentially expressed miRNAs in case group sperm, 4 of which were paternal miRNAs in embryos. RT-qPCR confirmed significant downregulation of sperm hsa-miR-34c-5p in cases (p = 0.001). Logistic regression identified low expression of hsa-miR-34c-5p in sperm was significantly associated with unexplained recurrent miscarriage (OR = 4.344, 95%CI 1.119-16.857, p < 0.05), with a ROC-AUC of 0.836. Its target genes were enriched in cellular membrane components, nervous system-related processes, Notch and Rap1 signaling pathways. CONCLUSION: This study reveals the association between low sperm miR-34c-5p expression and unexplained recurrent miscarriage, further advancing our understanding of sperm-derived small RNAs in regulating embryonic development and pregnancy outcomes. Nevertheless, the limited sample size means our findings require validation in large-scale multicenter cohorts.
The expression and clinical significance of miR-635 and miR-519d in gastric cancer patients.
Liu J, Gu Q, Chen C … +1 more , Liu X
Front Genet · 2026 · PMID 42294502 · Full text
OBJECTIVE: To investigate the expression and clinical significance of miR-635 and miR-519d in patients with gastric cancer. METHODS: A total of 116 patients with gastric cancer admitted between July 2018 and July 2020 we...
OBJECTIVE: To investigate the expression and clinical significance of miR-635 and miR-519d in patients with gastric cancer. METHODS: A total of 116 patients with gastric cancer admitted between July 2018 and July 2020 were enrolled. Gastric cancer tissues and matched adjacent tissues obtained during surgery were collected. The expression levels of miR-635 and miR-519d were detected by quantitative real-time PCR (qRT-PCR). Kaplan-Meier survival curves were used to analyze the relationship between miR-635 and miR-519d expression and patient prognosis. Cox regression analysis was performed to identify prognostic factors. ROC curves were plotted to assess the predictive value of miR-635 and miR-519d for prognosis, and the prognostic model was internally validated using the Bootstrap method. RESULTS: The expression levels of miR-635 and miR-519d differed significantly between gastric cancer tissues and adjacent tissues (P < 0.05). miR-635 and miR-519d were associated with TNM stage, degree of differentiation, lymph node metastasis, and depth of infiltration (P < 0.05). Their expression levels in the death group were significantly lower than those in the survival group (P < 0.05). The AUC of the combined detection of miR-635 and miR-519d for predicting prognosis was 0.935, which was superior to that of either marker alone (Z combination vs miR-635 = 2.321, Z combination vs miR-519d = 2.043, P < 0.05). The 3-year survival rates of patients with moderately decreased miR-635 or miR-519d expression were higher than those of patients with severely decreased expression (χ = 26.038 and 14.255, respectively; P < 0.05). Multivariate Cox regression analysis showed that TNM stage, degree of differentiation, lymph node metastasis, and depth of infiltration were risk factors affecting prognosis (P < 0.05), whereas miR-635 and miR-519d were protective factors (P < 0.05). Internal validation showed a C-index of 0.935, and the Hosmer-Lemeshow test yielded χ = 7.786, P = 0.742. CONCLUSION: miR-635 and miR-519d are significantly downregulated in gastric cancer tissues and are associated with clinicopathological characteristics and prognosis. Their combined detection can effectively predict the prognosis of patients with gastric cancer.
Glycogenin-1 deficiency: a case report and review of the literature.
Molitierno N, Velardo D, Salvucci G … +10 more , Abati E, Tumminello G, Ripolone M, Zanotti S, Napoli L, Ciscato P, Sciacco M, Comi GP, Corti S, Ronchi D
Front Genet · 2026 · PMID 42294501 · Full text
Pathogenic biallelic variants in , encoding for glycogenin-1, are associated with polyglucosan bodies myopathy characterized by muscle accumulation of deposits of amylopectin-like polysaccharides (MIM 616199). So far, on...
Pathogenic biallelic variants in , encoding for glycogenin-1, are associated with polyglucosan bodies myopathy characterized by muscle accumulation of deposits of amylopectin-like polysaccharides (MIM 616199). So far, only few cases (<50) with molecular defects in have been reported. The proband is a 79-year-old Italian woman presenting with subacute onset of diffuse soreness, weakness in the upper limbs and diffuse muscle atrophy without cardiac or respiratory involvement. Electromyography showed myopathic features. Muscle biopsy revealed several type I muscle fibers containing intensely PAS-positive, diastase-resistant vacuoles of variable dimension. Ultrastructural analysis showed vacuoles with granular-fibrillar storage material localized in subsarcolemmal and intermyofibrillar areas, small amounts of free glycogen and jagged Z-line appearance of some sarcomeres. Clinical exome sequencing revealed two heterozygous pathogenic variants in . Our findings provide clinical and molecular characterization of a novel case of -related polyglucosan bodies myopathy and highlight the histological clues leading to the diagnosis of this rare clinical phenotype.
Single-cell transcriptomic profiling reveals CD27 cytotoxic T Cell heterogeneity and exhaustion dynamics in colorectal cancer tumor microenvironment.
Xu W, Huang H, Mao L … +2 more , Zhu H, Feng Z
Front Genet · 2026 · PMID 42294500 · Full text
BACKGROUND: CD27 cytotoxic T cells play critical roles in anti-tumor immunity, yet their heterogeneity and functional states within the colorectal cancer (CRC) tumor microenvironment remain poorly characterized. Understa...
BACKGROUND: CD27 cytotoxic T cells play critical roles in anti-tumor immunity, yet their heterogeneity and functional states within the colorectal cancer (CRC) tumor microenvironment remain poorly characterized. Understanding the molecular mechanisms underlying T cell exhaustion is essential for developing effective immunotherapeutic strategies. METHODS: We performed comprehensive single-cell RNA sequencing analysis of CD27 cytotoxic T cells from CRC tumor tissues and matched normal adjacent tissues using the GSE144735 dataset. Multiple dimensional reduction techniques, trajectory inference algorithms, and functional characterization approaches were employed to dissect cellular heterogeneity, differentiation trajectories, and exhaustion dynamics. co-culture experiments using HCT116 and RKO (MSI-H), HCT15 and SW480 (MSS) colorectal cancer cell lines with activated PBMCs were conducted to validate computational findings. RESULTS: UMAP and t-SNE analyses identified 11 distinct CD27 T cell clusters with substantial phenotypic heterogeneity, including exhausted terminal, effector, and memory-like populations. Pseudotime trajectory analysis revealed progressive exhaustion pathways with three distinct differentiation fates. Exhausted CD27 T cells exhibited significantly elevated expression of checkpoint molecules (PDCD1, LAG3, HAVCR2, CTLA4) and reduced cytotoxic capacity compared to effector populations. RNA velocity and PAGA connectivity analysis demonstrated that exhaustion represents a terminal differentiation state with limited plasticity. Gene regulatory network analysis identified key transcription factors governing effector-to-exhausted transitions. Notably, exhausted CD27 T cells concentrated in tumor core regions, while effector populations distributed peripherally. Co-culture experiments confirmed that MSI-H cell lines (HCT116 and RKO) induced 2-3 times higher exhaustion marker expression compared to MSS cell lines (HCT15 and SW480). For MSI-H cells, PDCD1 showed 5.2-fold (HCT116) and 4.8-fold (RKO) upregulation, while LAG3 showed 4.8-fold (HCT116) and 4.2-fold (RKO) upregulation. In contrast, MSS cells showed lower induction: PDCD1 at 2.1-fold (SW480) and 1.9-fold (HCT15), LAG3 at 1.8-fold (SW480) and 1.6-fold (HCT15). Exploratory survival analysis (HR = 0.505, p = 0.673) did not reach statistical significance and is presented as hypothesis-generating only, highlighting the need for prospective validation in larger cohorts. PDCD1 and LAG3 were identified as prioritized immunotherapy targets based on their significant overexpression in exhausted T cell populations. CONCLUSION: This study provides a comprehensive single-cell atlas of CD27 cytotoxic T cell heterogeneity in CRC, revealing exhaustion dynamics, regulatory networks, and spatial organization patterns. Our findings highlight the differential immunogenic capacity between MSI-H and MSS tumors and identify potential therapeutic targets for reversing T cell exhaustion in colorectal cancer.
Turning back time: a comprehensive list of interventions that decrease next-generation epigenetic aging clocks in humans.
Johnson AA, Sinclair DA
Front Genet · 2026 · PMID 42294499 · Full text
Epigenetic aging clocks estimate age from DNA methylation patterns and have become central tools in longevity research. More recently, next-generation clocks have been developed to better compensate for the known diverge...
Epigenetic aging clocks estimate age from DNA methylation patterns and have become central tools in longevity research. More recently, next-generation clocks have been developed to better compensate for the known divergence between chronological age and epigenetic age in ways that relate to lifestyle, health, and age-related disease. Although epigenetic clocks represent investigational biomarkers, these newer models are more strongly associated with all-cause mortality risk than first-generation clocks. As such, interventions that modify them are of interest. To test this, we performed a series of systematic searches and identified 41 human studies reporting the effects of interventions on at least one next-generation epigenetic clock. Our data suggest that a diverse range of pharmaceutical, lifestyle, supplementation, non-pharmaceutical clinical, and psychosocial interventions can decrease epigenetic age, including exercise, a plant-rich diet, the GLP-1 receptor agonist semaglutide, caloric restriction, ketamine, omega-3 fatty acids, a multivitamin-multimineral supplement, umbilical cord plasma, and the cholesterol-lowering drug pitavastatin. Nicotinamide riboside, rapamycin, senolytics, and several other interventions showed no detectable effect, whereas plasmapheresis and other therapeutics accelerated epigenetic aging. We also summarize reported effect sizes and compare next-generation clocks with respect to their frequency of use and responsiveness to intervention.
Analysis of gene expression patterns modulated by tuberculous pleural effusion-derived exosomal miRNAs in lung cancer.
Park G, Kang HJ, Hong Y … +3 more , Lee JJ, Shin SH, Hong JY
Front Genet · 2026 · PMID 42294498 · Full text
INTRODUCTION: Previous pulmonary tuberculosis (TB) is a known risk factor for lung cancer. Earlier studies have demonstrated that tuberculous pleural effusion (TPE)-derived exosomal miRNAs are involved in lung cancer pro...
INTRODUCTION: Previous pulmonary tuberculosis (TB) is a known risk factor for lung cancer. Earlier studies have demonstrated that tuberculous pleural effusion (TPE)-derived exosomal miRNAs are involved in lung cancer progression. This study aimed to identify potential miRNA-mRNA regulatory pathways contributing to the pathogenesis of TB-associated lung cancer. METHODS: We isolated Exosomes from the lung effusions of patients with TB and injected intratumorally into lung cancer xenograft mice to model the TB-lung cancer interaction. To identify TB-associated regulators relevant to lung cancer, we first examined differentially expressed miRNAs (DEMs) in exosomes from patients with TB. In parallel, we identified differentially expressed genes (DEGs) in xenograft lung cancer following injection with TB-derived exosomes and analyzed their interactions with the DEMs. Network analysis was then applied to interpret miRNA-mRNA regulatory relationships, with TB-related sub-networks selected for further study. RESULTS: In total, five DEMs and 54 DEGs were identified. Pathway enrichment analysis indicated that these DEGs were linked to oxidative phosphorylation, ribosome biogenesis, mitochondrial adenosine triphosphate synthesis, and NADH dehydrogenase activity. Further network analysis with Cytoscape revealed a potential miRNA-mRNA regulatory network encompassing 94 genes expanded from the selected 54 DEGs and 4 DEMs. Finally, assays validated that the identified cancer-related genes (, , and ) are involved in regulating miRNA expression. CONCLUSION: In conclusion, our findings suggest potential indirect links between TB-derived exosomal miRNAs and lung cancer associated genes. These results provide a preliminary regulatory framework, and while further functional validation is warranted, they offer exploratory insights into the molecular landscape of TB-associated lung cancer.
Case Report: A case series of using whole exome sequencing to detect novel variants in Vietnamese patients with inborn errors of immunity.
Kim Lien NT, Van Tung N, Minh Huong LT … +6 more , Van Anh NT, Phuong Mai NT, Dien TM, Hien NT, Tao NT, Hoang NH
Front Genet · 2026 · PMID 42283036 · Full text
BACKGROUND: Inborn errors of immunity (IEIs) are rare diseases that affect the immune system. Variants in over 500 genes have been identified as causative of 555 IEIs, with clinical phenotypes that can be heterogeneous w...
BACKGROUND: Inborn errors of immunity (IEIs) are rare diseases that affect the immune system. Variants in over 500 genes have been identified as causative of 555 IEIs, with clinical phenotypes that can be heterogeneous within the same gene or even within the same variant. Therefore, these challenges make it difficult to determine the cause of IEI in individuals with immune disorders and to link clinical phenotypes to the precise genetic damage. An incorrect diagnosis can miss approximately 25% of IEI patients with overlapping initial manifestations. Accurate diagnosis and timely treatment are essential to improving quality of life and prolonging the lives of patients, as these patients often suffer from severe, life-threatening infections if left untreated. METHODS: In this study, whole exome sequencing (WES) was used to identify potentially pathogenic variants in six Vietnamese IEI patients. Variants in genes associated with IEIs were screened from WES data using criteria for known and/or novel pathogenic variants, and variants with minor allele frequency (MAF) < 0.001. The pathogenicity of the novel variant was assessed using The American College of Medical Genetics and Genomics (ACMG) criteria and predictive software. RESULTS: Six variants were identified as causative in six study patients, including c.116-2A>G (in the gene); c.215delA, p.Asn72Ilefs*49 and c.83G>A, p.Arg28His (in the gene); c.1110-3C>A (in the gene); c.1114G>A, p.Glu372Lys (in the gene); and c.526C>T, p.Arg176* (in the gene). Of these, the variant c.1110-3C>A in the gene was newly identified in an IEI patient. CONCLUSION: Although this study has limitations in analyzing the WES of six patients with different types of IEI, the results will contribute to a better understanding of the genetic causes of IEIs. Furthermore, the study emphasizes the importance of accurate diagnosis, which helped improve treatment outcomes and enhance the quality of care for individuals with IEIs.
A missense variant in Exon 9 of the gene causes splicing abnormality in an Infant with asparagine synthetase deficiency.
Zhang W, Chen F, Wang Z … +3 more , Ding H, Zhang Y, Zeng L
Front Genet · 2026 · PMID 42283035 · Full text
Asparagine Synthetase Deficiency (ASNSD) is a rare neurodevelopmental disorder primarily caused by pathogenic homozygous or compound heterozygous variants in the gene. Clinical manifestations typically include microceph...
Asparagine Synthetase Deficiency (ASNSD) is a rare neurodevelopmental disorder primarily caused by pathogenic homozygous or compound heterozygous variants in the gene. Clinical manifestations typically include microcephaly, severe psychomotor developmental delay, progressive encephalopathy, epilepsy, and other associated neurological abnormalities. Herein, we performed a comprehensive clinical assessment of a neonate presenting with microcephaly and hypotonia from a Chinese family. Whole-exome sequencing (WES) identified two novel compound heterozygous variants in the gene: c.1031-6_1041del (paternally inherited) and c.1049A>G (maternally inherited). The c.1031-6_1041del variant disrupts the canonical splice region and was classified as likely pathogenic. Notably, the c.1049A>G variant, localized to Exon 9, results in a missense substitution (p.Lys350Arg) and was predicted by tools to induce aberrant splicing. Furthermore, functional validation via splicing assays confirmed that this missense variant leads to partial deletion of Exon 9, thereby possibly impairing the normal expression and function of the gene. These findings expand the mutational spectrum of ASNSD and provide critical insights into the pathogenic mechanisms underlying splicing dysregulation caused by missense variants in the gene.
Decoding the human PBMC isonome: isoform-level resolution with single-cell long-read transcriptomics.
Doyle PH, Page ML, Brandon JA … +4 more , Aguzzoli Heberle B, White BJ, Stowe AM, Ebbert MTW
Front Genet · 2026 · PMID 42283034 · Full text
Long-read single-cell RNA sequencing provides an opportunity to understand human health and disease at a level difficult to resolve with bulk or short-read methods. This approach enables isoform-level investigation of ce...
Long-read single-cell RNA sequencing provides an opportunity to understand human health and disease at a level difficult to resolve with bulk or short-read methods. This approach enables isoform-level investigation of cellular diversity and disease mechanisms and definition of cell-types, rather than using genes alone. Using a modified, microfluidic-free PIPseq workflow and computational pipeline adapted for Oxford Nanopore long-read sequencing, we generated the largest long-read single-cell dataset of human peripheral blood mononuclear cells (PBMCs) from a single donor to date, the first with sufficient cell numbers to detect megakaryocytes. This study profiled isoform usage across immune cells, integrating marker expression and isoform discovery. We identified 126 novel isoforms from known and new genes, several with distinct cell-type-specific patterns, and characterized marker gene isoform expression across cell-types. Non-canonical protein-coding variants of and were enriched in unexpected cell-types, including megakaryocytes and monocyte-derived populations. We also discovered novel transcripts from and with cell-type-specific signatures that were also the predominantly expressed transcript within the gene. This study expands the versatility of long-read single-cell studies to not only relay changes in isoform signatures, but to position them within the functional context of the biology they impact. These results demonstrate the power of long-read single-cell sequencing for mapping the isoform landscape-the isonome-across tissues and disease contexts.
A 3'UTR polymorphism disrupts IRF2BP2 autoregulation through an eIF4H translational enhancer.
Duong A, Chen HH, Stewart AFR
Front Genet · 2026 · PMID 42283033 · Full text
INTRODUCTION: Interferon regulatory factor 2 binding protein 2 (IRF2BP2) suppresses the interferon response and inflammation. Individuals who carry 2 copies of a genetic variant (rs3045215) that deletes 9 nucleotides fro...
INTRODUCTION: Interferon regulatory factor 2 binding protein 2 (IRF2BP2) suppresses the interferon response and inflammation. Individuals who carry 2 copies of a genetic variant (rs3045215) that deletes 9 nucleotides from the long 3'UTR of IRF2BP2 have lower IRF2BP2 protein expression in white blood cells and increased risk of coronary atherosclerosis and calcification. METHODS AND RESULTS: RNAfold revealed that the deletion variant of IRF2BP2 disrupts an RNA stem-loop structure that can recruit the eukaryotic initiation factor 4H (eIF4H) to facilitate translation. siRNA knockdown of eIF4H reduced expression of endogenous IRF2BP2 protein. Similarly, it impaired translation of a luciferase reporter bearing the whole 3'UTR of IRF2BP2 but had no effect on one bearing the 9-nucleotide deletion variant (rs3045215). This deletion variant happens to be co-inherited with an IRF2BP2 coding variant that changes proline to serine at position 78. Overexpression of either isoform of IRF2BP2 (Pro or Ser) suppressed translation of the luciferase reporter containing the whole IRF2BP2 3'UTR to the same level but had no effect on the deletion-bearing reporter. RNA gel mobility shift assay using cytosolic extracts of LPS-stimulated THP1 macrophages revealed that the 9-nucleotide deletion variant prevents endogenous IRF2BP2 protein from interacting with its own 3'UTR RNA sequences. CONCLUSION: The rs3045215 9-nucleotide deletion that increases the risk of heart disease abolishes IRF2BP2 autoregulation through an eIF4H-dependent translational enhancer.
Genetic and non-genetic determinants of vitamin D status: a polygenic score analysis in elite athletes.
Hacker S, Reichert L, Lenz C … +5 more , Henne S, David F, Heilmann-Heimbach S, Zentgraf K, Krüger K
Front Genet · 2026 · PMID 42283032 · Full text
INTRODUCTION: Vitamin D plays a critical role in bone metabolism, immune regulation, and muscle performance. Serum 25-hydroxyvitamin D [25(OH)D] levels are shaped by both genetic and non-genetic determinants. To explore...
INTRODUCTION: Vitamin D plays a critical role in bone metabolism, immune regulation, and muscle performance. Serum 25-hydroxyvitamin D [25(OH)D] levels are shaped by both genetic and non-genetic determinants. To explore their combined role, we investigated the association between a polygenic score (PGS) for vitamin D metabolism and serum 25(OH)D concentrations in elite athletes. METHODS: Serum vitamin D status was measured in 473 German national squad athletes. PRSice-2 was used for PGS development. Linear regression models compared the predictive utility of an overall model (PGS plus covariates) versus a null model (covariates only). Covariates included age, sex, competition environment, ambient UVB dose, and supplementation. RESULTS: Serum 25(OH)D was significantly predicted by the standardized PGS (β = 4.04), age (β = 8.59), supplementation (β = 20.86), and cumulative weighted UVB dose (cw-D-UVB, β = 7.18; all p < 0.05). The full model explained 31.7% (12.1%) of variance (adjusted R2 = 0.235), with the PGS contributing an incremental 1% (1%). Model performance yielded a mean absolute error of 18.64 nmol/L (3.18 nmol/L) and root mean squared error of 25.27 nmol/L (4.24 nmol/L). No significant interactions were found for PGS × cw- D-UVB, PGS × supplementation status and PGS × competition environment. DISCUSSION: The findings indicate that genetic determinants account for a small proportion of the total variance in vitamin D status. Stronger predictors are non-genetic determinants such as supplementation, UVB exposure, and age, highlighting the predominant role of environmental influences. Given the limited explanatory power of the PGS, individualized management strategies should primarily focus on modifiable factors such as sun exposure and supplementation.
Single-cell transcriptomic profiling uncovers key molecular signatures in glioma pathogenesis.
Gu C, Wu X, Yang L
Front Genet · 2026 · PMID 42283031 · Full text
BACKGROUND: Glioma represents the most prevalent and lethal primary malignant tumor of the central nervous system, characterized by remarkable cellular heterogeneity and poor prognosis. Comprehensive characterization of...
BACKGROUND: Glioma represents the most prevalent and lethal primary malignant tumor of the central nervous system, characterized by remarkable cellular heterogeneity and poor prognosis. Comprehensive characterization of glioma at single-cell resolution is essential for identifying novel therapeutic targets and improving patient outcomes. METHODS: We performed comprehensive single-cell RNA sequencing (scRNA-seq) analysis on glioma samples obtained from the Gene Expression Omnibus (GEO) database. Advanced computational approaches including principal component analysis (PCA), uniform manifold approximation and projection (UMAP), t-distributed stochastic neighbor embedding (t-SNE), and differential expression analysis were employed to characterize cellular heterogeneity. Gene co-expression network construction and pathway enrichment analysis were conducted to identify functional modules. Candidate biomarkers were validated using quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) in GL261 glioma cells, C8-D1A normal glial cells, and intervertebral disc nucleus pulposus cells. RESULTS: Quality control analysis revealed high-quality single-cell data with median gene counts of 5,437 and UMI counts of 14,207 per cell. A total of 4,753 highly variable genes were identified, and 22 distinct cellular clusters were delineated using the Louvain algorithm. PCA loading analysis identified key contributing genes including cell cycle regulators (CDK1, TOP2A, BIRC5), immune-related genes (C1QA, C1QB, HLA-DRB6), and neural lineage markers (MOBP, MAG, GJB1). Cell type annotation identified seven major populations: astrocytes, oligodendrocytes, microglia, neural stem cells, OPC/immature neurons, pericytes, and T cells. Differential expression analysis uncovered 847 upregulated and 652 downregulated genes (|logFC| > 1, adjusted P < 0.05). Gene co-expression network analysis revealed five major functional modules centered on hub genes including CLEC12A, CLU, AQP4, and S100A16. Pathway enrichment demonstrated significant involvement of cell cycle, Notch signaling, MAPK pathway, and neurogenesis. Experimental validation confirmed that Plp1 was significantly downregulated in GL261 cells (0.38 ± 0.05-fold, P < 0.01), while th1 (2.15 ± 0.28-fold, P < 0.001) and Gm42418 (5.67 ± 0.52-fold, P < 0.001) were markedly upregulated compared to normal glial cells. CONCLUSION: This comprehensive single-cell transcriptomic analysis successfully characterized the cellular heterogeneity of glioma, identifying distinct cell populations and molecular signatures. PLP1, FTH1, and GM42418 were validated as potential molecular biomarkers, providing novel insights into glioma pathogenesis and potential therapeutic targets.
The multifaceted role of FAM13A in pulmonary diseases.
Luo Z, Lu K, Lai M … +3 more , Liang S, Ma G, Wang Y
Front Genet · 2026 · PMID 42266412 · Full text
, a lung-enriched gene encoding a protein with a characteristic RhoGAP domain, is increasingly recognized for its pleiotropic roles across multiple lung diseases, including chronic obstructive pulmonary disease (COPD), p...
, a lung-enriched gene encoding a protein with a characteristic RhoGAP domain, is increasingly recognized for its pleiotropic roles across multiple lung diseases, including chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), asthma, and lung cancer. Through modulation of Rho and Wnt/β-catenin signaling, regulates key cellular processes such as epithelial barrier maintenance, immune homeostasis, and cell-cycle regulation. Notably, exhibits context-dependent duality, associated with tissue destruction in COPD while linked to mitigated fibrotic remodeling in PF. In addition, the complexity introduced by multiple splice variants, interspecies expression differences, and environmental dependence poses significant challenges for further mechanistic studies of . By emphasizing the opposing roles of in COPD versus PF, the non-linear relationships linking single-nucleotide polymorphisms (SNPs), gene expression, signaling pathways, and disease phenotypes, as well as the combined influence of isoform diversity, species differences, and environmental exposures on functional outcomes, this review integrates current genetic, molecular, and functional evidence to provide a mechanistic framework for understanding 's roles in pulmonary diseases and refines current paradigms with implications for future research and precision medicine.
Malignant glomus tumor of the duodenum Harboring novel FOXP1 and KDM5A mutations: a case report and literature review.
Song H, Li Y, Liu Z … +3 more , Yu S, Wang Y, Liang S
Front Genet · 2026 · PMID 42266411 · Full text
BACKGROUND: Malignant glomus tumor (MGT) is an exceptionally rare mesenchymal neoplasm, accounting for less than 1% of all glomus tumors. Gastrointestinal involvement is unusual, and duodenal MGTs are exceedingly rare. A...
BACKGROUND: Malignant glomus tumor (MGT) is an exceptionally rare mesenchymal neoplasm, accounting for less than 1% of all glomus tumors. Gastrointestinal involvement is unusual, and duodenal MGTs are exceedingly rare. Accurate preoperative diagnosis is difficult due to nonspecific clinical manifestations and overlapping histological features. CASE PRESENTATION: We report the case of a 47-year-old woman presenting with intermittent upper abdominal pain, aggravated after meals. Imaging revealed a heterogeneous enhancing lesion in the descending duodenum, and endoscopy showed a large ulcerative lesion. Initial biopsy suggested a glomus tumor. Whipple resection was performed, and histopathological examination demonstrated diffuse tumor growth with moderate nuclear atypia, atypical mitoses, and infiltrative extension into the mucosa and muscularis propria. Immunohistochemistry showed positivity for SMA, h-caldesmon, and synaptophysin, with negativity for CD117 and CgA. These findings, consistent with WHO 2019 diagnostic criteria, confirmed the diagnosis of duodenal MGT. MOLECULAR FINDINGS: Next-generation sequencing revealed two class III variants of uncertain significance: FOXP1 exon7 c.250C>T (p.P84S, VAF 22.27%) and KDM5A exon19 c.2801C>T (p.P934L, VAF 24.59%). Both mutations have not been previously reported in MGT. Biomarker analysis indicated low TMB (1.4 mutations/Mb) and microsatellite stability (MSS). The co-occurrence of FOXP1 and KDM5A mutations suggests potential involvement of NOTCH signaling dysregulation in MGT pathogenesis. CONCLUSION: This case represents a rare duodenal MGT confirmed by histopathology and immunohistochemistry, with novel FOXP1 and KDM5A mutations identified for the first time. These findings broaden the molecular spectrum of MGT and highlight the importance of integrating molecular profiling into the diagnosis and management of rare tumors, while surgical resection remains the cornerstone of therapy.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe