Frontiers in Genetics最新文献

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is traditionally recognized as a risk factor for drug- or infection-induced hemolytic anemia. Emerging evidence implicates potential roles of G6PD in neurodevelopment, yet its association with rare neurological disorders remains underexplored in population-based genetic studies, especially within the Chinese population.

Methods: We conducted a retrospective case-control study utilizing whole-exome sequencing (WES) data from a Chinese cohort. Six most prevalent pathogenic G6PD variants in China were screended in children with rare neurological disorders (n = 211) and in controls without neurological involvement (n = 202). Genotype and carrier frequency comparisons were performed. Stratified analyses were performed based on diagnostic certainty and the presence of de novo mutations. Multivariable logistic regression was employed to calculate sex-adjusted odds ratios (ORs) to control for potential sex-related confounding.

Results: After adjusting for sex, the overall carrier rate of pathogenic G6PD variants was significantly higher in patients with neurological disorders than in controls (adjusted OR = 2.44, 95% CI: 1.18-5.06, p = 0.014). Further comparisons across specific groups revealed distinct patterns: affected male patients had a higher carrier rate than their own unaffected fathers (OR = 2.30, 95% CI: 1.08-4.91, p = 0.043), and mothers of case patients showed a higher carrier rate than mothers of controls (OR = 2.03, 95% CI: 1.09-3.78, p = 0.030). The variants NM_001042351.3: c.1376G>T (G6PD Canton) and NM_001042351.3:c.1388G>A (G6PD Kaiping) were the most prevalent across all groups.

Conclusion: This population-based genetic analysis provides preliminary evidence that G6PD deficiency may be a underrecognized genetic risk factor for rare neurological disorders in Chinese children. The findings suggest a potential maternal genetic contribution and indicate that the phenotypic spectrum of G6PD deficiency may extend beyond hematological manifestations to include neurodevelopmental vulnerability. Important limitations include the lack of functional validation and the use of a clinical control group. Further prospective studies incorporating G6PD enzyme activity assessment and functional investigations are warranted to elucidate the underlying mechanisms.

Introduction: Comprehensive care for autistic youth with severe symptoms and language impairment includes genetic testing to find underlying causes. Identifying a genetic diagnosis helps determine prognosis, guide treatment, assess recurrence risk, and connect families with targeted resources and support networks.

Methods: This cross-sectional study analyzed retrospectively data of a cohort of 60 Autism Spectrum Disorder Minimally Verbal (MV) past age 5 children and adolescents who underwent several genetic investigations and were included in an evaluation protocol including cognitive, adaptive, psychiatric, parental stress and autism characteristics' evaluations to identify whether there were any specific clinical or genetic characteristics in the group of minimally verbal autistic individuals.

Results: The percentage of genetic disorders detected in the series is 22.6%. Two groups of MV autistic individuals were defined: those without a known genetic cause (n = 46, neuropsychological data available for 32 individuals) and those with an associated genetic condition (n = 14, neuropsychological data available for 8 individuals). Most participants in both groups scored below 70 on Nonverbal Intelligence Quotient (NVIQ) (77.5% in the first group versus 77.7% in the latter) and adaptive functioning was impaired in both groups, without significant differences. Autism severity, measured by the ADOS-2, was significantly higher in individuals without causative alteration, particularly in Total Comparison Score. However, no differences were found between groups in restricted and repetitive behaviors. CBCL showed high levels of internalizing and externalizing problems in both groups, with no differences. Similarly, parental stress levels were high in both groups.

Discussion: This is the first study analyzing the genotype-phenotype correlation in MV autistic individuals. In this sample, the prevalence of genetic syndromes was found to be twice as high as in the general autistic population (22.6% versus 10%). Regarding the autistic characteristics' severity which appear to be higher in individuals without genetic causative alteration and the absence of significant differences in cognitive, functional and behavioural characteristics, we hypothesised that, in the MV autistic population without genetic causative alteration, there are specific and unknown characteristics of the MV profile which have a greater impact than the individual genetic condition reported.

Background: Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Understanding the molecular mechanisms underlying DN is crucial for developing new therapeutic targets and diagnostic biomarkers.

Methods: We utilized microarray data from the GEO database to identify differentially expressed genes related to DN. Machine learning algorithms, including LASSO regression and SVM-RFE, were employed to screen and validate telomere-related genes. We also predicted the transcription factors of the significant genes. Subsequently, correlation analysis and Receiver Operating Characteristic diagnostics were performed on the key genes, along with validation using external datasets. Additionally, GSEA enrichment analysis and immune infiltration analysis were conducted. Furthermore, we analyzed the expression of significant genes in cell subgroups using single-cell sequencing technology. Finally, key genes were validated in DN kidney biopsy tissues and normal kidney biopsy tissues.

Results: Through differential analysis and machine learning screening, we identified a total of 14 differentially expressed genes related to telomeres, among which TRIM22, ELOVL4, NLGN4X, and FOSB were highlighted as key genes. We also predicted seven related transcription factors (BCLAF1, HNRNPL, TAF15, STAT1, SRSF9, SAFB2, PTEN). The key gene TRIM22 showed a high correlation with NLGN4X, ELOVL4, and NLGN4X. ROC diagnostics demonstrated sufficient diagnostic accuracy in both the test and validation sets. GSEA enrichment analysis and immune infiltration analysis revealed significant differences among immune cells, such as PC cells, and preliminary expression validation was conducted using single-cell analysis (for example, TRIM22 exhibited high expression levels in EDC, PEC, MES, and IMC). Finally, we performed RT-PCR between DN samples and control samples, finding that the expression levels of key genes in both groups were consistent with the trends predicted by bioinformatics, indicating that these genes may serve as potential diagnostic biomarkers and therapeutic targets.

Conclusion: This study provides a comprehensive analysis of telomere-related DEGs in DN, enhancing our understanding of DN pathogenesis. The identified key genes offer potential for new diagnostic and therapeutic strategies, warranting further investigation into their biological roles in DN.

Objective: Rare subtypes of congenital adrenal hyperplasia (CAH) often present with heterogeneous and overlapping clinical features, leading to substantial diagnostic delays and misclassification. This study aimed to characterize the clinical, biochemical, and genetic profiles of rare CAH types in a Chinese cohort and to identify key diagnostic clues that support early differentiation of these uncommon forms.

Methods: We conducted a single-center retrospective study involving 12 confirmed Chinese cases with rare forms of CAH. Clinical data, including phenotypic features, hormonal profiles, and genetic mutations, were meticulously collected and analyzed.

Results: The cohort comprised 11β-hydroxylase deficiency (11-OHD, n = 3), 3β-hydroxysteroid dehydrogenase type 2 deficiency (3β-HSD2D, n = 1), lipoid CAH (LCAH, n = 4), aldosterone synthase deficiency (ASD, n = 2), and 17α-hydroxylase deficiency (17-OHD, n = 2). Distinctive clinical constellations that facilitated subtype differentiation included: low-renin hypertension with hyperandrogenism in 11-OHD; isolated hypospadias without salt-wasting in 3β-HSD2D; life-threatening neonatal salt-wasting with global steroid deficiency in LCAH; salt-wasting without virilization in ASD; and late-onset hypertension with sexual infantilism in 17-OHD. Molecular analysis identified six novel pathogenic variants across the CYP11B1, HSD3B2, StAR, CYP11A1, and CYP11B2 genes, expanding the mutational spectrum.

Conclusion: These results broaden the existing understanding of the mutational landscape underlying rare CAH and reaffirm that comprehensive clinical and genetic evaluation is essential for differentiating these diagnostically challenging subtypes. By improving early detection and enabling more precise, individualized management, this study provides valuable insights that may substantially advance clinical practice and patient care in rare endocrine disorders.

Accurate identification of 5-methylcytosine (5 mC) sites in promoter regions is crucial for understanding epigenetic regulation, but experimental methods remain costly and time-consuming, highlighting the need for reliable computational prediction tools. While existing deep learning approaches, such as BiLSTM-based, Transformer-based, and pretrained language models, have advanced the field, opportunities remain for further improvements in capturing long-range dependencies and handling imbalanced genomic data. Here, we present TCN-5mC, a deep learning model that integrates Temporal Convolutional Networks (TCN) inspired block with Bidirectional Gated Recurrent Units (BiGRU) and employs hybrid One-Hot and Nucleotide Chemical Property feature encoding. This architecture is designed to more effectively model both extended sequence contexts and local patterns. The model achieves high predictive performance on imbalanced datasets from lung cancer cell lines, with AUC values of 0.967 and 0.989 on two independent test sets, outperforming existing methods in specificity, accuracy, MCC, and AUC. The model thus provides a robust, high-throughput computational tool for 5 mC site prediction, with promising potential for epigenetic research and biomarker discovery.

Gastroesophageal reflux disease (GERD) exhibits significant epidemiological comorbidity with psychiatric disorders, yet their shared genetic architecture remains poorly characterized in East Asian populations. Leveraging ancestry-specific genome-wide association study (GWAS) summary statistics from East Asian cohorts, we employed linkage disequilibrium score regression and conditional false discovery rate (condFDR) approaches to investigate cross-trait genetic enrichment between GERD and major psychiatric disorders, including major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BIP). We identified significant genetic correlations between GERD and both MDD (r_g = 0.49, P = 0.03) and SCZ (r_g = 0.25, P = 0.02), but not with BIP. Through condFDR analysis, two novel loci were discovered: rs3980178 near MEIS1(associated with GERD-MDD pleiotropy) and rs9844126 near ZBTB20(associated with GERD-SCZ pleiotropy). These loci are implicated in neurodevelopment, autonomic regulation, and neural circuit formation, providing mechanistic insights into the gut-brain axis. Our findings demonstrate that cross-trait genetic enrichment significantly enhances locus discovery for GERD in underpowered East Asian GWAS and reveal ancestry-specific genetic links between gastrointestinal and psychiatric phenotypes.

Background: Global efforts to control and eventually eliminate malaria have been less effective for Plasmodium vivax relative to Plasmodium falciparum due to its unique biology, including dormant liver stages that cause later relapse, and earlier commitment to transmission stages. After the nationwide distribution of long-lasting insecticide treated nets (LLIN) in Papua New Guinea (PNG), P. vivax initially reduced to low prevalence, but again resurged to levels similar to those before LLIN distributions.

Method: To explore changes in P. vivax population structure and identify sources of resurgence over this period, we applied a previously validated genome-wide SNP barcode to genotype 336 P. vivax isolates obtained from serial cross-sectional surveys conducted over a decade in East Sepik (2005, 2012, 2016) and Madang Province (2006, 2010, 2014).

Results: Population genetic analyses of the resulting parasite genotypes revealed contrasting spatiotemporal patterns between the two provinces. In Madang, the complexity of infection, genetic diversity, and population structure varied with prevalence, with a possible population bottleneck and early clonal expansion at low transmission, and rapid recovery of the population with resurgence. In East Sepik, there was a less dramatic impact on the parasite population after prevalence decline, and ongoing transmission of multiple residual lineages throughout the study period. P. vivax decline was also accompanied by an increase in genetic differentiation between the two areas, which reduced with resurgence suggesting changes in parasite migration between areas associated with prevalence.

Conclusion: The earlier implementation of LLIN in East Sepik, smaller rebound, heterogeneity in transmission and relative isolation, compared to Madang may have contributed to these differing patterns. The results demonstrate that long term sustained control efforts are essential to make a lasting impact on the P. vivax population, and that SNP barcodes can provide valuable insights into parasite transmission dynamics as a result of control efforts.

Background: Vanishing white matter disease (VWMD; OMIM 603896), also known as childhood ataxia with central nervous system hypomyelination (CACH), is a rare autosomal recessive leukodystrophy caused by pathogenic variants in the EIF2B gene family (EIF2B1-EIF2B5). Clinical manifestations are highly heterogeneous, with onset ranging from fetal life to adulthood; adult-onset cases remain relatively rare and often present with atypical symptoms. Brain magnetic resonance imaging (MRI) and genetic testing are pivotal for diagnosis.

Case presentation: We report a 32-year-old Chinese female with adult-onset VWMD characterized by intermittent headaches, progressive cognitive decline, menstrual irregularities, and hearing loss. Cranial MRI with diffusion-weighted imaging (DWI) revealed symmetrical periventricular and centrum semiovale white matter abnormalities. Whole-exome sequencing (WES) identified a homozygous missense variant in the EIF2B5 gene, formatted per Human Genome Variation Society (HGVS) guidelines as NM_001414.4:c.185A>T (p.Asp62Val). This variant was previously documented exclusively in a pediatric patient, representing the first report in an adult.

Conclusion: Our case expands the phenotypic and age-related spectrum of EIF2B5-associated VWMD, highlighting that the c.185A>T variant is capable of manifesting in adulthood with non-classical features (e.g., headache as the initial symptom). Prior studies have confirmed that this variant impairs EIF2B complex function, which reinforces its pathogenic role in disrupting the integrated stress response (ISR) and maintaining white matter homeostasis. A literature review of 99 genetically confirmed adult-onset VWMD cases further underscores genotype-phenotype correlations: EIF2B5 is the most frequently mutated subunit in adult patients, with cerebellar ataxia, cognitive decline, and psychiatric symptoms as the predominant initial manifestations. Female patients often present with premature ovarian failure, a key diagnostic hallmark. Early genetic testing is crucial for definitive diagnosis, prenatal counseling, and symptomatic management. Notably, this study has limitations, including the lack of investigation into gene-gene interactions-factors that may modulate disease severity and phenotypic variability-and the unavailability of parental genetic data to fully validate zygosity.

Introduction: Ulcerative colitis (UC) is a lifelong, chronic inflammatory disorder, characterized by recurrent and diffuse inflammation of the rectal and colonic mucosa. Increasing evidence suggests that impaired mitophagy contributes to immune dysregulation and epithelial injury in UC. However, the mitophagy-related molecular landscape and its therapeutic potential remain largely unexplored.

Methods: Mitophagy-related genes (MRGs) were intersected with differentially expressed genes to identify UC-associated MRGs. Functional enrichment, immune infiltration, and consensus clustering analyses were performed to characterize molecular subtypes. Three machine learning methods were employed to identify diagnostic models. Candidate therapeutic agents were identified by the CMap database.

Results: A total of 35 UC-associated MRGs were identified, enriched in cell activation, fatty acid metabolism, and the PPAR signaling pathway, revealing strong immunometabolic coupling in UC. Consensus clustering stratified UC patients into two subtypes: a metabolism-dominant subtype (C1) and an inflammation-activated subtype (C2). Three hub genes-CD55, CPT1A, and SLC16A1-were screened and validated as robust diagnostic markers. Drug prediction and molecular docking revealed strong binding between galunisertib and CD55, which was further validated by molecular dynamics simulations. In vitro, galunisertib significantly suppressed inflammatory cytokine release in LPS-induced UC cell models.

Discussion: This study delineated the mitophagy-related molecular signatures of UC and identified CD55, CPT1A, and SLC16A1 as key biomarkers linking mitochondrial dysfunction, metabolic reprogramming, and immune activation. Furthermore, galunisertib was proposed as a potential therapeutic agent, providing a theoretical basis for UC therapy.

[This corrects the article DOI: 10.3389/fgene.2024.1455502.].