Frontiers in Genetics最新文献

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.].

Dietary restriction (DR), defined as reduced caloric intake or selective limitation of specific nutrients without malnutrition, is one of the most robust interventions known to extend lifespan and healthspan across species. Studies from yeast to mammals demonstrate that DR elicits conserved genetic, transcriptional, and epigenetic programs that promote cellular maintenance and stress resistance. At the molecular level, DR engages evolutionarily conserved nutrient-sensing pathways, including insulin/IGF-1 signaling (IIS), the mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and NAD⁺-dependent sirtuins, which converge on key transcription factors (TFs) and transcriptional coactivators (TCs) to coordinate metabolic and longevity-associated gene expression. Downstream, these pathways enhance autophagy and proteostasis, remodel mitochondrial function and redox balance, reshape immune and inflammatory networks, and induce epigenetic and transcriptional reprogramming. Recent work further highlights amino acid-specific sensing mechanisms, endocrine mediators such as fibroblast growth factor 21 (FGF21), the gut microbiome, circadian regulators, and nuclear pore-associated transcriptional plasticity as integral components of DR responses. Importantly, the physiological outcomes of DR are context dependent and influenced by genetic background, sex, age at intervention, and the type and duration of restriction. In this review, we summarize current knowledge on the genetic and molecular architecture underlying DR-induced longevity and health benefits across species, discuss implications for aging-related diseases, and outline future directions toward precision nutrition and safe translational strategies.

Objectives: Hyperuricemia and gout are common public health problems, stemming from both genetic and lifestyle factors. Evidence from multi-ethnic regions in Yunnan Province remains limited. This preliminary study examined hyperuricemia and gout prevalence, related biomarkers, lifestyle patterns, and SLC2A9/SLC22A12 genetics variations among 88 participants from the Miao community in Yunnan Province China.

Methods: A cross-sectional survey and biochemical study were conducted. Demographic and lifestyle data were collected, and blood samples were analyzed for serum biochemical indicators. Eight SNPs in SLC2A9 and SLC22A12 were genotyped. Logistic regression models were applied to allele and genotype data.

Results: Demographic and clinical analyses for Miao villagers (n = 88) suggested that the morbidities of hyperuricemia and gout were more frequent in male and showed significant association with alcohol consumption, smoking, and elevated BMI. While dietary patterns showed no significant differences. Compared with non-hyperuricemia/non-gout individuals (n = 56), the hyperuricemia/gout group (n = 57) showed 56% higher uric acid (553.13 vs. 354.73 μmol/L), 37% elevated creatinine (84.66 vs. 61.80 μmol/L), and higher triglycerides (3.35 vs. 1.80 mmol/L), along with hematological abnormalities, e.g., elevated hemoglobin (162.77 vs. 147.50 g/L) and lower platelets counts (161.09 vs. 194.14 × 10⁹/L). Preliminary genetic analyses indicated a possible association between SLC2A9_rs10939650 and hyperuricemia/gout risk, whereas variant SLC22A12 polymorphisms showed no association. After Bonferroni correction, no SNPs remained statistically significant.

Conclusion: This preliminary study suggested that the relatively higher burden of hyperuricemia and gout in the Miao population may be influenced by ethnicity, sex, lifestyle factors, metabolic alteration, and potential genetic components. Given the small sample size, the genetic findings should be interpreted cautiously and validated in larger studies for that disease (hyperuricemia and gout) and for similar ethnic community.