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G6PD deficiency as a underrecognized genetic risk factor for rare neurological disorders: evidence from a population-based genetic analysis. G6PD缺乏症作为罕见神经系统疾病未被充分认识的遗传风险因素:来自基于人群的遗传分析的证据
IF 2.8 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-02-05 eCollection Date: 2026-01-01 DOI: 10.3389/fgene.2026.1766081
Qi Peng, Siping Li, Fen Lv, Xiaomei Zeng, Qingqiu Cheng, Baimao Zhong, Xiaomei Lu

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.

背景:葡萄糖-6-磷酸脱氢酶(G6PD)缺乏传统上被认为是药物或感染引起的溶血性贫血的危险因素。新出现的证据暗示G6PD在神经发育中的潜在作用,但其与罕见神经疾病的关联在基于人群的遗传研究中仍未得到充分探索,特别是在中国人群中。方法:我们利用来自中国队列的全外显子组测序(WES)数据进行了一项回顾性病例对照研究。在中国筛查了6种最常见的致病性G6PD变异,这些变异在患有罕见神经系统疾病的儿童(n = 211)和没有神经系统疾病的对照组(n = 202)中进行。进行基因型和载体频率比较。根据诊断确定性和新生突变的存在进行分层分析。采用多变量逻辑回归计算性别校正的优势比(ORs),以控制潜在的性别相关混杂。结果:经性别调整后,神经系统疾病患者G6PD致病变异的总体携带率明显高于对照组(校正OR = 2.44, 95% CI: 1.18-5.06, p = 0.014)。在特定组之间的进一步比较揭示了不同的模式:受影响的男性患者的携带率高于其未受影响的父亲(OR = 2.30, 95% CI: 1.08-4.91, p = 0.043),病例患者的母亲的携带率高于对照组的母亲(OR = 2.03, 95% CI: 1.09-3.78, p = 0.030)。改型NM_001042351.3:c. 1376g >T (G6PD Canton)和NM_001042351.3:c。1388G b> A (G6PD开平)在所有组中最普遍。结论:这项基于人群的遗传分析提供了初步证据,表明G6PD缺乏症可能是中国儿童罕见神经系统疾病的一个未被充分认识的遗传危险因素。研究结果表明,潜在的母体遗传贡献,并表明G6PD缺乏症的表型谱可能超出血液表现,包括神经发育易感性。重要的限制包括缺乏功能验证和使用临床对照组。进一步的前瞻性研究包括G6PD酶活性评估和功能研究,以阐明潜在的机制是必要的。
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引用次数: 0
Analyzing the genetic profile of autistic children and adolescents with minimal verbal abilities. 分析自闭症儿童和青少年语言能力低下的基因特征。
IF 2.8 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-02-04 eCollection Date: 2026-01-01 DOI: 10.3389/fgene.2026.1647481
Silvia Guerrera, Ilaria Venezia, Maria Grazia Logrieco, Laura Casula, Rossella Capolino, Maria Cristina Digilio, Maria Lisa Dentici, Marina Macchiaiolo, Federico Casciani, Fabiana Cortellessa, Lorenzo Sinibaldi, Andrea Bartuli, Silvia Di Tommaso, Gemma D'Elia, Viola Alesi, Cristina Roberti, Antonio Novelli, Giovanni Valeri, Stefano Vicari

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.

对有严重症状和语言障碍的自闭症青少年的全面护理包括基因检测以发现潜在的原因。确定基因诊断有助于确定预后,指导治疗,评估复发风险,并将家庭与目标资源和支持网络联系起来。方法:本横断面研究回顾性分析了60名5岁以上自闭症谱系障碍最小言语障碍(MV)儿童和青少年的数据,这些儿童和青少年接受了多项遗传调查,并纳入了评估方案,包括认知、适应性、精神病学、父母压力和自闭症特征评估,以确定最小言语自闭症个体群体是否存在任何特定的临床或遗传特征。结果:遗传疾病检出率为22.6%。将MV自闭症患者分为两组:没有已知遗传原因的患者(n = 46,可获得32例神经心理学数据)和有相关遗传疾病的患者(n = 14,可获得8例神经心理学数据)。两组大多数参与者的非语言智商(NVIQ)得分低于70分(第一组为77.5%,第二组为77.7%),两组的适应功能受损,但无显著差异。用ADOS-2来衡量的自闭症严重程度,在没有致病变异的个体中明显更高,特别是在总比较分数中。然而,在限制性和重复性行为方面,两组之间没有发现差异。两组CBCL均表现出高水平的内化和外化问题,差异无统计学意义。同样,父母的压力水平在两组中都很高。讨论:这是第一个分析MV自闭症个体基因型-表型相关性的研究。在这个样本中,发现遗传综合征的患病率是普通自闭症人群的两倍(22.6%对10%)。鉴于自闭症特征的严重程度似乎在没有遗传致病改变的个体中更高,并且在认知、功能和行为特征方面没有显着差异,我们假设,在没有遗传致病改变的MV自闭症人群中,存在特定的和未知的MV特征,这些特征比所报道的个体遗传状况具有更大的影响。
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引用次数: 0
Identification of key biomarkers of telomere-related genes in diabetic nephropathy via bioinformatic analysis. 通过生物信息学分析鉴定糖尿病肾病端粒相关基因的关键生物标志物。
IF 2.8 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-02-04 eCollection Date: 2026-01-01 DOI: 10.3389/fgene.2026.1566012
Dan Yu, Zhipeng Feng, Huan Yao, Ke An

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.

背景:糖尿病肾病(DN)是终末期肾脏疾病的主要病因。了解DN的分子机制对于开发新的治疗靶点和诊断性生物标志物至关重要。方法:利用GEO数据库中的微阵列数据,鉴定与DN相关的差异表达基因。使用LASSO回归和SVM-RFE等机器学习算法筛选和验证端粒相关基因。我们还预测了重要基因的转录因子。随后,对关键基因进行相关性分析和接受者操作特征诊断,并使用外部数据集进行验证。并进行GSEA富集分析和免疫浸润分析。此外,我们使用单细胞测序技术分析了细胞亚群中重要基因的表达。最后,在DN肾活检组织和正常肾活检组织中验证关键基因。结果:通过差异分析和机器学习筛选,我们共鉴定出14个与端粒相关的差异表达基因,其中TRIM22、ELOVL4、NLGN4X和FOSB是重点基因。我们还预测了7个相关的转录因子(BCLAF1, HNRNPL, TAF15, STAT1, SRSF9, SAFB2, PTEN)。其中关键基因TRIM22与NLGN4X、ELOVL4、NLGN4X具有高度相关性。ROC诊断在测试和验证集中都显示出足够的诊断准确性。GSEA富集分析和免疫浸润分析显示免疫细胞(如PC细胞)之间存在显著差异,通过单细胞分析进行初步表达验证(如TRIM22在EDC、PEC、MES和IMC中表现出高表达水平)。最后,我们对DN样本和对照样本进行了RT-PCR,发现两组关键基因的表达水平与生物信息学预测的趋势一致,表明这些基因可能作为潜在的诊断生物标志物和治疗靶点。结论:本研究提供了对DN端粒相关基因的全面分析,增强了我们对DN发病机制的认识。发现的关键基因为新的诊断和治疗策略提供了潜力,值得进一步研究它们在DN中的生物学作用。
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引用次数: 0
Clinical and genetic characteristics of rare congenital adrenal hyperplasia: a retrospective analysis in a Chinese population. 罕见先天性肾上腺增生症的临床和遗传特征:中国人群的回顾性分析。
IF 2.8 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-02-04 eCollection Date: 2026-01-01 DOI: 10.3389/fgene.2026.1709951
Kam Chan, Ying Guo, Shaoling Zhang, Li Yan

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.

目的:先天性肾上腺增生症(CAH)的罕见亚型常表现出异质和重叠的临床特征,导致大量的诊断延误和误诊。本研究旨在描述中国人群中罕见CAH类型的临床、生化和遗传特征,并确定支持这些罕见类型早期分化的关键诊断线索。方法:我们进行了一项单中心回顾性研究,涉及12例确诊的罕见形式的CAH。临床数据,包括表型特征、激素谱和基因突变,被仔细收集和分析。结果:11β-羟化酶缺乏症(11-OHD, n = 3)、3β-羟基类固醇脱氢酶2型缺乏症(3β- hsd2d, n = 1)、脂质CAH缺乏症(LCAH, n = 4)、醛固酮合成酶缺乏症(ASD, n = 2)、17α-羟化酶缺乏症(17-OHD, n = 2)。促进亚型分化的独特临床星座包括:11-OHD患者伴高雄激素血症的低肾素高血压;孤立性尿道下裂3β-HSD2D无盐耗;危及生命的新生儿盐耗伴LCAH整体类固醇缺乏症;ASD患者无细胞化的盐浪费;17-OHD患者迟发性高血压伴性婴儿症。分子分析鉴定出CYP11B1、HSD3B2、StAR、CYP11A1和CYP11B2基因的6个新的致病变异,扩大了突变谱。结论:这些结果扩大了对罕见CAH突变景观的现有理解,并重申了综合临床和遗传评估对于区分这些诊断上具有挑战性的亚型至关重要。通过改进早期检测和实现更精确、个性化的管理,本研究提供了有价值的见解,可能会大大推进罕见内分泌疾病的临床实践和患者护理。
{"title":"Clinical and genetic characteristics of rare congenital adrenal hyperplasia: a retrospective analysis in a Chinese population.","authors":"Kam Chan, Ying Guo, Shaoling Zhang, Li Yan","doi":"10.3389/fgene.2026.1709951","DOIUrl":"https://doi.org/10.3389/fgene.2026.1709951","url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"17 ","pages":"1709951"},"PeriodicalIF":2.8,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12912711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146219524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
TCN-5mC: a predictor of 5-methylcytosine sites based on multi-feature fusion and TCN-inspired block networks. TCN-5mC:基于多特征融合和tcn启发的块网络的5-甲基胞嘧啶位点预测因子。
IF 2.8 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-02-03 eCollection Date: 2026-01-01 DOI: 10.3389/fgene.2026.1739720
Cunwen Liu, Xuan Xiao, LongChang Wan, WeiZhong Lin

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.

启动子区域5-甲基胞嘧啶(5mc)位点的准确鉴定对于理解表观遗传调控至关重要,但实验方法仍然昂贵且耗时,突出了对可靠的计算预测工具的需求。虽然现有的深度学习方法,如基于bilstm、基于transformer和预训练语言模型,已经推动了该领域的发展,但在捕获远程依赖关系和处理不平衡基因组数据方面仍有进一步改进的机会。在这里,我们提出了TCN- 5mc,这是一种深度学习模型,它将时序卷积网络(TCN)启发块与双向门控循环单元(BiGRU)集成在一起,并采用混合One-Hot和核苷酸化学性质特征编码。该体系结构旨在更有效地为扩展序列上下文和局部模式建模。该模型在来自肺癌细胞系的不平衡数据集上具有较高的预测性能,在两个独立测试集上的AUC值分别为0.967和0.989,在特异性、准确性、MCC和AUC方面均优于现有方法。因此,该模型为5mc位点预测提供了一个强大的、高通量的计算工具,在表观遗传学研究和生物标志物发现方面具有很大的潜力。
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引用次数: 0
Cross-trait genetic enrichment between GERD and psychiatric disorders in East Asian populations. 东亚人群GERD与精神疾病的交叉性状遗传富集。
IF 2.8 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-02-03 eCollection Date: 2026-01-01 DOI: 10.3389/fgene.2026.1770067
Zhihao Gao, Xianjin Wang, Zekun Liu, Fen Hu, Yidi Zhou, Kalim Ullah, Ruiwei Wang, Meng Zhang, Xiao Chang, Yongsen Wang

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 (rg = 0.49, P = 0.03) and SCZ (rg = 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.

胃食管反流病(GERD)与精神疾病具有显著的流行病学共病性,但在东亚人群中,它们共同的遗传结构仍然缺乏特征。利用来自东亚队列的谱系特异性全基因组关联研究(GWAS)汇总统计数据,我们采用连锁不平衡评分回归和条件错误发现率(condFDR)方法来研究GERD与主要精神疾病(包括重度抑郁症(MDD)、精神分裂症(SCZ)和双相情感障碍(BIP)之间的跨性状遗传富集。我们发现GERD与MDD (rg = 0.49, P = 0.03)和SCZ (rg = 0.25, P = 0.02)之间存在显著的遗传相关性,但与BIP无关。通过condFDR分析,我们发现了两个新的位点:靠近MEIS1的rs3980178位点(与GERD-MDD多效性相关)和靠近ZBTB20的rs9844126位点(与GERD-SCZ多效性相关)。这些基因座与神经发育、自主调节和神经回路形成有关,为肠脑轴提供了机制见解。我们的研究结果表明,交叉性状遗传富集显著提高了东亚GWAS患者的GERD基因座发现,并揭示了胃肠道和精神表型之间的遗传联系。
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引用次数: 0
Population genetics of Plasmodium vivax with transmission decline and rebound in two endemic areas of Papua New Guinea. 巴布亚新几内亚两个流行区间日疟原虫传播下降和反弹的种群遗传学。
IF 2.8 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-02-03 eCollection Date: 2025-01-01 DOI: 10.3389/fgene.2025.1621920
Abebe A Fola, Somya Mehra, Zahra Razook, Dulcie Lautu-Gumal, Elma Nate, Stuart Lee, Johanna Helena Kattenberg, Cristian Koepfli, James Kazura, Maria Ome-Kaius, Moses Laman, Leanne J Robinson, Ivo Mueller, Alyssa E Barry

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.

背景:相对于恶性疟原虫,全球控制和最终消除疟疾的努力对间日疟原虫的效果较差,这是因为间日疟原虫具有独特的生物学特性,包括可导致后期复发的休眠肝期,以及较早进入传播期。在巴布亚新几内亚全国范围内分发长效杀虫剂处理过的蚊帐(LLIN)后,间日疟原虫的流行率最初降至较低水平,但再次回升至与长效杀虫剂处理过的蚊帐分发之前相似的水平。方法:为了探索间日疟原虫种群结构的变化并确定这一时期的复苏来源,我们对在东塞匹克(2005年、2012年、2016年)和马当省(2006年、2010年、2014年)进行的连续横断面调查中获得的336株间日疟原虫基因型应用了先前验证的全基因组SNP条形码。结果:寄生虫基因型的种群遗传分析揭示了两省间不同的时空格局。在马当,感染的复杂性、遗传多样性和种群结构随流行程度而变化,在低传播时可能出现种群瓶颈和早期克隆扩张,在卷土重来时种群迅速恢复。在东塞皮克,在流行率下降后,对寄生虫种群的影响较小,并且在整个研究期间持续传播多个残余谱系。间日疟原虫的减少还伴随着两个地区之间遗传分化的增加,随着重新出现而减少,这表明与流行有关的地区之间寄生虫迁移的变化。结论:与Madang相比,东塞尔维亚较早实施LLIN,回弹较小,传播异质性和相对隔离可能是造成这些不同模式的原因。结果表明,长期持续的控制工作对于对间日疟原虫种群产生持久影响至关重要,SNP条形码可以为控制工作的结果提供有价值的寄生虫传播动态见解。
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引用次数: 0
Adult-onset vanishing white matter disease caused by the EIF2B5 c.185A>T (p.Asp62Val) variant. 由EIF2B5 c.185A>T (p.Asp62Val)变异引起的成人发病的消失性白质疾病。
IF 2.8 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-02-02 eCollection Date: 2026-01-01 DOI: 10.3389/fgene.2026.1739328
Jie Zhou, Chunbo Ji, Siqing Ma, Jianying Zhu, Ping Yang

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.

背景:消失性白质病(VWMD, OMIM 603896),又称儿童期共济失调伴中枢神经系统髓鞘退化(CACH),是一种罕见的常染色体隐性白质营养不良,由EIF2B基因家族(EIF2B1-EIF2B5)的致病变异引起。临床表现是高度异质性的,起病时间从胎儿期到成年期;成人发病病例仍然相对罕见,通常表现为非典型症状。脑磁共振成像(MRI)和基因检测是诊断的关键。病例介绍:我们报告了一名32岁的中国女性成人发病VWMD,其特征是间歇性头痛,进行性认知能力下降,月经不规则和听力丧失。头颅MRI弥散加权成像(DWI)显示对称的脑室周围和半瓣叶中心白质异常。全外显子组测序(WES)鉴定出EIF2B5基因的纯合子错义变异,按照人类基因组变异学会(HGVS)指南格式化为NM_001414.4:c。185 > T (p.Asp62Val)。这种变异以前仅在一名儿科患者中记录,代表了成人的首次报告。结论:我们的病例扩展了eif2b5相关VWMD的表型和年龄相关谱,强调了c.185A>T变异能够在成年期表现出非经典特征(例如,头痛作为初始症状)。先前的研究已经证实,该变体损害了EIF2B复合物的功能,这加强了其在破坏综合应激反应(ISR)和维持白质稳态中的致病作用。对99例经遗传证实的成人发病的病毒性病毒性疾病病例的文献回顾进一步强调了基因型-表型相关性:EIF2B5是成人患者中最常见的突变亚基,以小脑性共济失调、认知能力下降和精神症状为主要的初始表现。女性患者通常表现为卵巢早衰,这是一个关键的诊断标志。早期基因检测对于明确诊断、产前咨询和症状管理至关重要。值得注意的是,本研究存在局限性,包括缺乏对基因-基因相互作用(可能调节疾病严重程度和表型变异性的因素)的调查,以及缺乏亲本遗传数据来充分验证合子性。
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引用次数: 0
Mitophagy-related molecular signatures in ulcerative colitis revealed by machine learning and molecular dynamics. 机器学习和分子动力学揭示的溃疡性结肠炎中线粒体自噬相关的分子特征。
IF 2.8 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-02-02 eCollection Date: 2026-01-01 DOI: 10.3389/fgene.2026.1760869
Yanru Han, Weihua Ren, Sujuan Li, Zhenxia Zhao, Zhiqiang Lin, Fucheng Zhao

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.

简介:溃疡性结肠炎(UC)是一种终身性慢性炎症性疾病,以直肠和结肠粘膜复发性弥漫性炎症为特征。越来越多的证据表明,自噬受损导致UC的免疫失调和上皮损伤。然而,与线粒体自噬相关的分子景观及其治疗潜力在很大程度上仍未被探索。方法:将有丝分裂相关基因(Mitophagy-related genes, MRGs)与差异表达基因交叉,鉴定uc相关MRGs。功能富集、免疫浸润和一致聚类分析来表征分子亚型。采用三种机器学习方法来识别诊断模型。候选治疗剂由CMap数据库确定。结果:共鉴定出35个UC相关MRGs,富集于细胞活化、脂肪酸代谢和PPAR信号通路,揭示了UC中强烈的免疫代谢偶联。共识聚类将UC患者分为两种亚型:代谢主导亚型(C1)和炎症激活亚型(C2)。三个中心基因- cd55, CPT1A和slc16a1 -被筛选并验证为可靠的诊断标记。药物预测和分子对接显示galunisertib与CD55的强结合,并通过分子动力学模拟进一步验证。在体外,galunisertib显著抑制lps诱导的UC细胞模型中炎症细胞因子的释放。讨论:本研究描述了UC的线粒体自噬相关分子特征,并确定了CD55、CPT1A和SLC16A1是连接线粒体功能障碍、代谢重编程和免疫激活的关键生物标志物。此外,galunisertib被认为是一种潜在的治疗药物,为UC的治疗提供了理论基础。
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引用次数: 0
Correction: Driver gene alterations in NSCLC patients in southern China and their correlation with clinicopathologic characteristics. 更正:中国南方NSCLC患者驱动基因改变及其与临床病理特征的相关性。
IF 2.8 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-01-30 eCollection Date: 2026-01-01 DOI: 10.3389/fgene.2026.1794164
Lingna Deng, Jinbang Li, Zhanlong Qiu, Yanfen Wang

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

[这更正了文章DOI: 10.3389/fgene.2024.1455502.]。
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引用次数: 0
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