Pub Date : 2026-02-04eCollection Date: 2026-01-01DOI: 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}
Pub Date : 2026-02-03eCollection Date: 2026-01-01DOI: 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.
{"title":"TCN-5mC: a predictor of 5-methylcytosine sites based on multi-feature fusion and TCN-inspired block networks.","authors":"Cunwen Liu, Xuan Xiao, LongChang Wan, WeiZhong Lin","doi":"10.3389/fgene.2026.1739720","DOIUrl":"https://doi.org/10.3389/fgene.2026.1739720","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"17 ","pages":"1739720"},"PeriodicalIF":2.8,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12908921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212943","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}
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。
{"title":"Cross-trait genetic enrichment between GERD and psychiatric disorders in East Asian populations.","authors":"Zhihao Gao, Xianjin Wang, Zekun Liu, Fen Hu, Yidi Zhou, Kalim Ullah, Ruiwei Wang, Meng Zhang, Xiao Chang, Yongsen Wang","doi":"10.3389/fgene.2026.1770067","DOIUrl":"https://doi.org/10.3389/fgene.2026.1770067","url":null,"abstract":"<p><p>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<sub>g</sub> = 0.49, <i>P</i> = 0.03) and SCZ (r<sub>g</sub> = 0.25, <i>P</i> = 0.02), but not with BIP. Through condFDR analysis, two novel loci were discovered: rs3980178 near <i>MEIS1</i>(associated with GERD-MDD pleiotropy) and rs9844126 near <i>ZBTB20</i>(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.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"17 ","pages":"1770067"},"PeriodicalIF":2.8,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12908923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212973","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}
Pub Date : 2026-02-03eCollection Date: 2025-01-01DOI: 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.
{"title":"Population genetics of <i>Plasmodium vivax</i> with transmission decline and rebound in two endemic areas of Papua New Guinea.","authors":"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","doi":"10.3389/fgene.2025.1621920","DOIUrl":"10.3389/fgene.2025.1621920","url":null,"abstract":"<p><strong>Background: </strong>Global efforts to control and eventually eliminate malaria have been less effective for <i>Plasmodium vivax</i> relative to <i>Plasmodium falciparum</i> 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), <i>P. vivax</i> initially reduced to low prevalence, but again resurged to levels similar to those before LLIN distributions.</p><p><strong>Method: </strong>To explore changes in <i>P. vivax</i> population structure and identify sources of resurgence over this period, we applied a previously validated genome-wide SNP barcode to genotype 336 <i>P. vivax</i> isolates obtained from serial cross-sectional surveys conducted over a decade in East Sepik (2005, 2012, 2016) and Madang Province (2006, 2010, 2014).</p><p><strong>Results: </strong>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. <i>P. vivax</i> 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.</p><p><strong>Conclusion: </strong>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 <i>P. vivax</i> population, and that SNP barcodes can provide valuable insights into parasite transmission dynamics as a result of control efforts.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1621920"},"PeriodicalIF":2.8,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147347501","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}
Pub Date : 2026-02-02eCollection Date: 2026-01-01DOI: 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。
{"title":"Adult-onset vanishing white matter disease caused by the EIF2B5 c.185A>T (p.Asp62Val) variant.","authors":"Jie Zhou, Chunbo Ji, Siqing Ma, Jianying Zhu, Ping Yang","doi":"10.3389/fgene.2026.1739328","DOIUrl":"https://doi.org/10.3389/fgene.2026.1739328","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Case presentation: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"17 ","pages":"1739328"},"PeriodicalIF":2.8,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12906900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146206806","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}
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.
{"title":"Mitophagy-related molecular signatures in ulcerative colitis revealed by machine learning and molecular dynamics.","authors":"Yanru Han, Weihua Ren, Sujuan Li, Zhenxia Zhao, Zhiqiang Lin, Fucheng Zhao","doi":"10.3389/fgene.2026.1760869","DOIUrl":"https://doi.org/10.3389/fgene.2026.1760869","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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. <i>In vitro</i>, galunisertib significantly suppressed inflammatory cytokine release in LPS-induced UC cell models.</p><p><strong>Discussion: </strong>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.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"17 ","pages":"1760869"},"PeriodicalIF":2.8,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12906901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146206797","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}
Pub Date : 2026-01-30eCollection Date: 2026-01-01DOI: 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.]。
{"title":"Correction: Driver gene alterations in NSCLC patients in southern China and their correlation with clinicopathologic characteristics.","authors":"Lingna Deng, Jinbang Li, Zhanlong Qiu, Yanfen Wang","doi":"10.3389/fgene.2026.1794164","DOIUrl":"https://doi.org/10.3389/fgene.2026.1794164","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fgene.2024.1455502.].</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"17 ","pages":"1794164"},"PeriodicalIF":2.8,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12903916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146201316","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}
Pub Date : 2026-01-30eCollection Date: 2026-01-01DOI: 10.3389/fgene.2026.1771707
Jialin Fan, Yunpeng Xu
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.
{"title":"Molecular mechanisms underlying the lifespan and healthspan benefits of dietary restriction across species.","authors":"Jialin Fan, Yunpeng Xu","doi":"10.3389/fgene.2026.1771707","DOIUrl":"10.3389/fgene.2026.1771707","url":null,"abstract":"<p><p>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<sup>+</sup>-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.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"17 ","pages":"1771707"},"PeriodicalIF":2.8,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12900492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146201341","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}
Pub Date : 2026-01-29eCollection Date: 2026-01-01DOI: 10.3389/fgene.2026.1729712
Qiaohong Li, Salma Saeed Khan, Hao Yan, Weiying Kong, Lu Qin, Linmei Wu, Lingjie Li, Weijun Gong, Hua Zheng, Haiyan Li
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.
目的:高尿酸血症和痛风是常见的公共卫生问题,源于遗传和生活方式因素。来自云南省多民族地区的证据仍然有限。这项初步研究调查了来自中国云南省苗族社区的88名参与者的高尿酸血症和痛风患病率、相关生物标志物、生活方式和SLC2A9/SLC22A12遗传变异。方法:采用横断面调查和生化研究。收集人口统计学和生活方式资料,分析血液样本的血清生化指标。SLC2A9和SLC22A12的8个snp进行了基因分型。对等位基因和基因型数据采用Logistic回归模型。结果:对苗族村民(88例)的人口统计学和临床分析表明,高尿酸血症和痛风的发病率在男性中更为常见,并与饮酒、吸烟和BMI升高有显著关联。而饮食模式没有显著差异。与非高尿酸血症/非痛风组(n = 56)相比,高尿酸血症/痛风组(n = 57)尿酸升高56% (553.13 μmol/L vs. 354.73 μmol/L),肌酐升高37% (84.66 μmol/L vs. 61.80 μmol/L),甘油三酯升高(3.35 vs. 1.80 mmol/L),血液学异常,如血红蛋白升高(162.77 vs. 147.50 g/L)和血小板计数降低(161.09 vs. 194.14 × 109/L)。初步的遗传分析表明SLC2A9_rs10939650与高尿酸血症/痛风风险之间可能存在关联,而SLC22A12变异多态性则没有关联。经Bonferroni校正后,没有snp仍然具有统计学意义。结论:苗族人群较高的高尿酸血症和痛风负担可能与民族、性别、生活方式、代谢改变和潜在的遗传因素有关。鉴于样本量小,基因研究结果应谨慎解释,并在针对该疾病(高尿酸血症和痛风)和类似种族社区的更大规模研究中得到验证。
{"title":"Preliminary analysis of lifestyle and genetic factors for hyperuricemia and gout prevalence in the Yunnan Miao population of China.","authors":"Qiaohong Li, Salma Saeed Khan, Hao Yan, Weiying Kong, Lu Qin, Linmei Wu, Lingjie Li, Weijun Gong, Hua Zheng, Haiyan Li","doi":"10.3389/fgene.2026.1729712","DOIUrl":"10.3389/fgene.2026.1729712","url":null,"abstract":"<p><strong>Objectives: </strong>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 <i>SLC2A9/SLC22A12</i> genetics variations among 88 participants from the Miao community in Yunnan Province China.</p><p><strong>Methods: </strong>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 <i>SLC2A9</i> and <i>SLC22A12</i> were genotyped. Logistic regression models were applied to allele and genotype data.</p><p><strong>Results: </strong>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 × 10<sup>9</sup>/L). Preliminary genetic analyses indicated a possible association between <i>SLC2A9_</i>rs10939650 and hyperuricemia/gout risk, whereas variant <i>SLC22A12</i> polymorphisms showed no association. After Bonferroni correction, no SNPs remained statistically significant.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"17 ","pages":"1729712"},"PeriodicalIF":2.8,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12893670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179055","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}
Pub Date : 2026-01-29eCollection Date: 2026-01-01DOI: 10.3389/fgene.2026.1778745
Maya S Safarova, Katherine Athayde Teixeira de Carvalho, Cornelie Nienaber-Rousseau
{"title":"Editorial: Vascular aging through understanding of inherited basis of aortic disease.","authors":"Maya S Safarova, Katherine Athayde Teixeira de Carvalho, Cornelie Nienaber-Rousseau","doi":"10.3389/fgene.2026.1778745","DOIUrl":"10.3389/fgene.2026.1778745","url":null,"abstract":"","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"17 ","pages":"1778745"},"PeriodicalIF":2.8,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12894271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146201325","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}