Human Genomics最新文献

{"title":"Machine learning and multi-omics clustering to map cellular rewiring and immune evasion in ccRCC.","authors":"Zhe Wang, YingJian Wang, Jiayi Zhang, Yuechang Zhang, Shaoyang Xv, Long Zhang, Feng Wang, Dao Xin","doi":"10.1186/s40246-026-01024-8","DOIUrl":"10.1186/s40246-026-01024-8","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) efficacy in clear cell renal cell carcinoma (ccRCC) is limited by tumor microenvironment (TME) heterogeneity. Because traditional bulk-derived models lack spatial resolution, we developed an integrated framework connecting macroscopic survival risks to microscopic TME structures. We applied ten algorithms to establish multi-omics subtypes and evaluated 101 machine-learning combinations across three independent cohorts to generate a Consensus Machine Learning-driven Signature (CMLS). The signature's spatial and cellular origins were decoded using spatial transcriptomics (ST) and a 140,000-cell scRNA-seq atlas. Expression of key genes was experimentally validated via RT-qPCR in 17 paired ccRCC clinical tissues. We identified two molecular subtypes with distinct clinical and epigenetic profiles. SuperPC optimization yielded a 24-gene CMLS serving as an independent prognostic factor. scRNA-seq and ST deconvolution revealed these signals predominantly originate from cancer-associated fibroblasts (CAFs) and malignant epithelial cells, which collaborate to drive spatial immune exclusion. RT-qPCR confirmed significant overexpression of five core CMLS genes in ccRCC versus adjacent normal tissues. Low CMLS scores correlated with enhanced ICB responsiveness, whereas high-CMLS tumors demonstrated specific vulnerability to dasatinib and dabrafenib. The CMLS translates spatial immune-exclusion dynamics into a quantifiable metric, outperforming tumor mutational burden in predicting ICB benefits, providing a robust tool for patient stratification in ccRCC.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"20 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13576295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-powered histopathology classifiers identify transcriptomic biomarkers associated with cell cycle regulation and increased mitotic activity in poorly differentiated neuroendocrine carcinoma.","authors":"Timothy Khumpan, Kasonde Chewe, Namrata Vijayvergia, Eric Eleam, Juan Nicolas Quiñones-Romero, Suraj Peri, Gong Yulan, Paul F Engstrom, Kathy Q Cai, Jianming Pei, Gulnaz D Alekbaeva, Kerry S Campbell, Johnathan R Whetstine, Igor Astsaturov, Hayan Lee","doi":"10.1186/s40246-026-01032-8","DOIUrl":"10.1186/s40246-026-01032-8","url":null,"abstract":"<p><strong>Background: </strong>Neuroendocrine neoplasms (NENs) are a biologically heterogeneous group of epithelial malignancies arising from neuroendocrine cells across multiple organs. Although considered rare in comparison to other solid tumors, their incidence has increased more than six-fold in recent decades. A major clinical challenge is the accurate stratification between aggressive, poorly differentiated (PD) neuroendocrine carcinomas (NECs) and slow growing well-differentiated (WD) neuroendocrine tumors (NETs), which differ significantly in prognostic outcomes and treatment response. Conventional histopathology is often insufficient for reliable classification or determination of tumor origin, motivating the need for molecularly informed diagnostic approaches.</p><p><strong>Methods: </strong>We performed transcriptomic profiling of 36 neuroendocrine neoplasms (NENs) including 21 well-differentiated neuroendocrine tumors (WD-NETs) and 15 poorly differentiated neuroendocrine carcinomas (PD-NECs) from 11 distinct anatomical sites. We developed an interpretable AI-based histology classifier achieving an area under the receiver operating characteristic curve (AUC-ROC) of 0.87-0.93.</p><p><strong>Results: </strong>PD-NECs exhibited upregulation of genes involved in cell-cycle regulation and DNA damage response, including SFN, CHEK1, E2F1, CDC6, and TTK. In contrast, neuroendocrine lineage-associated genes such as CAMK2B and PAK3, which are preferentially expressed in neural tissues, were enriched in WD-NETs. AI-derived transcriptomic biomarkers distinguishing WD-NET and PD-NEC (PAK3 and EZH2, respectively) were orthogonally validated by immunohistochemistry. Our findings were further supported by independent validation in an publicly available NEN DNA methylation dataset. Moreover, DNA methylation-based mitotic age analysis demonstrated significantly higher mitotic activity and proliferative potential in lung NECs compared with lung NETs, consistent with our transcriptomic findings. Our analysis is publicly available at https://nen-pd-wd-hist.epigenomeocean.org/.</p><p><strong>Conclusions: </strong>This study establishes an integrative multi-omics framework for molecular classification of NENs that complements traditional histopathological assessment. By combining transcriptomic profiling, interpretable machine learning, and epigenetic validation, our approach enables improved tumor stratification, identification of mixed or misclassified cases and supports the development of biomarker-driven diagnostic and therapeutic strategies.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"20 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Clinical, genetic and bioinformatic analysis of Saudi families with Joubert syndrome and related disorders.","authors":"Riman Alafghani, Deema Aljeaid, Noor Ahmad Shaik, Babajan Banaganapalli, Ramu Elango, Ghayah Khard, Wisam Habhab, Ghada Jadkarim, Dalal Sameer Alshaer, Mahmoud Almutadares, Nuha Mohammad Alrayes, Noha M Issa","doi":"10.1186/s40246-026-01046-2","DOIUrl":"10.1186/s40246-026-01046-2","url":null,"abstract":"","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"20 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13570498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ExposoGenomics: integrating genome and exposome as jointly dynamic systems for causal discovery and precision health.","authors":"Vasilis Vasiliou, Nicholas Katsanis, Giuseppe Novelli, Juergen K V Reichardt, Bassam R Ali, Maria Gazouli, Sek Won Kong, Hongyu Zhao, Kiril Veselkov, Bhramar Mukherjee, Dimosthenis Sarigiannis","doi":"10.1186/s40246-026-01014-w","DOIUrl":"10.1186/s40246-026-01014-w","url":null,"abstract":"<p><p>The past decade has witnessed an unprecedented convergence of exposomic technologies, population-scale genomics, and AI-enabled data science, creating the conditions for a new integrative discipline. Here we introduce ExposoGenomics, defined as the integrative study of how the genome and exposome, treated as jointly dynamic systems, interact across the life course to shape health and disease. ExposoGenomics moves beyond classical gene-environment interaction models by embedding high-dimensional, temporally resolved exposure data within a multi-omic and AI-enabled analytical architecture oriented toward causal discovery, mechanistic understanding, and translational application. We describe the conceptual foundations of this framework, its mechanistic architecture linking external exposures to genomic responses through physiologically based kinetic models and adverse outcome networks, and the analytical approaches, including causal machine learning, graph-based integration, and foundation models, required to realize its potential. We emphasize that computational prediction must be accompanied by rigorous empirical validation, and that findings must be grounded in biologically plausible, causally supported mechanisms. In conjunction with this Perspective, Human Genomics formally launches ExposoGenomics as a dedicated article category and invites submissions that advance this integrative agenda.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of APOC2 upstream variant rs10425530 with BMI predicted to overlap with NR2C2, GCM2 and NR2C1 binding sites.","authors":"Suzanne A Al-Bustan, Babitha G Annice, Hasan Alhaddad","doi":"10.1186/s40246-026-01015-9","DOIUrl":"10.1186/s40246-026-01015-9","url":null,"abstract":"<p><strong>Background: </strong>Lipid metabolism involves multiple genes that contribute to various diseases including metabolic disorders. Although extensive research has focused on identifying large-effect variants in coding regions, few studies have examined the effects of variations in regulatory and non-coding regions. Apolipoprotein C2 (APOC2) gene plays a central role in activating lipoprotein lipase; however, the effect of upstream variants on its transcriptional regulation remains unclear. We aimed to (1) identify genetic variants in a targeted APOC2 upstream region of, (2) annotate and characterize predicted cis-regulatory elements (CREs) in-silico, (3) map identified variants to transcription factor binding sites (TFBS), and (4) evaluate the association of selected variants with dyslipidemia and body mass index (BMI).</p><p><strong>Results: </strong>Twelve variants were identified by sequencing of the APOC2 targeted region in a Kuwaiti cohort (n = 600). In-silico annotation using multiple tools identified 626 putative CRE within the targeted region which were prioritized into 48 predicted TFBS of functional relevance. Four variants (rs10425530, rs111782345, rs112698600, and rs2288912) met the criteria for association testing. A significant independent association, employing multivariate analysis, was observed between rs10425530 and BMI under a dominant model (β = 2.26; p = 0.022) among the Kuwaiti Arabs that requires further investigation in a large cohort. Motif-based analyses predicted that the rs10425530 A allele may alter the binding affinity of NR2C2, NR2C1, and GCM2 motifs by 21.10%, 23.80% and 20.40%, respectively.</p><p><strong>Conclusions: </strong>Two hypothetical models have been proposed to explain the observed association between rs10425530 and increased BMI and the predicted effect on TFBS: (1) disruption of NR2C1/NR2C2 binding sites may influence APOC2 regulation via interactions with nuclear receptors involved in energy balance and/or (2) disruption of a GCM2 binding site may act via long-range regulatory effects on parathyroid hormone pathways. These findings are exploratory and require replication in larger independent cohorts and warrants further in-vitro and in-situ investigations to elucidate definitive functional assignments in regulatory activity and chromatin accessibility. The analytical framework applied in this study could provide basis for improving the interpretation of non-coding genomic variations and groundwork for future studies combining in-silico functional predictions and experimental analysis.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding dry eye disease based on bioinformatics and in vitro experimental: the role of immune responses and natural product intervention.","authors":"Xi Long, Guicheng Liu, Pei Liu, Pengfei Jiang, Jun Peng, Qinghua Peng","doi":"10.1186/s40246-026-00992-1","DOIUrl":"10.1186/s40246-026-00992-1","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Dry eye disease (DED), a prevalent ocular condition, has seen rising incidence rates. Aberrant inflammation and immune dysregulation are key pathogenic factors in DED. However, the underlying mechanisms linking autoimmunity to DED therapy remain incompletely understood. Herbal medicine's potential in treating DED warrants further exploration due to rendering monotherapy insufficient for clinical needs.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;DED-related datasets and genes were initially identified from the GEO database and other public repositories. After retrieving the data, differential gene expression analysis and functional enrichment analysis were performed. Subsequently, a protein-protein interaction network was constructed to identify core modules and hub genes. To enhance the reliability and diagnostic value of these findings, the hub genes were further validated using independent external datasets and refined through machine learning algorithms (LASSO and SVM-RFE) to extract characteristic genes. These characteristic genes were then used for reverse prediction of potential Traditional Chinese Medicine natural products, leading to the construction of a gene-natural products network. Following this, molecular docking was employed to screen for promising natural products based on binding affinity. In parallel, immune cell infiltration was estimated using CIBERSORTx, and single-cell RNA sequencing data were analyzed to elucidate cell-type-specific expression patterns of the characteristic genes. Finally, the therapeutic potential of the top-predicted natural product was validated using an in vitro cellular model of DED.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;GSE44101 was selected as the base dataset. Differential gene analysis identified 1089 differential genes and 3504 DED-related genes from five databases, with 235 overlapping genes. Enrichment analysis linked DED to Cytokine-Cytokine receptor interaction, PI3K-Akt, IL-17, and JAK-STAT signaling pathways. The PPI network yielded 20 hub genes, validated and refined using other GEO datasets and machine learning, resulting in 10 characteristic genes: CDK1, CCNA2, CXCL13, CCR1, FEN1, CCR7, SELL, RAD51, CXCL1, and KIF11. Genistein was identified as the key TCM natural product. Molecular docking revealed stable interactions between Genistein and CDK1, IL-1β, CDC20, and CCNA2, with CDC20 showing the highest stability. CIBERSORT analysis demonstrated associations between characteristic genes and specific immune cell infiltration in DED. Single-cell RNA sequencing localized their expression to key corneal cell types, with IL-1β predominantly expressed in macrophages. Cell experiments confirmed that Genistein at a concentration of 12.5 μmol/L could protect human corneal epithelial cells from NaCl-induced hyperosmotic damage and TNF-α-induced immune injury, reducing the cell detachment rate and decreasing the area of cell death loss. Genistein downregulated the expression of CDK1, IL","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic reconstruction of the Pakistani Roma reveals dual South Asian ancestry, medieval bottlenecks, and the early dispersal routes of the Romani people.","authors":"Atif Adnan, Hao Dong Chen, Allah Rakha, Muhammad Ilyas, Chuan-Chao Wang","doi":"10.1186/s40246-026-00965-4","DOIUrl":"10.1186/s40246-026-00965-4","url":null,"abstract":"<p><p>The Roma people represent one of the largest and most historically enigmatic diasporas in Eurasia, illuminating human migration patterns and cultural resilience across continents. Despite extensive research on European Roma as the diaspora endpoint, the genetic legacy of their putative South Asian source populations remains critically underexplored, leaving fundamental gaps in understanding the pre-diaspora demographic structure and early dispersal dynamics. This study uniquely positions Pakistani Roma as a potential ancestral reservoir, offering a rare window into the pre-migration phase distinct from derived European Roma populations shaped by centuries of post-dispersal admixture. We analyze 82 Pakistani Roma from Punjab using high-resolution genome-wide SNP data and comprehensive mitochondrial haplogroup profiling to reconstruct their genetic origins, population structure, and historical trajectory. Analyses reveal a dual ancestry profile comprising 50-82% Indus Valley related, 20-30% Onge related, and up to 26% Steppe derived components, with three distinct subgroups exhibiting varying affinities along a South Asian to Central Western Eurasian continuum reflecting jati-like endogamy. A severe demographic bottleneck ~800 years ago coincides with medieval socio-political upheavals, while major Eurasian admixture is dated to ~660 years ago. Mitochondrial haplogroups H (45.12%) and M (26.83%) underscore dual maternal influences from West and South Eurasia. Pakistani Roma retain substantially higher South Asian ancestry than their European counterparts, establishing them as a genetically distinct population preserving the ancestral pre-diaspora state. These findings redefine the Romani origin narrative and underscore the critical value of understudied South Asian minorities in reconstructing complex human migration pathways and diaspora formation mechanisms.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148420914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ancestry specific polygenic risk score, dietary patterns, physical activity and incident type 2 diabetes.","authors":"Dale S Hardy, Jane T Garvin, Tennille S Leak-Johnson, Tesfaye B Mersha","doi":"10.1186/s40246-025-00900-z","DOIUrl":"10.1186/s40246-025-00900-z","url":null,"abstract":"<p><strong>Background: </strong>It is unknown whether the impact of lifestyle could mitigate the genetically driven high-risk polygenic risk score (PRS) in different ancestries.</p><p><strong>Objectives: </strong>We determined associations and interactions between high-risk PRS, dietary patterns, physical activity, and metabolic burden and their impact on incident type 2 diabetes mellitus (T2DM) in European Americans and African Americans. A secondary aim determined ancestry-specific PRS-mapped genes associated molecular pathways.</p><p><strong>Methods: </strong>Our longitudinal study (1976-2015) utilized de-identified data for European American (n = 8,283) and African American (n = 1,205) from 7-National Heart, Lung, and Blood Institute Candidate Gene Association Resource studies from the Database of Genotypes and Phenotypes. We assessed results using biased-corrected odds ratios (OR) and 95% confidence intervals (CI).</p><p><strong>Results: </strong>African Americans had a higher magnitude of incident T2DM risk for the high-risk PRS alone (OR = 1.61; 95% CI:1.22-2.12) than European Americans (OR = 1.24; 95% CI:1.06-1.45) in highest tertile compared to lowest tertile. We observed protective risks from incident T2DM with the Dietary Approaches to Stop High Blood Pressure (DASH) and Mediterranean diets (p < 0.025). However, entangling effects from the high-quality DASH/Mediterranean diets with the low-quality Southern diet and the high-risk PRS further increased T2DM risks (p < 0.025). The PRS-diet-physical activity associations had 9% protective T2DM risk for Mediterranean diet in African Americans and at least 5% for European Americans (p < 0.025). Interactions revealed the second tertile DASH and highest tertile Mediterranean diets in high-risk PRS-high metabolic burden, attenuated incident T2DM risk. Gene enrichment molecular pathways common to ancestries included neurogenerative diseases, lipid metabolism, and glucose metabolism.</p><p><strong>Conclusions: </strong>Patients in the highest PRS tertiles with high metabolic burden could be targeted for early intervention to decrease T2DM risk. The DASH and Mediterranean diets with high physical activity should be recommended by clinicians for better prevention, detrimental molecular pathway reversal, and to decrease worsening of T2DM from high metabolic burden.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"20 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13343712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148404520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis-related TFRC: a potential therapeutic target in sepsis and regulatory effect of γ-Tocotrienol.","authors":"Yandong Yao, Gege Ke, Yuanxin Wu, Haili Li, Yingchun Hu, Muhu Chen","doi":"10.1186/s40246-026-01003-z","DOIUrl":"10.1186/s40246-026-01003-z","url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis, an iron-dependent regulated cell death, plays a critical role in the pathophysiology of sepsis. This study aimed to identify core targets and therapeutic agents related to ferroptosis in sepsis.</p><p><strong>Methods: </strong>Differential analysis of peripheral blood RNA-sequencing data from 19 patients with sepsis and 10 healthy controls was performed. Ferroptosis-related hub genes were identified via a PPI network and validated by Mendelian randomization, protein cohort studies, and survival/meta-analyses. Single-cell sequencing localized core genes, and in vitro/in vivo experiments explored targeted drugs.</p><p><strong>Results: </strong>High TFRC expression correlated with poor sepsis prognosis. TFRC was predominantly expressed in monocytes and B cells, with more monocytes in non-survivors. γ‑Tocotrienol (γ‑T3) treatment was associated with reduced TFRC expression, lower ROS and IL‑1β levels, and improved survival in septic zebrafish and mice.</p><p><strong>Conclusion: </strong>TFRC is a potential therapeutic target for ferroptosis in sepsis. γ‑T3 alleviates LPS-induced TFRC upregulation and improves survival in septic mice, suggesting its potential as a therapeutic agent.</p><p><strong>Study registration: </strong>ChiCTR1900021261 (Chinese Clinical Trial Registry), registered February 4, 2019.</p><p><strong>Type of study: </strong>retrospective observational study using archived biological samples.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutational spectrum of SLC26A4 and SLC26A5 associated with hereditary hearing loss in Moroccan families.","authors":"Assia Idyahia, Salaheddine Redouane, Fatima Ezzahra Chentoufi, Hicham Charoute, Adil El Hamouchi, Houda Benrahma, Abdelhamid Barakat","doi":"10.1186/s40246-026-01010-0","DOIUrl":"10.1186/s40246-026-01010-0","url":null,"abstract":"<p><strong>Background: </strong>The solute carrier family 26 (SLC26) encodes multifunctional anion transporters that mediate the transmembrane exchange of monovalent and divalent anions. While pathogenic variants in several SLC26 genes cause inherited disorders, only SLC26A4 and SLC26A5 have been linked to hereditary hearing loss (HHL).</p><p><strong>Results: </strong>Exome sequencing performed in probands from nine unrelated Moroccan families with sensorineural hearing loss identified eight SLC26A4 variants, including previously reported and novel variants, as well as a homozygous canonical splice-site variant in SLC26A5 (c.1311 + 1G > T). Sanger sequencing confirmed co-segregation of all identified variants, and in silico prediction tools consistently supported their pathogenicity. Molecular dynamics simulations performed on three SLC26A4 missense variants (p. Ser353Ala, p. Phe555Cys, and p. Leu582Pro) indicated significant, state-dependent alteration in pendrin's structural stability, suggesting impaired conformational transitions required for efficient Cl⁻/HCO₃⁻ exchange.</p><p><strong>Conclusion: </strong>This study provides a comprehensive molecular characterization of SLC26A4- and SLC26A5-related hearing loss in Moroccan families and significantly expands the mutational landscape of hereditary hearing loss in North Africa.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148368254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}