Human Genomics最新文献

{"title":"HMGCR genetic variation and risk of new-onset type 2 diabetes in statin users.","authors":"Areej S Albawa'neh, Mais N Alqasrawi, Zeina N Al-Mahayri, Nour Al Dain Marzouka, Lilas Dabaghie, Dana Hamza, Lubna Q Khasawneh, Virendra Misra, Husam Ouda, Bassam R Ali","doi":"10.1186/s40246-026-00962-7","DOIUrl":"10.1186/s40246-026-00962-7","url":null,"abstract":"<p><p>BACKGROUND: Statins are widely prescribed lipid-lowering agents, but their use is associated with an increased risk of new-onset type 2 diabetes mellitus (NO-T2DM) ranging from 9% to 13%. While genetic variants in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the pharmacological target of statins, and the solute carrier organic anion transporter family, member 1B1 (SLCO1B1), a key hepatic transporter, have been implicated in statin response and toxicity, their role in statin-associated diabetogenesis remains unclear. OBJECTIVE: To investigate the association of four common HMGCR variants (rs17671591, rs12916, rs17238484, and rs2303152) and the SLCO1B1 (rs4149056) with the risk of NO-T2DM among statin-treated cohort. METHODS: In a matched case-control study, 194 adults receiving atorvastatin or rosuvastatin were enrolled. The cases were patients who developed NO-T2DM within four years of initiating statin therapy (n = 97), while controls remained diabetes-free after four years of use (n = 97). Participants were matched for age, sex, ethnicity, BMI, and statin intensity. Genotyping was performed using TaqMan assays, and associations were evaluated using genetic models, linkage disequilibrium (LD), and haplotype analyses. RESULTS: The HMGCR rs17238484 variant showed a nominal association with NO-T2DM in statin users. Carriers of the T allele (GT + TT) showed a lower risk compared with the GG genotype (OR = 0.56, 95% CI: 0.36–0.99, P = 0.044); however, this association did not remain significant after correction for multiple testing. Haplotype analysis identified that the T–T–T haplotype of rs17671591–rs17238484–rs12916 was significantly associated with reduced risk of NO-T2DM (OR = 0.12, 95% CI: 0.02–0.58, P = 0.009). Other HMGCR SNPs and SLCO1B1 rs4149056 showed no significant associations. CONCLUSION: These findings suggest that HMGCR haplotypes may be associated with NO-T2DM risk among statin users, further studies in larger and more diverse populations are needed to validate these results. </p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13200291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662493","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":"Integrated multiomics profiling of amniotic fluid exosomes reveals dysregulated lipid and protein signatures in fetal 22q11.2 deletion syndrome.","authors":"Hai Xiao, Tao Li, Mengting Zhang, Xue Lv, Yue Gao, Qiannan Guo, Zhenglong Guo, Hongdan Wang, Liangjie Guo, Hongyan Liu, Shixiu Liao, Dong Wu","doi":"10.1186/s40246-026-00963-6","DOIUrl":"10.1186/s40246-026-00963-6","url":null,"abstract":"<p><strong>Background: </strong>Amniotic fluid exosomes (AF-Exos) are pivotal carriers of biological information during fetal development; however, their role in 22q11.2 Deletion Syndrome (22q11.2DS) remains unclear. To elucidate the molecular mechanisms underlying fetal anomalies in 22q11.2DS, this study performed a comprehensive multiomics analysis of AF-Exos obtained from 22q11.2DS fetuses (n = 5) and matched controls (n = 5).</p><p><strong>Results: </strong>While exosomal morphology and size distribution remained unaltered, integrated lipidomic and proteomic profiling revealed profound molecular remodeling. Lipidomics analysis revealed a specific suppression of diacylglycerols, triacylglycerols, and ceramides, accompanied by a shift in carbon chain length distribution. Concurrently, data-independent acquisition proteomics identified 329 differentially expressed proteins, highlighting a significant downregulation of PI4KA and widespread perturbations in pathways governing cardiovascular morphogenesis, angiogenesis, and SNARE-mediated vesicular transport. Integrated network analysis revealed strong correlations between the depletion of key lipids and reduced abundance of PI4KA and SNARE complex components, suggesting a potential interplay between lipid metabolism and vesicle trafficking.</p><p><strong>Conclusions: </strong>These findings, extending beyond the primary genetic driver TBX1, point to distinct alterations in lipid signaling and exosomal transport machinery in 22q11.2DS, suggesting a novel parallel pathogenic mechanism. This study provides a novel multiomics resource for understanding 22q11.2DS pathogenesis and generates valuable hypothesis-driven candidates for future mechanistic investigation.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13196005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638719","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":"The novel (TCTG)_n motif in CNBP expanded alleles: composition, dynamics and genotype-phenotype correlation in Myotonic dystrophy type 2 (DM2).","authors":"Federica Centofanti, Virginia Veronica Visconti, Maria Rosaria D'Apice, Marco Carlomagno, Simone Maestri, Dario Ciabini, Mario Bengala, Enrica Marchionni, Erica Frezza, Roberto Massa, Antonio Petrucci, Francesca Lupidi, Elena Pegoraro, Gabriele Siciliano, Matteo Garibaldi, Paola Origone, Massimo Delledonne, Marzia Rossato, Annalisa Botta, Giuseppe Novelli","doi":"10.1186/s40246-026-00954-7","DOIUrl":"10.1186/s40246-026-00954-7","url":null,"abstract":"<p><p>Introduction. Myotonic dystrophy type 2 (DM2) is an autosomal dominant disorder caused by (CCTG)n repeat expansions in intron 1 of the CNBP gene. Recent evidence from long-read sequencing suggests these expansions may be more complex than previously recognized. Aim. To comprehensively characterize the composition, intergenerational dynamics, and clinical impact of novel (TCTG)n motifs within the CNBP expanded alleles in a large DM2 cohort. Methods. We analyzed 100 genetically confirmed DM2 individuals (45 sporadic, 55 familial). The presence of (TCTG)n blocks was detected using an optimized quadruplet-repeat primed PCR (QP-PCR) assay coupled with Sanger sequencing. In a subset of nine patients, Cas9-mediated enrichment followed by Nanopore Long-Read Sequencing (LRS) provided nucleotide-level resolution of the expanded alleles. Haplotype analysis was performed using STR markers. Results. We identified (TCTG)n blocks at the 3′ end of the expansion in 88% of patients. This refined assay corrected nine initial false-negative diagnoses from standard testing. LRS analysis confirmed the composition and revealed the dynamics of the (TCTG)n tract in familial transmission, showing a tendency for contraction and, in one case, complete loss. Genotype–phenotype correlation analysis indicated that the presence of the (TCTG)n motif acts as a disease modifier, significantly influencing the age of onset. Conclusion. The detailed characterization of the CNBP expansion reveals the novel (TCTG)n component that is integral to the DM2 genotype. Understanding its composition and dynamics enhances diagnostic accuracy and provides a new framework for genetic counselling, prognostic stratification and future personalized therapies. .</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13195993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147622789","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":"Compound heterozygous structural variants resulting in CNTNAP2 biallelic loss-of-function: rare mechanisms unveiled by genome sequencing.","authors":"Jade Fauqueux, Roseline Caumes, Cindy Colson, Adeline Trauffler, Pierre Cleuziou, Caroline Thuillier, Pauline Planté-Bordeneuve, Marine Tessarech, Jamal Ghoumid, Thomas Smol","doi":"10.1186/s40246-026-00952-9","DOIUrl":"10.1186/s40246-026-00952-9","url":null,"abstract":"<p><p>The CNTNAP2 gene encodes CASPR2, a transmembrane protein essential for neuronal development and synaptic function. Biallelic pathogenic variants cause Pitt-Hopkins-like syndrome, characterized by intellectual disability, epilepsy, and autistic features. We report two patients with a Pitt-Hopkins-like phenotype carrying compound heterozygous structural variants: an intragenic deletion in trans with a paracentric inversion. Short-read genome sequencing detected both variants, and long-read sequencing refined one breakpoint. Non-reccurent deletions involved exon 3, while CNTNAP2 breakpoints for both inversions were located in intron 1. These findings broaden the mutational spectrum of CNTNAP2 and underscore the value of genome sequencing in identifying complex structural variants.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13196119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147622835","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":"Comprehensive overview of the global pharmacogenetic and functional variability in NUDT15.","authors":"Yitian Zhou, Lukas M Lauschke, Volker M Lauschke","doi":"10.1186/s40246-026-00959-2","DOIUrl":"10.1186/s40246-026-00959-2","url":null,"abstract":"<p><p>Thiopurine medications are widely used for the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. However, thiopurine-induced hemotoxicity occurs in up to 30% of patients, which causes substantial morbidity and limits therapeutic success. These adverse effects are associated with genetic variation in TPMT and NUDT15, which encode key enzymes involved in thiopurine metabolism. While the global distribution of TPMT variability has been extensively studied, less is known about the ethnogeographic variability of NUDT15, and no meta-analysis of available population frequencies has been reported. In this study, we aggregated genetic data from 150 studies and repositories comprising genotypes from a total of 1,401,592 individuals across 55 countries. We further synthesize the available clinical evidence for functional effects of NUDT15*5 and NUDT15*6, which are currently considered as variants with indeterminate functional effects. This synthesis indicates that both alleles significantly increase thiopurine adverse event risk. We aggregate the genetic information to spectra of functional variability to generate the first global maps of NUDT15 metabolizer phenotypes. We observe a graded distribution of NUDT15 deficiency, peaking in East Asia (46% of all individuals exhibit reduced NUDT15 activity) and declining across Central Asia (13.6%), Middle Eastern populations (3.8%) and Europe (2.1%). NUDT15 deficiency is furthermore prevalent on the Western coast of South and Central America but absent in Africa. Overall, our results provide a valuable resource for population-specific NUDT15 allele and metabolizer phenotype distributions, which can guide thiopurine risk assessment on a global scale.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13069803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618601","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":"Rare variants in FAT3 as possible contributors to non-syndromic orofacial cleft risk.","authors":"Qianying Kong, Chunhui Qi, Qian Zhao, Huifang Peng, Yanying Dong, Hongwei Jiang, Xuechen Zhu","doi":"10.1186/s40246-026-00956-5","DOIUrl":"10.1186/s40246-026-00956-5","url":null,"abstract":"<p><p>Non-syndromic orofacial clefts (NSOFCs) represent the most common human craniofacial malformations, yet the majority of their genetic causes remain unclear. This study, by analyzing whole-exome sequencing (WES) data from multiple patients with NSOFCs, identified eight de novo low-frequency missense variants in the FAT3 gene, all of which were located within the extracellular cadherin domains of the FAT3 protein. Sanger sequencing confirmed the authenticity of these variants, while bioinformatic predictions and protein structural modeling suggested potential disruption of FAT3 function.Using in vivo animal models, we demonstrated that reduced fat3 function impairs cranial neural crest cells (CNCCs) induction and migration processes. Further investigation revealed that fat3 knockdown leads to reduced β-catenin levels, a key regulator of craniofacial development and CNCCs induction, migration, and fate determination. Collectively, these findings suggest that FAT3 represents a previously underappreciated genetic contributor to NSOFCs risk and may influence craniofacial development, at least in part, through modulation of β-catenin abundance and canonical Wnt/β-catenin signaling.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13173973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615973","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 interplay between deployment exposures and Gulf War illness in Million Veteran Program participants.","authors":"Dan Qiu, Brenda Cabrera-Mendoza, Jun He, Lea Steele, Rachel Quaden, Kelly M Harrington, Sarah T Ahmed, J Michael Gaziano, Elizabeth J Gifford, Mihaela Aslan, Drew A Helmer, Elizabeth R Hauser, Renato Polimanti","doi":"10.1186/s40246-026-00951-w","DOIUrl":"10.1186/s40246-026-00951-w","url":null,"abstract":"<p><p>Veterans of the 1990–1991 Gulf War (GW) experienced an elevated burden of chronic health conditions, most notably Gulf War Illness (GWI). While the disease etiology remains unclear, it is hypothesized that both genetic susceptibility and deployment exposures contribute to GWI risk. We investigated 6,882 GW-deployed Veterans, assessing genetic and epigenetic interactions with GW exposures (ground combat, insect baits, oil well smoke exposure, pyridostigmine bromide pills, biological/chemical warfare agents, and pesticides). We observed nominal evidence of a genome-wide gene–environment interaction variance component (0.38 ± 0.22) related to biological/chemical warfare-agent exposure and identified three loci showing genome-wide significant interactions (p < 5 × 10− 8; rs78441512, rs145790544, and rs117997207). Also, type-2 diabetes polygenic risk association with GWI is reduced in Veterans exposed to biological/chemical warfare agents, pesticides, and oil well fire smoke during GW deployment. An exploratory computational drug-repurposing analysis highlighted clebopride, rifampicin, and fisetin as compounds potentially targeting GWI-associated molecular pathways. Our GWI epigenome-wide association study identified five sites showing epigenetic interaction with four GW exposures: ground combat, biological/chemical warfare agents, pyridostigmine bromide pill use, and pesticide use. In conclusion, our study demonstrates that both genetic and epigenetic factors interact with GW military exposures to influence GWI vulnerability, highlighting potential druggable pathways to develop novel therapeutic interventions.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147528531","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":"Update of the Methyltransferase Gene Family: Classification, Evolution and Biological Functions.","authors":"Angeliki I Katsafadou, Pål Ø Falnes, Elspeth Bruford, Bryony Braschi, Quinlin M Hanson, Matthew D Hall, David C Thompson, Daniel W Nebert, Vasilis Vasiliou","doi":"10.1186/s40246-026-00949-4","DOIUrl":"10.1186/s40246-026-00949-4","url":null,"abstract":"<p><p>Methylation is a crucial biochemical reaction involved in a wide range of processes including gene regulation, signal transduction, epigenetics, metabolism and detoxification. A number of methyltransferases (MTases) catalyze transfer of methyl groups from S-adenosyl-L-methionine (AdoMet or SAM) to nucleic acids, proteins, and small molecules, affecting chromatin structure, RNA function, and metabolic pathways. MTase dysregulation is associated with maladies such as cancer, neurodevelopmental disorders, and metabolic syndromes. Advancements in bioinformatics and high-throughput genomics have resulted in identification of ~ 200 human MTase genes, and most of the encoded proteins have now been characterized biochemically. Here, we have classified the human MTases into nine structural homology groups, including a distinct category of methyltransferases with unique structures. Major groups include the versatile seven-β-strand (7BS) MTases, the SET domain MTases which mainly mediate protein lysine methylation, and the SPOUT MTases involved in RNA modification. In addition, we categorized the MTases based on substrate specificity (e.g., nucleic acids, protein, and small-molecule MTases). This article provides a comprehensive classification and structural overview of human MTases, integrating recent nomenclature updates from the HUGO Gene Nomenclature Committee (HGNC). The evolutionary relationships and diversification of methyltransferases are also discussed in the context of structural classification and functional specialization. Emphasis is placed on biological functions, disease associations, and emerging therapeutic potential of the human MTases, particularly in oncology and neurodegenerative research. Despite significant progress, the biological function of many MTases remainselusive, necessitating further research to elucidate their enzymatic mechanisms and potential as drug targets. Understanding the MTase landscape is crucial for advancing biomedical research and developing targeted therapies for methylation-related disorders.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13137591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147511938","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":"Translating multi-omics into healthcare: requisites for scalable and equitable implementation.","authors":"Birute Tumiene, David R Adams, Robert Allaway, Maria J Barrero, Chun-Hung Chan, Víctor Faundes, Vanessa S Fear, Polina Glezer, Claudia Fuchs, Tudor Groza, Elisa J F Houwink, Saumya Shekhar Jamuar, Mary Catherine V Letinturier, Richa Madan Lomash, Ratna Dua Puri, Juergen K V Reichardt, Ruty Mehrian-Shai, Francois H van der Westhuizen, Gaurav K Varshney, Shinya Yamamoto, Gareth Baynam","doi":"10.1186/s40246-025-00902-x","DOIUrl":"10.1186/s40246-025-00902-x","url":null,"abstract":"<p><p>Multi-omics in combination with advanced computational methodologies synthesizes diverse omics data to provide deeper insights into molecular interactions and offers transformative potential for unravelling phenomenon behind disease complexities, improving diagnostics, disease prevention, and personalized treatments. This integrative strategy enables our understanding of gene-environment relationships, chronic disease progression, and the intricate molecular pathways involved in health. Effective multi-omics analyses require robust data sharing, accessibility, interoperability, and governance, which are critical for linking genomic elements to phenotypic traits. The Global Alliance for Genomics and Health advocates for responsible data-sharing practices, by promoting key principles such as transparency and equity. By emphasizing a collaborative approach to data utilization, our proposed framework seeks to advance improved disease prevention and treatment strategies. Multi-disciplinary collaboration, encompassing researchers, clinicians, policy makers, and patient representatives, is pivotal for driving innovation and addressing rare disease diagnostics. The success of multi-omics applications hinges on the establishment of comprehensive datasets, understanding the functional implications of multi-omic variation, adherence to findable, accessible, interoperable, reusable (FAIR) and Collective Benefit, Authority to Control, Responsibility, and Ethics (CARE) principles, and the strengthening of global genomic commons, benefiting scientific research, drug development, and broader health initiatives. Our review highlights essential components of multi-omics integration, underscoring its potential to transform the landscape of precision medicine and improved patient outcomes worldwide.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13085408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147511927","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":"Genetic diagnosis in fetal hydronephrosis: assessment using chromosomal microarray analysis and whole-genome sequencing.","authors":"Jing Wang, Jingyu Zhao, Wei Wang, Xinmei Zhu, Bin Zhang, Bin Yu","doi":"10.1186/s40246-026-00950-x","DOIUrl":"10.1186/s40246-026-00950-x","url":null,"abstract":"<p><p>BACKGROUND: Antenatal hydronephrosis (AHN) is a common urological abnormality identified during prenatal ultrasound examination, with heterogeneous underlying causes. This study aimed to investigate the genetic etiologies of AHN using chromosomal microarray analysis (CMA) and whole-genome sequencing (WGS), and to identify the relationship between changes in AHN severity and genetic abnormalities. METHODS: Fetuses with AHN underwent CMA, followed by retrospective WGS. Detection rates of chromosomal abnormalities and monogenic variants were compared among different AHN types and between fetuses with downgraded versus persistent or upgraded hydronephrosis. A variant of uncertain significance (VUS) affecting a splice site was functionally validated using a minigene-splicing assay, leading to reclassification. RESULTS: Chromosomal abnormalities were detected in five of 54 fetuses (9.26%) using CMA, while WGS identified monogenic variants and chromosomal abnormalities in 10 of 54 (18.52%). The detection rate was significantly higher in AHN with extrarenal system malformations than in isolated AHN or AHN with renal tract malformations (p < 0.05). Fetuses with downgraded AHN had a lower detection rate (6.25%) than those with persistent or upgraded hydronephrosis (23.68%, p = 0.249). A novel GREB1L splice-site variant (c.2557G > A) caused aberrant splicing and was reclassified as likely pathogenic. CONCLUSIONS: WGS demonstrates higher diagnostic efficiency over CMA for AHN. Persistent or worsening AHN warrants timely genetic testing, and functional assays are critical for resolving VUS in prenatal diagnosis.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13126830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490838","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}