Human Genomics最新文献

{"title":"Rare variant analyses provide insights into the genetic architecture of endometriosis.","authors":"Yuanyuan Gui, Yuhan Xie, Xiaomei Tong, Hongyu Zhao","doi":"10.1186/s40246-026-00934-x","DOIUrl":"10.1186/s40246-026-00934-x","url":null,"abstract":"<p><p>BACKGROUND: Endometriosis (EMs) is a prevalent gynecologic disorder that often causes severe chronic pelvic pain and infertility. Although genome-wide association studies have identified common variants of EMs, the contribution of rare variants remains unclear. RESULTS: We conducted an exome-wide analysis in 87,100 unrelated female participants of European ancestry from the UK Biobank. Single variant association tests for rare variants and gene-based analyses were performed, with replication in the FinnGen and Biobank Japan cohorts. No single rare variants achieved genome-wide significance ([Formula: see text]). While gene-based analyses identified SOGA1 significantly associated with EMs at the Bonferroni-corrected threshold of [Formula: see text], which was replicated in both external cohorts. Functional analyses indicated involvement of implicated genes and interaction networks in regulating gluconeogenesis, muscle filament sliding, and autophagosome. We also observed expression differences of SOGA1 across various cell types and found significant cell type-specific enrichments for EMs. CONCLUSIONS: This study establishes the contribution of rare genetic variants to endometriosis pathogenesis through the discovery of a novel susceptibility gene, advancing the genetic understanding of this disease. </p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13001359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283470","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":"Identification of miRNA biomarkers and development of predictive signatures for early detection and prognosis in cervical precancer and cancer.","authors":"Ebuka Onyenobi, Michael Zhong, Josephine Peitz, Kiranpreet Chawla, Amy Plotkin, Clement Adebamowo, Sally N Adebamowo","doi":"10.1186/s40246-026-00924-z","DOIUrl":"10.1186/s40246-026-00924-z","url":null,"abstract":"<p><p>BACKGROUND: Aberrant microRNA expression has been implicated in cervical carcinogenesis, making miRNAs promising biomarkers for early detection and risk stratification of cervical precancer and cancer. This study aimed to identify and validate miRNA expression profiles and signatures that distinguish benign, precancer, and cancer cervical tissues, providing insights into their potential utility in cervical cancer screening and diagnosis. METHODS: We analyzed miRNA expression from archival FFPE cervical tissues of 272 women (100 benign, 89 precancer, 83 invasive cancer) using next-generation sequencing. Differential expression was assessed using DESeq2 with significant miRNAs defined by an absolute log2 fold change ≥ 1 and an adjusted p-value < 0.05. Functional enrichment of miRNA targets was performed using multiMiR and DAVID, and protein-protein interaction (PPI) networks were constructed using STRING and Cytoscape. Machine learning classifiers were developed with recursive feature elimination (RFE) and XGBoost and evaluated in internal and external cohorts. miRNA signatures were further assessed for association with overall survival in the TCGA cervical cancer cohort using multivariable Cox regression models. RESULTS: Notably, hsa-miR-1246 was the most significant miRNA in cancer vs. benign (log₂FC = 5.58, p = 3.20 × 10⁻41) and cancer vs. precancer (log₂FC = 4.89, p = 5.23 × 10⁻33). hsa-miR-149-5p was most significant in benign vs. precancer (log₂FC = −1.48, p = 1.53 × 10⁻¹⁴). Enrichment analyses highlighted cancer-related pathways with hub genes including TP53, BCL2, STAT3, ESR1, and MYC. RFE with XGBoost identified a 26-miRNA panel for multiclass classification and a 4-miRNA panel for binary cancer vs. benign classification. The binary model achieved strong performance with an AUC of 0.97 and 0.91 in internal and external validation sets respectively. Both the 26-miRNA (p < 0.001) and 4-miRNA (p = 0.01) signatures were associated with poorer overall survival. CONCLUSION: Our findings identify distinct miRNAs and miRNA-based signatures that differentiate benign, precancer, and cancer cervical tissues, highlighting their potential clinical utility as diagnostic and prognostic biomarkers. Furthermore, the development of compact, biologically interpretable miRNA signatures demonstrates strong promise as robust classifiers for early cancer detection and tissue characterization, with possible therapeutic relevance. </p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13032331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776254","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":"Genotype-phenotype correlations in phenylketonuria: PAH variants and BH4 responsiveness for treatment design.","authors":"Meryem Karaca, Asuman Gedikbasi, Arzu Selamioğlu, Alihan Yesil, Guven Toksoy, Cagri Gulec, Mehmet Cihan Balci, Dilek Güneş, Behiye Tuğçe Yıldırım, Gizem Kına, Volkan Karaman, Ayca Dilruba Aslanger, Birsen Karaman, Mubeccel Demirkol, Zehra Oya Uyguner, Gulden Fatma Gokcay","doi":"10.1186/s40246-026-00936-9","DOIUrl":"10.1186/s40246-026-00936-9","url":null,"abstract":"<p><p>BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive disorder caused by PAH alterations, leading to elevated phenylalanine (Phe) and neurotoxicity. Newborn screening (NBS) and early therapy improve outcomes. This study aimed to characterize the molecular and phenotypic spectrum of PKU, explore genotype–phenotype correlations, and evaluate the relationship between PAH variants and BH4 responsiveness to guide personalized treatment. METHODS: Medical and genetic records of 171 patients diagnosed with hyperphenylalaninemia via NBS were reviewed. Demographic data, diagnostic Phe and tyrosine (Tyr) levels, BH4 loading test results, and genetic analyses including Sanger sequencing, MLPA, and array CGH were assessed. Allelic and genotype–phenotype values were used to estimate variant severity. RESULTS: 168 carried ≥ 1 PAH variant; three had BH4 metabolism disorders. A total of 63 distinct PAH variants were identified; MLPA detected large deletions in three patients. Five variants (c.1066-11G > A, c.782G > A, c.143T > C, c.898G > T, c.1208 C > T) accounted for > 50% of the cohort. Among 100 patients tested, 41% responded to BH4, with c.782G > A most common (21%). Overall, 68.5% received dietary and/or BH4 therapy. CONCLUSION: This study contributes to our understanding of PKU’s molecular and phenotypic landscape, highlighting the importance of utilising both genotype and response to the BH4 loading test in the design of personalised treatments, beyond the initial Phe level. </p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13081264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776277","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":"Addressing the diagnostic gap through deep phenotyping.","authors":"John Guozhuang Li, Kexin Xu, Bin Xiao, Jingnan Li, Yi-Cheng Zhu, Hongzhong Jin, Qingwei Qi, Lianlei Wang, Lina Zhao, Zhihong Wu, Sen Zhao, Terry Jianguo Zhang, Nan Wu","doi":"10.1186/s40246-026-00925-y","DOIUrl":"10.1186/s40246-026-00925-y","url":null,"abstract":"<p><p>BACKGROUND: Rare diseases remain a substantial challenge for healthcare systems worldwide, and 80% are attributable to genetic factors. Although exome sequencing (ES) and genome sequencing (GS) have become routine and widely accessible in our current clinical practice due to reduced costs and policy support, progress in systematically capturing deep and structured phenotypic data has lagged behind, limiting diagnostic accuracy. Integrating deep phenotyping with genomic analysis may help close the diagnostic gap. However, its value has not been comprehensively assessed in clinical practice, particularly in the absence of a systematic medical geneticist program in our current clinical settings. METHODS: We accessed and reviewed the clinical and sequencing data of patients with a rare or suspected genetic disorder assessed at our center between 2022 and 2024. Through detailed case vignettes, we evaluated how granular bedside data influenced the diagnostic outcomes. Expert consensus and literature review were then used to construct a continually updated Recommended Phenotypes Panel and to build a nine-domain framework termed iDREAMS (integrating Deep phenotyping with genetic analysis for Rare disease Evaluation And Management Strategies). RESULTS: Deep phenotyping uncovered diagnostic clues missed by standard assessments across all nine domains, guiding genome analysis, shortening the diagnostic odyssey, and refining counselling in numerous cases. The panel streamlined data capture for clinicians, improved multidisciplinary case discussions, and fed directly into the iDREAMS framework, offering a reproducible pathway from phenotype to genotype. CONCLUSIONS: Systematic deep phenotyping is pivotal for closing the “sequencing-analysis” gap in rare disease diagnostics. The iDREAMS framework provides a practical, scalable model that enhances diagnostic accuracy, lowers the entry barrier for resource-limited settings, and extends the reach of precision medicine to patients who had long remained undiagnosed.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13019781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146226572","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":"Integrative genomics establishes GNL3 as a pleiotropic hub and causal gene for osteoarthritis.","authors":"Tianhao Qu, Yan Zhong, Yonghuan Zhou, Lin Liu, Zheng Ye","doi":"10.1186/s40246-026-00920-3","DOIUrl":"10.1186/s40246-026-00920-3","url":null,"abstract":"<p><p>BACKGROUND: Osteoarthritis (OA) is a leading cause of disability, yet there are no approved disease-modifying therapies (DMOADs) capable of halting its progression. While genome-wide association studies (GWAS) have robustly linked the 3q21 locus to OA, the causal effector gene and its underlying mechanism have remained elusive, hindering translational progress. METHODS: We implemented a multi-tiered, systematic integrative genomics strategy to proceed from genetic association to causal mechanism. By integrating summary statistics from large-scale OA GWAS with multi-tissue molecular quantitative trait loci (QTL) and single-cell expression QTL (sc-eQTL) data, we employed a combination of Bayesian colocalization and Mendelian randomization (MR) to establish a robust chain of causal evidence. RESULTS: Our analysis identifies GNL3 as the causal effector gene at the 3q21 locus. MR analysis formally demonstrated that genetically predicted higher GNL3 expression is causally protective against both knee and hip OA (e.g., Knee OA: Odds Ratio = 0.85, p = 4.4e-4). Further single-cell causal inference pinpointed this protective effect to specific cellular contexts, most prominently in activated T-cells, neural cells under cellular stress, and developmental progenitors. Moreover, we establish this locus as a pleiotropic hub, showing that its causal variants are shared with systemic OA risk factors, including Body Mass Index (BMI) and vitamin D levels. CONCLUSION: This study establishes, for the first time, a coherent chain of evidence from a shared genetic signal to the regulation of GNL3 expression in specific cell types and, ultimately, to a causal impact on OA risk. Our findings converge on a novel mechanistic model: GNL3 acts as a master regulator of systemic homeostasis, where its genetically determined expression level modulates immune and neural cell responses to stress, thereby dictating an individual’s susceptibility to OA. This work validates GNL3 as a high-confidence therapeutic target and provides a new framework for developing DMOADs aimed at reinforcing systemic homeostatic pathways. </p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13014845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146206970","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":"From enrichment to interpretation: PS4-driven reclassification in Taiwanese inherited retinal degeneration.","authors":"Yu-Shu Huang, Chien-Yu Lin, Yu-An Chen, Chieh-Yu Lee, Chang-Hao Yang, Jacob Shujui Hsu, Ta-Ching Chen, Pei-Lung Chen","doi":"10.1186/s40246-026-00923-0","DOIUrl":"10.1186/s40246-026-00923-0","url":null,"abstract":"<p><strong>Background: </strong>Inherited retinal degeneration (IRD) comprises a diverse group of monogenic disorders characterized by marked genetic and phenotypic heterogeneity. Although next-generation sequencing (NGS) enables the identification of candidate variants, many remain classified as variants of uncertain significance (VUS). Ancestry-matched population data can strengthen comparative evidence, and the emergence of national biobanks provides new opportunities to operationalize ACMG/AMP criterion PS4 through case-control analyses.</p><p><strong>Methods: </strong>We integrated an IRD cohort of 802 probands with whole-genome allele frequency data from 1,492 individuals in the Taiwan Biobank. An allele-based case-control framework was applied, assigning PS4 when the Haldane-Anscombe-corrected odds ratio was ≥ 5 and the 95% confidence interval excluded 1. Post-PS4 triage required variants to: (i) reside in IRD-associated genes, (ii) be rare in East Asian populations in gnomAD v4.1, and (iii) be annotated in RefSeq as exonic, untranslated regions, or splicing (± 20 bp). Baseline ACMG/AMP classifications were generated using GeneBe and finalized through expert curation.</p><p><strong>Results: </strong>Incorporation of PS4 substantially refined variant interpretation, upgrading two variants from Likely Pathogenic to Pathogenic and six from VUS to Likely Pathogenic. Homozygous exemplar variants, including CNGB1 (NM_001297.5): c.2921T > G and CFAP410 (NM_004928.3): c.340_351dup, demonstrated strong genotype-phenotype concordance with confirmatory sequencing, illustrating an end-to-end workflow from statistical enrichment to clinical reporting.</p><p><strong>Conclusion: </strong>An ancestry-aware case-control framework enables effective implementation of PS4 and improves the accuracy of IRD variant classification. This reproducible strategy supports the integration of population-specific genomic data into clinical workflows and is applicable to other monogenic disorders.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13011756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146201472","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 spectrum analysis of high-carrier-frequency monogenic disorders based on whole-exome sequencing in the Chinese general population.","authors":"Na Hao, Yan Lü, Jiaxin Bian, Kaili Yin, Rou Xiao, Ping Hu, Ying Peng, Mingtao Huang, Fengchang Qiao, Rui Xiao, Yanbo Liu, Yanqin You, Yulin Jiang","doi":"10.1186/s40246-026-00933-y","DOIUrl":"10.1186/s40246-026-00933-y","url":null,"abstract":"<p><p>BACKGROUND: Carrier screening serves as an effective measure for reproductive planning. Given ancestry/regional variations in genetic spectra, this study aimed to comprehensively identify high carrier frequency genes/variants in the Chinese population, thereby providing evidence for developing tailored expanded carrier screening (ECS) strategies. In this retrospective study, 5,018 healthy participants from Eastern China who visited Peking Union Medical College Hospital between January 2013 and December 2023 underwent ECS. Whole exome sequencing (WES) was employed to detect over 3,000 monogenic disorders with autosomal recessive (AR), X-linked (XL), or X-linked recessive (XLR) inheritance patterns, followed by comprehensive analysis of the WES data. RESULTS: The cumulative carrier rate in the study population was 84% (4,213/5,018), with an average of 1.84 pathogenic/likely pathogenic variants per participant. The study identified 204 at-risk couples, representing an overall risk rate of 8.54%. Additionally, 62 high-frequency genes (carrier frequency ≥ 1/200) were detected, including some ACMG-recommended genes previously excluded from Chinese ECS panels due to unclear carrier frequencies. Further analysis proposed an optimized Chinese ECS strategy incorporating 200–300 key high-frequency pathogenic genes for panel size design and utilizing hybridization capture sequencing to maximize panel efficiency. CONCLUSION: This study revealed distinctive genetic characteristics of the Chinese population and provides foundation for developing population-specific ECS strategies.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13011434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197467","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":"Exon skipping as a potential diagnostic biomarker in colorectal cancer: an integrated epigenomic-transcriptomic analysis​.","authors":"Lili Zhang, Jian Cui, Jinxin Shi, Jiahui Cai, Tianhan Sun, Gaoyuan Sun, Yifei Li, Hexin Li, Siyuan Xu, Xiaokun Tang, Ziwei Chen, Hongyuan Cui, Fei Xiao, Gang Zhao","doi":"10.1186/s40246-026-00931-0","DOIUrl":"10.1186/s40246-026-00931-0","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is the third most common cancer globally. Alternative splicing contributes significantly to CRC tumorigenesis through aberrant transcript generation. However, the regulatory influence of RNA modifications on splicing remains poorly understood, largely due to technical difficulty. Nanopore direct RNA sequencing addresses this by enabling simultaneous detection of RNA modifications and Alternative splicing events (ASEs).</p><p><strong>Methods: </strong>We conducted Nanopore direct RNA sequencing on paired tumor and normal tissues from surgical resections at Beijing Hospital. Differential putative RNA modification sites and ASEs linked to CRC were systematically identified. To validate the key findings, we utilized a large patient cohort from The Cancer Genome Atlas (TCGA) and predicted 3D protein structures with AlphaFold3. The predicted structures were then compared using TM-align. Regulatory relationships between RNA modifications and splicing were explored through predictive modeling of potential cis-regulatory pairs. The splicing events were also validated.</p><p><strong>Results: </strong>The MYH11-201 transcript of the MYH11 gene contains an additional exon (ENSE00001632812) compared to the MYH11-203 isoform. Both bioinformatic analysis and experimental validation confirmed frequent loss of this exon in tumor tissues. This finding was further validated in the TCGA cohort, demonstrating a significant preference for exon skipping in tumor tissues. These results suggest that the skipping of ENSE00001632812 is a promising candidate biomarker associated with CRC pathogenesis. Notably, this exon's PF00063 domain interacts with multiple tumor suppressor genes and oncogenes domains, suggesting its functional importance. The structures revealed pronounced rotational divergence within a putative C-terminal transmembrane domain-like region. Furthermore, we utilized Nanopore sequencing to explore the potential interplay between alternative splicing and RNA modifications. We implemented an integrated analytical workflow (available at https://github.com/lelelililele/Nanopore-ASEs-and-RNA-modification ) combining modification calling and splicing analysis tools to investigate RNA modification-related enzymes and splicing-related proteins in CRC.</p><p><strong>Conclusions: </strong>This pilot study utilizes Nanopore direct RNA sequencing to characterize exon skipping events and RNA modifications in CRC. We identified the skipping of MYH11 exon ENSE00001632812 as a potential candidate for future diagnostic investigation. By integrating modification and splicing data, we highlighted putative regulatory pairs that warrant further functional exploration. While our findings offer new insights into CRC molecular mechanisms, extensive validation in independent large-scale cohorts and functional assays is essential to confirm the diagnostic utility and mechanistic roles of these targets.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13005353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179393","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":"Concurrent physiologic and gene-based genetic newborn hearing screening in a general population.","authors":"Yun Sun, Jingyu Zhao, Liping Meng, Tao Jiang, Jiale Xiang, Xin Wang, Xianwei Guan, Jingjing Zhang, Ye Fan, Jing Xu, Zibin Lin, Xiangzhong Sun, Hui Huang, Chunna Fan, Jing Yang, Zhiyu Peng, Zhengfeng Xu","doi":"10.1186/s40246-026-00912-3","DOIUrl":"10.1186/s40246-026-00912-3","url":null,"abstract":"<p><p>BACKGROUND: Physiologic newborn hearing screening (NBHS) has several weaknesses requiring improvement. Studies have explored variant-based genetic NBHS as a complement to physiologic NBHS. However, this genetic NBHS strategy has fundamental limitations that challenge logistics. METHODS: Given findings that a small set of genes accounts for the majority of genetic etiologies of hearing loss (HL), we designed a gene-based genetic NBHS strategy that screens for genes instead of limited variants, targeting the coding regions of twelve HL-related genes and the aminoglycoside-induced HL risk gene MT-RNR1. Our cohort study was conducted at Nanjing Women and Children’s Healthcare Hospital in China, between March 2022 and July 2023. All participants were offered concurrent physiologic and gene-based genetic NBHS. Infants with positive physiologic or genetic NBHS results were scheduled for audiological assessments. RESULTS: Of 20,997 participants with eligible physiologic and genetic NBHS results, 164 (0.8%) had positive physiologic or genetic NBHS results. Of 150 who underwent audiological assessments, 77 had confirmed HL. Among them, 32 were identified by genetic NBHS only, 24 by both physiologic and genetic NBHS, and 21 by physiologic NBHS only. Compared with conventional physiologic NBHS protocol (identified 45 HL cases), incorporating gene-based genetic NBHS into physiologic NBHS (additionally identified 32 HL cases) only required an additional 0.4% (87/20,997) of infants to undergo audiological assessments, yet achieved a 71% (32/45) increase in HL identification and provided genetic etiological information for 73% (56/77) of all HL cases. For 21 HL cases identified by physiologic NBHS only, genome sequencing identified genetic findings in three additional cases, showing that up to 77% (59/77) of infants with HL were caused by genetic factors in this general newborn population. CONCLUSIONS: Our new comprehensive NBHS protocol, concurrent physiologic and gene-based genetic NBHS, significantly improved the identification of infants with HL. The results demonstrated that the gene-based genetic NBHS addressed fundamental limitations of the variant-based strategy and was a powerful complement to physiologic NBHS.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13005339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146194626","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 findings in ten Ecuadorian patients with suspected Wilson's disease.","authors":"Vanessa I Romero, Martina Armas Samaniego, Paúl León, Benjamín Arias-Almeida, Rino Sasaki, Yoko Iwauchi, Kazuyoshi Hosomichi","doi":"10.1186/s40246-026-00926-x","DOIUrl":"10.1186/s40246-026-00926-x","url":null,"abstract":"<p><strong>Background: </strong>Wilson disease is a rare autosomal recessive disorder caused by variations in ATP7B, leading to copper accumulation and multisystemic damage. Diagnosis is often delayed due to its heterogeneous clinical presentation and limited genetic data in underrepresented populations.</p><p><strong>Methods: </strong>We characterized ten Ecuadorian patients with clinical suspicion of Wilson disease using whole-exome sequencing (WES), selected to enable simultaneous assessment of ATP7B and other metabolic genes relevant to Wilson-like phenotypes. Variants were interpreted following HGNC and ACMG/AMP guidelines. Ancestry was examined in nine patients using ADMIXTURE and PCA with a reference panel of 968 individuals from African, European, and Indigenous American populations. ATP7B expression was quantified by RT-qPCR in the one patient lacking identifiable coding-region variants.</p><p><strong>Results: </strong>Six patients were homozygous and two were compound heterozygous for pathogenic or likely pathogenic ATP7B variants. The recurrent alleles c.2052dupC p.(Met685*) (Guayaquil) and c.2012_2013insAT p.(Met671Ilefs*) (Cañar/Cuenca) showed geographic and ancestry patterns consistent with known demographic structure in Ecuador, though not sufficient to infer founder effects. Additional variants included c.3188 C > T p.(Ala1603Val), c.3727 C > G p.(Leu1243Val), c.2318G > A p.(Cys773Tyr), and c.2080 C > T p.(Arg694Trp). One patient with no detectable ATP7B coding-region variation demonstrated ~ 9.8-fold reduced ATP7B expression, supporting the clinical diagnosis.</p><p><strong>Conclusions: </strong>This study provides an integrated clinical, molecular, and ancestry framework for characterizing Wilson disease in an underrepresented population. The identification of regionally recurrent ATP7B variants, together with the diversity of clinical presentations, highlights the need for comprehensive diagnostic approaches in admixed populations. Larger studies incorporating segregation and functional assays will be essential to refine variant interpretation and improve access to molecular diagnosis in Latin America.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12998073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179324","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}