Human Genomics最新文献

{"title":"Editing regulatory network in non-small cell lung cancer: implications for immunity and metastasis.","authors":"Jiajin Zhang, Liyu Huang, Sijia Wu","doi":"10.1186/s40246-026-00999-8","DOIUrl":"10.1186/s40246-026-00999-8","url":null,"abstract":"<p><strong>Background: </strong>RNA editing plays critical roles in cancer development, and multiple editing events collectively exert greater effects than individual events. However, the coordinated impact of RNA editing remains poorly understood.</p><p><strong>Methods: </strong>A comprehensive framework was proposed to investigate interactions among RNA editing events, capturing both the global editing landscape and site-specific functional effects. The resulting RNA editing modules were further explored to reveal gene interactions and regulatory mechanisms from the perspective of RNA editing.</p><p><strong>Results: </strong>Using non-small cell lung cancer as an example, we identified more than 12 modules involved in immune regulation and metastasis-related processes, demonstrating their clinical relevance. Mechanistically, RNA editing influenced miRNA-mediated regulation of EIF2AK2 and PRKAR2A, transcription factor activity of AHR, and RNA-binding regulation of DDX3X, highlighting its role in shaping gene regulatory networks.</p><p><strong>Conclusions: </strong>Collectively, this study provides a systematic, module-based framework for understanding coordinated RNA editing, offering new insights into RNA editing-mediated gene interactions and revealing a complementary approach to study molecular mechanisms of diseases.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13491626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217605","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":"An example for potentially underrated causes of recessive disease in the Greater Middle East: integrative long-read genome and transcriptome sequencing pinpoint a deep-intronic homozygous HEXB candidate founder variant in GM2-gangliosidosis.","authors":"Angelika Bolte, Clara Velmans, Christian Netzer, Eva Thimm, Ali Tunҫ Tuncel, Friederike Bürger, Milan Hiersche, Christian Betz, Hanno Jörn Bolz","doi":"10.1186/s40246-026-00995-y","DOIUrl":"10.1186/s40246-026-00995-y","url":null,"abstract":"<p><strong>Background: </strong>Consanguinity provides shortcuts to identify homozygous recessive mutations. However, deep-intronic variants escape standard sequencing (panel; exome/WES), and their pathogenicity cannot be inferred from genomic data. We applied WES, long-read genome and long-read-RNA-sequencing (LR-WGS, LR-RNA-Seq) in a Syrian patient with biochemically evident GM2-gangliosidosis.</p><p><strong>Results: </strong>No exonic HEXA, HEXB and GM2A mutations were found. LR-WGS/LR-RNA-Seq revealed a homozygous HEXB variant, c.771 + 985G > A, activating a 97 bp pseudo-exon.</p><p><strong>Conclusions: </strong>Integrative genome and transcriptome sequencing unlocked a deep-intronic, database-annotated HEXB mutation and proved causality. This illustrates the diagnostic challenges in patients from the Middle East with its prevalent consanguinity and hidden (candidate founder) mutations which are potential targets for splice-modulating therapies.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"20 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13251226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217582","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":"Clinical and functional characterization of a novel homozygous non-canonical splice mutation (c.1910-15_1910-11delinsTTACA) in CEP290 causing Joubert syndrome.","authors":"Valeriia A Kovalskaia, Dmitriy N Maslennikov, Ksenia A Svirepova, Vyacheslav Y Tabakov, Polina N Tsabai, Evgenii V Shchoka, Nikita S Beskorovainiy, Jekaterina Shubina, Dmitry Y Trofimov, Oxana P Ryzhkova","doi":"10.1186/s40246-026-01002-0","DOIUrl":"10.1186/s40246-026-01002-0","url":null,"abstract":"<p><strong>Background: </strong>Joubert syndrome (JS) is a rare, predominantly autosomal recessive neurodevelopmental disorder characterized by hypotonia, motor delay, intellectual disability, oculomotor apraxia, and the hallmark \"molar tooth sign\" on axial view of MRI. JS is genetically heterogeneous, with pathogenic variants identified in more than 40 genes involved in primary cilia function. Among these, CEP290 is one of the most frequently mutated genes.</p><p><strong>Results: </strong>In this study, we investigated two children-an 11-year-old boy (the proband) and his 5-year-old sister-both presenting with a similar phenotype consistent with JS. The parents, who self-identified as Chechen, reported distant consanguinity. The family also included a healthy 13-year-old daughter. The proband had previously been evaluated by a neurologist and underwent whole-genome sequencing (WGS); however, no causative variants were identified initially. After phenotype reassessment by a clinical geneticist, we performed a reanalysis of the raw WGS data and identified a novel homozygous intronic variant of uncertain significance (VUS), c.1910-15_1910-11delinsTTACA in CEP290 (NM_025114.4). Sanger sequencing confirmed that both the proband and his affected sister were homozygous for this variant, which they inherited from their heterozygous parents. Their healthy sister did not carry the variant. mRNA-sequencing and targeted cDNA sequencing (read depth ~ 100,000x) demonstrated that this intronic variant causes completely aberrant splicing of CEP290 pre-mRNA. Predominantly this variant causes the skipping of exon 20 in the main CEP290 transcript. Alternatively, the variant results in partial inclusion of intron 19 into the mRNA, elongation of exon 20 by 58 nucleotides, and a homozygous substitution chr12:88114573 (ACTGTGTA> TTACAGTA). No canonical mRNA isoform was detected when the variant was homozygous. Both the predicted severe truncation and the likely degradation of aberrant transcripts through nonsense-mediated decay (NMD) would correspond to complete loss of CEP290 function. Following the reclassification of this VUS to likely pathogenic, the family was able to pursue in vitro fertilization (IVF) with preimplantation genetic testing for monogenic disorders (PGT-M).</p><p><strong>Conclusion: </strong>Our study highlights the critical importance of proper phenotyping prior to referral for WES/WGS as well as of combining NGS with functional mRNA studies to achieve a molecular diagnosis for patients with predicted splice-site mutations in JS-associated genes. It also emphasizes the need for functional reassessment of VUS when genomic data are expected to guide reproductive decision-making within affected families.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217588","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":"Deciphering the role of cell-free extrachromosomal circular DNA in human heart failure.","authors":"Zhenhao Lin, Enyong Su, Junfeng Zhang, Peng Yu, Changqian Wang","doi":"10.1186/s40246-026-00996-x","DOIUrl":"10.1186/s40246-026-00996-x","url":null,"abstract":"<p><strong>Background: </strong>Extrachromosomal circular DNAs (eccDNAs) are well-established drivers of tumorigenesis, yet their landscape and functional significance in human heart failure (HF) remain largely unknown.</p><p><strong>Methods: </strong>Using Tn5 transposase-based sequencing, we comprehensively profiled plasma eccDNAs from healthy controls and HF patients with myocardial ischemia (MI-HF) or non-myocardial ischemia (NMI-HF). Bioinformatics was employed to probe their chromosomal origins, genomic features, and potential roles in the development of HF. Circular structures of candidate eccDNAs were validated by inward and outward PCR followed by Sanger sequencing. Their clinical prognostic value was assessed by Kaplan-Meier and Cox regression analyses in a patient cohort.</p><p><strong>Results: </strong>Most plasma eccDNAs were shorter than 1 kb and originated from all chromosomes, with selective enrichment from specific genomic regions including 5' UTRs, CpG islands, and Alu elements. Characteristic nucleotide repeats were identified at eccDNA junction sites. The circular structure of eccDNAs was confirmed. Furthermore, we discovered that the eccDNA ENPP1^{circle exon 25} was specifically detected in MI-HF patients. Its presence was significantly associated with a higher incidence of major adverse cardiac events (MACEs), and it served as an independent prognostic biomarker in multivariate analysis.</p><p><strong>Conclusions: </strong>This study delineates the first detailed landscape of plasma eccDNAs in HF and reveals their potential as noninvasive biomarkers for risk stratification. Our findings lay a crucial foundation for future research into eccDNA biology and their translational applications in cardiovascular disease.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148163096","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":"Linking childhood interstitial lung disease to IARS-related disorder: clinical and preliminary functional studies in four new cases.","authors":"Dan Dai, Weitao Zhou, Gaoli Jiang, Zhuoyao Guo, Huixian Wang, Jinglong Chen, Mei Mei, Yi Lu, Libo Wang, Liling Qian","doi":"10.1186/s40246-026-00998-9","DOIUrl":"10.1186/s40246-026-00998-9","url":null,"abstract":"<p><strong>Background: </strong>Biallelic mutations in aminoacyl-tRNA synthetase genes have been implicated in a variety of multisystem disorders. Nonetheless, the correlation between cytosolic IARS (which encodes isoleucyl-tRNA synthetase) and childhood interstitial lung disease (chILD) as well as pulmonary alveolar proteinosis (PAP) has yet to be established.</p><p><strong>Methods: </strong>We characterized the clinical features of four pediatric patients exhibiting progressive chILD/PAP alongside extrapulmonary manifestations (growth retardation, intellectual impairment, hypotonia, and liver disease). Whole exome sequencing was performed to confirm that biallelic IARS mutations are the etiological cause of the disease, and protein structural prediction was conducted for the identified pathogenic mutations via AlphaFold modeling. Periodic-Acid Schiff (PAS) and Oil-Red O (ORO) staining, along with western blotting and transmission electron microscopy of bronchoalveolar lavage fluid (BALF) and single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) were used to characterize the disease phenotype and explore potential pathogenic mechanisms.</p><p><strong>Results: </strong>All four patients were confirmed to possess compound heterozygous IARS variants, inherited in trans from unaffected parents. Analysis of BALF revealed characteristic lipoprotein accumulation associated with PAP, evidenced by positive PAS and ORO staining. Additionally, surfactant proteins exhibited abnormal expression, accompanied by notable secondary lysosome formation and vacuolization within alveolar macrophages. scRNA-seq of PBMCs identified a specific depletion of CD14 + CD16+ intermediate monocytes and a transcriptional downregulation of phagosome/lysosome pathways in CD14 + classic monocytes. These findings suggest a potential intrinsic defect in the monocyte/macrophage lineage, potentially contributing to surfactant clearance dysfunction.</p><p><strong>Conclusion: </strong>Our findings expand the phenotypic spectrum of IARS-related disorder by identifying chILD/PAP as a core and clinically significant pulmonary manifestation of biallelic IARS mutations. This study establishes IARS as a novel pathogenic gene for chILD/PAP and provides preliminary insights into the immune-related pathogenic mechanisms, highlighting the need for genetic screening of IARS variants in pediatric patients with unexplained respiratory failure and multisystem involvement.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148156359","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":"Prenatal diagnosis and estimated penetrance of 15q11.2 BP1-BP2 microdeletion syndrome in a Chinese cohort: a retrospective study and literature review.","authors":"Yiqing Yu, Mengmeng Li, Jiazhen Chang, Hanzhe Zhang, Xiya Zhou, Yulin Jiang, Na Hao, Xueting Yang, Kaili Yin, Yan Lü, Qingwei Qi","doi":"10.1186/s40246-026-00997-w","DOIUrl":"10.1186/s40246-026-00997-w","url":null,"abstract":"<p><strong>Background: </strong>The 15q11.2 BP1-BP2 microdeletion (Burnside-Butler syndrome) is a recurrent copy number variation associated with variable neurodevelopmental outcomes. Its incomplete penetrance and broad phenotypic spectrum challenge prenatal genetic counseling. This study aimed to characterize prenatal and postnatal clinical outcomes associated with the 15q11.2 BP1-BP2 microdeletion and to provide evidence to inform prenatal genetic counseling.</p><p><strong>Results: </strong>Among 5246 high-risk pregnancies undergoing invasive prenatal diagnosis at a single center between January 2022 and February 2026, 25 fetuses with 15q11.2 BP1-BP2 microdeletion were identified by chromosomal microarray analysis. Of these, 9 fetuses showed soft ultrasound markers, 3 had fetal growth restriction, and 3 had major structural anomalies. Five pregnancies were electively terminated, whereas 20 were continued. Postnatal follow-up ranging from 3 months to 3 years and 8 months revealed no developmental or growth abnormalities among live-born children (penetrance 0%). A literature review of prenatally diagnosed cases showed that 65 of 127 fetuses had abnormal prenatal ultrasound findings, while postnatal phenotypic abnormalities were reported in 12 of 77 live-born children. When the analysis was restricted to cases with standardized pediatric follow-up (n = 55), the penetrance decreased to 5.5%.</p><p><strong>Conclusions: </strong>Our data indicate that 15q11.2 BP1-BP2 microdeletion generally has favorable early postnatal outcomes. Given the low penetrance observed in prenatally ascertained cohorts and the mild effect size of this copy number variation, our findings suggest that the clinical implications of routinely reporting isolated 15q11.2 BP1-BP2 microdeletion in the prenatal setting may need to be interpreted with caution. Longer-term follow-up studies remain necessary to further clarify the neurodevelopmental impact of this microdeletion.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148149686","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":"QuaDB: A streamlined web tool for identifier-based rapid prediction of putative quadruplex sequences.","authors":"Auroni Deep, Utsab Das, Perumal Vivekanandan, Saran Kumar","doi":"10.1186/s40246-026-00988-x","DOIUrl":"10.1186/s40246-026-00988-x","url":null,"abstract":"<p><strong>Background: </strong>Non-canonical DNA structures, such as G-Quadruplexes (G4s) and i-Motifs (iMs), are pivotal in gene regulation and cellular processes. However, current computational methods for identifying their genomic precursors, Putative G4 Sequences (PGS) and Putative iM Sequences (PIS), primarily rely on manual sequence retrieval and input, thus hindering large-scale analyses essential for deciphering their biological functions. To address this, we present QuaDB, a user-friendly web application designed for identifier-based, rapid prediction of Putative Quadruplex Sequences (PQS).</p><p><strong>Results: </strong>QuaDB streamlines the analytical workflow by enabling real-time sequence retrieval from Ensembl and NCBI using gene identifiers, coupled with automated region-specific analysis across promoter, gene body, and 3' downstream regions. The tool employs a robust, biologically informed scoring model that accurately identifies and scores quadruplex structures, aligning with experimental validation through circular dichroism and thermal melting studies. This validation demonstrated a direct correlation between QuaDB scores and thermal stability.</p><p><strong>Conclusion: </strong>With its efficient processing and intuitive interface, QuaDB facilitates comprehensive, large-scale genomic investigations, complementing existing tools by offering a unique identifier-based retrieval and region-aware analytical pipeline for exploring the widespread biological significance of these intriguing DNA structures. The web application can be accessed through: quadb.iitd.ac.in.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148149680","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":"Functional validation of spliceogenic COL4A3 and COL4A4 variants by minigene assays refines molecular diagnosis of Alport syndrome.","authors":"Lina Wang, Zhi Wang, Yan Zhao, Xuyan Liu, Qiaomei Cui, Shuimi Zhang, Ran Zhang, Leping Shao","doi":"10.1186/s40246-026-00989-w","DOIUrl":"10.1186/s40246-026-00989-w","url":null,"abstract":"<p><strong>Background: </strong>Alport syndrome (AS) is a hereditary progressive kidney disease caused by pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes. Aberrant pre-mRNA splicing represents a major disease mechanism in AS, and both synonymous and intronic variants can disrupt splice-site recognition or regulatory elements, leading to exon skipping or intron retention. However, the clinical interpretation of putative spliceogenic variants remains challenging, particularly when subtle splicing changes coexist with background alternative splicing.</p><p><strong>Results: </strong>Fourteen synonymous and intronic variants in COL4A3 and COL4A4 were screened using in silico splicing prediction tools and subsequently functionally evaluated by minigene assays in HEK293T and HeLa cells. Thirteen variants exhibited aberrant splicing, most commonly as exon skipping, with variable effects on transcript structure and abundance. Several variants predominantly generated frameshift transcripts with premature termination codons, whereas others resulted in in-frame exon skipping or produced low-level aberrant transcripts comparable to wild-type splicing. By integrating quantitative splicing outcomes with population frequency data and predicted protein consequences, all variants were reclassified according to ACMG/AMP guidelines, resulting in four pathogenic, nine likely pathogenic, and one likely benign variant.</p><p><strong>Conclusions: </strong>This study demonstrates that synonymous and intronic variants in COL4A3 and COL4A4 can exert pathogenic effects primarily through disruption of pre-mRNA splicing rather than through direct alteration of the coding sequence. Incorporation of quantitative functional splicing data into ACMG/AMP variant interpretation provides a robust framework for resolving variants of uncertain significance and improves the molecular diagnosis of AS.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13430759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148042123","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":"Lens tissue transcriptome analysis in patients with total congenital cataract.","authors":"Xiaolei Lin, Huiyu Chen, Xin Liu, Fan Fan, Yulan Wang, Yi Luo","doi":"10.1186/s40246-026-00993-0","DOIUrl":"10.1186/s40246-026-00993-0","url":null,"abstract":"<p><strong>Background: </strong>Total congenital cataract (TCC), a leading cause of childhood visual impairment. We analyzed transcriptome profiles of lens epithelial cells (LECs) and lens fiber cells (LFCs) in pediatric patients with TCC to identify differentially expressed genes (DEGs) and potential pathogenic pathways.</p><p><strong>Results: </strong>In LECs, 1,645 DEGs were identified, enriched in structural constituents of the eye lens extracellular matrix component and extracellular matrix organization. LFCs exhibited 2,708 DEGs, enriched in SRP-dependent cotranslational protein targeting to membrane, protein targeting to ER, and cotranslational protein targeting to membrane. Cross-referencing with iSyTE2.0 highlighted HOPX, SUSD2, SH3BGR, BIRC7, and GSS as top candidates. All five candidate genes were significantly downregulated in both LECs and LFCs that were lens-enriched genes during embryonic development.</p><p><strong>Conclusions: </strong>This study reveals distinct transcriptomic profiles in LECs and LFCs of TCC patients, implicating novel genes in lens development, oxidative stress, and apoptosis.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148029793","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 genetic insights of sporadic male infertility: a systematic review of WES and WGS studies (2014-2024).","authors":"Hoda Zahi, Fatima Sfifou, Meriem Slaoui, Lamyae Chentoufi, Redouane Abouqal, Houyam Hardizi","doi":"10.1186/s40246-026-00991-2","DOIUrl":"10.1186/s40246-026-00991-2","url":null,"abstract":"<p><p>Male infertility is a complex and heterogeneous disorder. It has a significant genetic component, although some cases remain idiopathic. Next-generation sequencing, particularly whole-exome (WES) and whole-genome sequencing (WGS) has become a powerful tool for uncovering new genetic causes. This systematic review aimed to identify and synthesize genes linked to male infertility reported in WES or WGS studies. The review was registered on PROSPERO (CRD42024597301). A bibliographic search was conducted on PubMed, Scopus, and Web of Science (2014-2024). We included human studies that used WES or WGS to investigate the genetics of male infertility. Two reviewers independently performed screening, data extraction, and risk-of-bias assessment with JBI checklists. Out of 8018 identified records, 23 studies met the inclusion criteria. In total, 169 unique genes were reported; after removing duplicates, 143 genes remained. The most frequently implicated phenotypes were multiple morphological abnormalities of the flagella (MMAF) and non-obstructive azoospermia (NOA). Genes were stratified by recurrence across independent cohorts and by functional validation status. Of the 143 genes, five were replicated with functional validation, 22 demonstrated either replication or functional validation, and 116 were reported in single studies with only in silico support. In studies applying the criteria of American College of Medical Genetics and Genomics (ACMG), the diagnostic yield was 48% for MMAF and 12-23% for NOA, with an average variant-of-uncertain-significance (VUS) burden of 47%. ACMG classification was inconsistently applied across studies. MMAF-associated genes were predominantly autosomal recessive (95%), whereas NOA-associated genes exhibited greater diversity: 60% autosomal recessive, 25% X-linked, and 15% autosomal dominant. Only 34% of genes had undergone functional validation. In summary, among WES and WGS studies of predominantly sporadic cohorts, most identified genes were reported in single studies without functional validation, and standardized variant classification was implemented in only a minority of studies.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13386772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148014986","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}