Human Mutation最新文献

{"title":"Insights Into RP2-Associated Retinopathy: From Molecular Basis to Clinical Translation","authors":"Nina Bögershausen,&nbsp;Patricia Döring,&nbsp;Maximilian Gerhardt,&nbsp;Alisa Fedorenko,&nbsp;Carolin Strohmeyer,&nbsp;Rozhin Bayati,&nbsp;Yun Li,&nbsp;Gökhan Yigit,&nbsp;Emrah Kaygusuz,&nbsp;Oscar Gutiérrez-Gutiérrez,&nbsp;Marianne Gaubert,&nbsp;Behnam Javanmardi,&nbsp;Karin Boss,&nbsp;Antonia Kowallick,&nbsp;Peter Krawitz,&nbsp;Stylianos Michalakis,&nbsp;Marius Ueffing,&nbsp;Wolfram-Hubertus Zimmermann,&nbsp;Hans Hoerauf,&nbsp;Hildegard Büning,&nbsp;Nicolas Feltgen,&nbsp;Lukas Cyganek,&nbsp;Bernd Wollnik","doi":"10.1155/humu/1839164","DOIUrl":"https://doi.org/10.1155/humu/1839164","url":null,"abstract":"<p>Pathogenic variants in <i>RP2</i> cause X-linked <i>RP2</i>-associated retinopathy, a rare inherited retinal disorder typically characterized by childhood onset and progression to severe visual impairment within the first three decades of life. Despite its clinical severity, comprehensive clinical and genetic data on <i>RP2</i>-associated retinopathy remain limited and no therapeutic approaches have yet progressed toward clinical application. Here, we provide an overview of current molecular, clinical, and therapeutic knowledge on <i>RP2</i>-associated retinopathy together with an analysis of the spectrum and distribution of clinically classified, ClinVar-curated variants. Analysis of 325 ACMG/AMP Class 3–5 variants revealed that among pathogenic and likely pathogenic variants, frameshift and nonsense variants predominated, supporting loss of RP2 function as the major disease mechanism as previously described. In contrast, variants of uncertain significance were largely missense variants, underscoring the particular challenge of missense variant interpretation in RP2. Exon distribution of <i>RP2</i> variants did not deviate from expectation for Class 3 variants, or for Class 4 and 5 variants in exons 2–4. However, we observed a significant enrichment of Class 4/5 variants in exon 1, driven mainly by initiator codon variants, and a depletion of Class 4/5 variants in exon 5. By integrating published knowledge on molecular mechanisms, genetic variants, clinical progression, and therapeutic development, with a detailed analysis of ClinVar-annotated <i>RP2</i> variants, this narrative review outlines the current understanding of <i>RP2</i>-associated retinopathy and identifies key gaps that will need to be addressed for therapeutic development and clinical translation.</p><p><b>Trial Registration</b>: ClinicalTrials.gov: NCT06982417</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/1839164","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next-Generation Sequencing to Identify Genetic Causes of Chinese Patients Affected With Non-retinal Developmental Eye Disorders","authors":"Xiaozhen Liu,&nbsp;Ruixuan Jia,&nbsp;Yaning Zhao,&nbsp;Shicheng Yu,&nbsp;Boling Xu,&nbsp;Liping Yang,&nbsp;Jing Hong","doi":"10.1155/humu/4035027","DOIUrl":"https://doi.org/10.1155/humu/4035027","url":null,"abstract":"<p>To investigate the genetic causes of non-retinal developmental eye disorders in 14 Chinese different families, we subjected participants to a specific hereditary eye disease enrichment panel (HEDEP) or whole exome sequencing. We further validated disease-causing variants and performed co-segregation analyses on the available family members by Sanger sequencing. We classified sequence changes according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant interpretation guidelines. Fourteen probands with diverse clinical diagnoses were analyzed, including microphthalmia (with or without microcornea and congenital cataract or congenital corneal opacification (CCO), four cases), anterior segment dysgenesis (ASD, six cases)—including Peter′s anomaly (PA, one case), PA and microphthalmia (one case), iridocoloboma or aniridia (with microcornea and/or congenital cataract, two cases), and primary congenital glaucoma (PCG, two cases)—congenital cataract (with CCO or microcornea, three cases), and Rubinstein–Taybi syndrome (RSTS, one case). Initial inheritance patterns for 1, 5, and 8 cases were autosomal recessive, autosomal dominant, and sporadic, respectively. We identified 17 (likely) pathogenic variants and one variant of uncertain significance (VUS) in 16 genes, including <i>BMP4</i>, <i>BCOR</i>, <i>PITX3</i>, and <i>PAX6</i>. Among them, eight were novel variants, and two were <i>de novo</i>. We confirmed the pathogenicity of <i>PAX6</i> intronic mutation using <i>in vitro</i> splice assays and redefined the pathogenicity of the variants of uncertain significance as likely pathogenic. Patients with developmental eye diseases typically have complex ocular and systemic phenotypes, possibly leading to significant visual impairment and high blindness rates. Identifying the genetic causes facilitates early diagnosis and effective treatment and rehabilitation strategies, thereby providing valuable insights for genetic and clinical counseling of these patients.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/4035027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapid and Sensitive Detection of USP26 Cluster Variants Based on CRISPR/Cas12a","authors":"Ning Li,&nbsp;Yongkun Huo,&nbsp;Yanan Zhao,&nbsp;Chao Liu,&nbsp;Zhe Zhang,&nbsp;Kaizhao Chen,&nbsp;Longjun Chen,&nbsp;Xiaonan Liu,&nbsp;Ziyang Lin,&nbsp;Ling Sun,&nbsp;Hui Jiang,&nbsp;Xinjie Wang,&nbsp;Wei Li","doi":"10.1155/humu/5152235","DOIUrl":"10.1155/humu/5152235","url":null,"abstract":"<p><i>USP26</i> gene variants have been reported to be associated with male infertility, such as non-obstructive azoospermia (NOA), oligozoospermia, and asthenoteratozoospermia, and may be associated with altered sperm sex chromosome segregation patterns. Among the reported variants, <i>USP26</i> cluster variants (c.370_371insACA/c.494 T &gt; C/c.1423C &gt; T) represent a frequently reported variant pattern in certain populations. Rapid and convenient detection of <i>USP26</i> cluster variants may serve as a powerful tool for male infertility-associated cohorts. Here, we develop a CRISPR/Cas12a-based assay to rapid detection <i>USP26</i> variants in human samples. Candidate CRISPR RNAs (crRNAs) and RPA primers were screened and optimized, followed by incorporation of restriction enzymes to reduce wild-type–derived amplification interference. Using controlled artificial DNA mixtures, the assay detected mutant-template fractions down to 5% under the tested conditions. The complete workflow could be performed within 60 min using basic laboratory equipment. The results of the CRISPR/Cas12a system are consistent with Sanger sequencing in 91 male infertility research samples. Overall, our study establishes a rapid molecular detection method for detecting <i>USP26</i> cluster variants and provides an alternative approach for genetic studies of male infertility-associated cohorts.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Somatic Mutation–Informed Transcriptional Architecture of Hepatocellular Carcinoma: A Multiomics Study Centered on TP53","authors":"Sheng Zhang,&nbsp;Guojun Zhang,&nbsp;Wenxuan Wang,&nbsp;Hong Luo,&nbsp;Huaping Chen","doi":"10.1155/humu/2377057","DOIUrl":"https://doi.org/10.1155/humu/2377057","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is characterized by extensive somatic mutation heterogeneity, yet the cellular contexts in which recurrent driver mutation–associated transcriptional programs operate remain incompletely defined. In this study, we applied a mutation-informed multiomics framework centered on <i>TP53</i> to connect somatic mutation status, bulk transcriptional programs, and hepatocyte-like cell states at single-cell resolution. Somatic mutation profiles and transcriptomic data from the TCGA-LIHC cohort were used to construct directional mutation-associated transcriptional signatures, with <i>CTNNB1</i> retained as a reference driver signature and <i>AXIN1</i> and <i>ARID1A</i> retained for descriptive comparison. These bulk-derived transcriptional programs were then projected into single-cell RNA sequencing data to evaluate inferred <i>TP53</i>-associated transcriptional activity across hepatocyte-like populations. <i>TP53</i> mutation-associated transcriptional programs were enriched in proliferation-related pathways, DNA repair processes, and stress–response programs and were associated with adverse clinical outcomes. At the single-cell level, inferred <i>TP53</i>-associated transcriptional activity showed heterogeneous distribution across hepatocyte-like populations and was preferentially enriched in putative malignant hepatocyte-like states. Pseudobulk and functional program analyses further supported the association between <i>TP53</i>-high signature states, cell-cycle activity, DNA repair, stress programs, and altered tumor-cell communication patterns. Integrated prioritization identified <i>CDCA8</i>, <i>MCM10</i>, and <i>TRIP13</i> as representative genes associated with <i>TP53</i>-related transcriptional programs; these genes should be interpreted as components of a <i>TP53</i>-associated proliferative transcriptional state rather than as experimentally validated drivers. These findings provide a mutation-informed view of transcriptional architecture in HCC and illustrate how bulk mutation-associated signatures can be integrated with single-cell data to improve biological interpretation of somatic variation.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/2377057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VarSim: A Python Toolkit for HGVS Variant Description Validation, Normalization, and Representation Conversion","authors":"Liu Sun,&nbsp;Rongshu Wang,&nbsp;Jian Yang","doi":"10.1155/humu/6006096","DOIUrl":"https://doi.org/10.1155/humu/6006096","url":null,"abstract":"<p>Accurate and reproducible representation of genetic variants is essential for clinical genomics, variant databases, and genomic research. The Human Genome Variation Society (HGVS) recommendations provide a standardized framework for describing sequence variants, but practical HGVS processing commonly involves multiple interdependent tasks, including parsing, validation, normalization, coordinate transformation, protein consequence inference, and conversion between variant representation formats. We developed VarSim, a lightweight Python toolkit that integrates these operations within a reference-aware workflow based on version-pinned Matched Annotation from NCBI and EMBL-EBI (MANE) transcripts retrieved from NCBI Entrez. VarSim provides programmatic functions for HGVS parsing, syntactic and semantic validation, normalization, sequence extraction, backtranslation, coordinate mapping, protein consequence prediction, genome-assembly liftover, and conversion between HGVS, VCF, and SPDI representations. We benchmarked the toolkit using 1458 HGVS descriptions across five MANE transcripts, comprising 500 coding single-nucleotide variants, 250 frameshift insertions/deletions, and 708 intronic splice-site substitutions. All 1458 descriptions passed VarSim syntactic validation, and all 750 coding descriptions passed semantic validation against the corresponding reference sequences. VariantValidator accepted all 1458 descriptions, whereas the Mutalyzer normalization endpoint processed the 750 coding descriptions. VarSim normalization agreed with Mutalyzer for all 750 coding variants and with VariantValidator for 749 of 750 variants. Protein consequence predictions agreed with VariantValidator for all 500 coding single-nucleotide variants. Format conversion between HGVS, VCF, and SPDI was exact for the tested variants, whereas transcript-to-genome projection showed substantial discrepancies relative to VariantValidator and therefore remains a limitation of the current implementation. VarSim provides a complementary, programmatic framework for reproducible HGVS processing and variant representation interoperability.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6006096","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenic Mechanisms of Two Novel Variants in the GJB1 Gene","authors":"Fenliang Xiao,&nbsp;Miaojing Xu,&nbsp;Wei Li,&nbsp;Zijian Xu,&nbsp;Haishan Jiang,&nbsp;Shaogang Qu","doi":"10.1155/humu/7388252","DOIUrl":"https://doi.org/10.1155/humu/7388252","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Charcot–Marie–Tooth disease X-linked Type 1 (CMTX1), caused by <i>GJB1</i> mutations, presents diagnostic challenges due to phenotypic heterogeneity and novel variants. This study reviews clinical data from 2021–2024 and investigates the mechanisms of two novel <i>GJB1</i> variants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We retrospectively analyzed eight male patients, evaluating clinical signs, electrophysiology, and sural nerve biopsies. Pathogenicity of novel variants was assessed via bioinformatics, ChimeraX molecular modeling, and HeLa cell models focusing on protein localization and channel function (scratch-loading/DAPI assays).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patients showed typical distal muscle atrophy and intermediate conduction velocities; three exhibited rare CNS white matter abnormalities. Two novel variants were identified: c.130dupT and c.124A &gt; G. c.130dupT led to a complete “loss of expression” of the full-length Cx32 protein. c.124A &gt; G resulted in significant cytoplasmic protein retention (<i>p</i> &lt; 0.05). Molecular modeling revealed a physical constriction (1.229 Å) in the channel bottleneck and an increased electrostatic barrier. Functional assays confirmed significant impairment in both gap junction and hemichannel activity (<i>p</i> &lt; 0.01).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This study identifies two previously unreported <i>GJB1</i> variants and elucidates their distinct pathogenic mechanisms: c.130dupT acts through loss of expression, whereas c.124A &gt; G causes functional defect via structural channel constriction. These findings expand the genetic spectrum of CMTX1 and provide a basis for precise molecular diagnosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7388252","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Xeroderma Pigmentosum Monozygotic Twins: Same Mutation Divergent Clinical Outcomes","authors":"José Pereira dos Santos Júnior,&nbsp;Maria Carolina Fernandes Cabral dos Santos,&nbsp;Lidiane Gomes da Silva,&nbsp;Wilson José da Silva Júnior,&nbsp;Camila Corradi,&nbsp;Veridiana Munford,&nbsp;Valdir de Queiroz Balbino,&nbsp;Túlio de Lima Campos,&nbsp;Carlos Frederico Martins Menck,&nbsp;Jaqueline de Azevêdo Silva","doi":"10.1155/humu/7247751","DOIUrl":"10.1155/humu/7247751","url":null,"abstract":"<p>Xeroderma pigmentosum (XP) is a rare monogenic disorder characterized by UV sensitivity and skin cancer predisposition, caused by mutations in the NER pathway or the gene encoding DNA polymerase eta (Pol <i>η</i>), which acts in translesion synthesis (TLS). Although XP is a monogenic disorder, differences in clinical severity may occur even between monozygotic twins. Here, we present monozygotic twins (M3 and M6) with the XP variant (XP-V) displaying differences in clinical severity despite sharing similar environments and habits. Using whole genome sequencing (WGS), we evaluated their mutational burden and the impact of therapeutic strategies. Our results confirmed their kinship and the expected presence of the same <i>POLH</i> mutation in both patients. The somatic mutation profiles showed that Patient M3 harbored a significantly higher number of somatic mutations (<i>p</i> ≤ 0.0001), including the exclusive detection of the ID8 signature. Despite these differences, the mutational spectrum remained remarkably consistent between twins (cosine similarity &gt; 0.98). In addition, as one of the patients was submitted to cisplatin (CDDP) therapy, we confirmed in vitro the impact of CDDP on the cell cycle of TLS-deficient cells. Therefore, the analyses of the genome sequences of these twin XP-V patients revealed that during their lifetime endogenous DNA damage and therapeutic treatments may lead to high levels of mutations and phenotype divergency in their genome.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Characterization and Genotype-Phenotype Correlation of Androgen Receptor Variants in Patients With Androgen Insensitivity Syndrome","authors":"Di Mao,&nbsp;Lijun Fan,&nbsp;Yueni Zhang,&nbsp;Chunxiu Gong","doi":"10.1155/humu/1882678","DOIUrl":"10.1155/humu/1882678","url":null,"abstract":"<p>Androgen insensitivity syndrome (AIS) is a 46,XY disorder of sex development caused by pathogenic variants in the androgen receptor (<i>AR</i>) gene. This study is aimed at characterizing the clinical features and investigating the functional consequences of <i>AR</i> variants identified in a Chinese AIS cohort. A systematic literature review was conducted to compare existing functional assays and pathogenic mechanisms. Multiple in silico tools were applied to predict the functional impact of <i>AR</i> variants, followed by in vitro functional analyses of missense variants in MLTC-1 cells. Protein expression was evaluated by Western blotting, subcellular localization by immunofluorescence, and transcriptional activity using a pGL4.11-(ARE)₃-TATA-luc dual-luciferase reporter assay. Among reported <i>AR</i> missense variants, only 28% (141/504) had undergone functional evaluation, comprising 274 assays, mainly ligand-binding and transcriptional activity analyses. In the present cohort, 33 patients with AIS harboring <i>AR</i> variants were analyzed, including 15 patients with complete AIS and 18 patients with partial AIS. Seventeen missense variants were further evaluated using in vitro functional assays. Reduced AR protein expression was observed in 82% (14/17) of variants, impaired nuclear localization in 59% (10/17), and reduced transcriptional activity in 53% (9/17), whereas increased transcriptional activity was observed in 12% (2/17) of variants. Nuclear localization was positively correlated with transcriptional activity, and residual transcriptional activity was positively associated with EMS scores. These findings demonstrate that <i>AR</i> variants cause AIS through heterogeneous molecular mechanisms and that residual AR function contributes to phenotypic variability.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13636658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Regulator SNP Affecting the Transcription Factor SP1 Binding Site in the PIK3R3 Gene Contributes to Noise-Induced Hearing Loss Risk","authors":"Long Miao,&nbsp;Jiaxuan Zhou,&nbsp;Man Qu,&nbsp;Yu Xue,&nbsp;Xiuli Zhao,&nbsp;Xiaoqin Li,&nbsp;Yang Wang,&nbsp;Shuang Qiu","doi":"10.1155/humu/7010704","DOIUrl":"10.1155/humu/7010704","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Noise-induced hearing loss (NIHL) is a key occupational hazard, and its specific pathogenic mechanism is not fully elucidated. Here, we performed this study to explore the potential role of single nucleotide polymorphisms (SNPs) located in the <i>PI3K/AKT</i> pathway in human susceptibility to NIHL.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A case-control study including 688 NIHL patients and 667 normal subjects was conducted. Genotype analysis was tested by multiplex polymerase chain reaction (PCR) with next generation sequencing. Luciferase assays were conducted to explore the effect of <i>SP1</i> on <i>PIK3R3</i> promoter activity. siRNA and cell transfection were used to determine the regulatory effect of <i>SP1/PIK3R3</i> on HEI-OC1 cells. qRT-PCR and Western blotting were used to determine the expression of genes and proteins related to <i>PI3K/AKT</i>, autophagy, and apoptosis. Cell counting kit 8 (CCK-8) assay was used to detect cell viability.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Subjects with <i>PIK3R3</i> rs7536272 GG genotype were more sensitive to NIHL than those with the AA/AG genotypes and had a lower expression level of <i>PIK3R3</i>. Luciferase assay indicated that rs7536272 regulated <i>PIK3R3</i> expression by binding to <i>SP1</i>. Knockdown of <i>SP1</i> by siRNA and transfection into HEI-OC1 cells inhibited the <i>PI3K/AKT</i> pathway, indicated by the decreased phosphorylation levels of <i>PI3K</i> and <i>AKT</i>. Concurrently, <i>SP1</i> deficiency promoted autophagy, as evidenced by an elevated <i>LC3-II/LC3-I</i> ratio and induced apoptosis, characterized by the reduction of <i>Bcl2</i> and the increase of <i>Bax</i> and <i>caspase-3</i>. Overexpression of <i>PIK3R3</i> partially restored the decreased activity of <i>PI3K/AKT</i> pathway and attenuated the enhanced autophagy and apoptosis caused by <i>SP1</i> deficiency. CCK-8 assay revealed that <i>SP1</i> knockdown led to a time-dependent decrease in cell viability, which was significantly rescued by the overexpression of <i>PIK3R3</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>All findings demonstrate that rs7536272 influences NIHL susceptibility by regulating <i>PIK3R3</i> expression in an allele-specific manner by binding to <i>SP1</i>. <i>SP1</i> inhibits autophagy and apoptosis by activating <i>PIK3R3</i>-mediated <i>PI3K/AKT</i> pathway.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 and Their Implications for Personalized Genetic Counseling in 103 Patients With PRRT2 Mutations","authors":"Shangyu Wang,&nbsp;Xiaohui Min,&nbsp;Gege Yuan,&nbsp;Mingying He,&nbsp;Bing Wu,&nbsp;Xiaoyu Liu,&nbsp;Bixia Zheng,&nbsp;Yang Li,&nbsp;Aihua Zhang,&nbsp;Gang Zhang","doi":"10.1155/humu/8968480","DOIUrl":"10.1155/humu/8968480","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p><i>PRRT2</i> mutations are associated with a wide spectrum of paroxysmal neurologic disorders. In this study, we analyze clinical and genetic data from a large pediatric cohort to define genotype–phenotype correlations and to provide a basis for individualized genetic counseling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective study included 103 children with <i>PRRT2</i> mutations treated at the Children′s Hospital Affiliated to Nanjing Medical University from August 2018 to August 2023. Detailed clinical data and genetic results were collected and systematically analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among the 103 children, self-limited familial infantile epilepsy (SeLFIE) was the most common phenotype. A total of 26 different <i>PRRT2</i> mutations were identified, 93.2% of which were predicted loss-of-function (LOF) mutations. These mutations were highly enriched in the N-terminal cytoplasmic region of the protein, particularly in the proline-rich domain. Predicted LOF mutations accounted for nearly all cases of SeLFIE and infantile convulsions with paroxysmal choreoathetosis. Clinical features, including age of onset, rates of abnormal EEG and brain MRI findings, and treatment response, showed a gradient across the three phenotypic groups, with the most pronounced abnormalities in SeLFIE and the mildest in paroxysmal kinesigenic dyskinesia. Additionally, 12 novel variants were identified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study confirms that <i>PRRT2</i>-associated disorders are primarily driven by predicted LOF mutations and, using a large cohort, establishes a genotype-phenotype-treatment response continuum model based on residual PRRT2 protein activity. This model provides a critical framework for prognosis assessment and personalized genetic counseling.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13636657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}