Human Mutation最新文献

{"title":"A Novel Homozygous Mutation in ARL2BP Causes Multiple Morphological Abnormalities of the Flagella and Primary Ciliary Dyskinesia","authors":"Ming Li,&nbsp;Wen Tao,&nbsp;Qingshan Ji,&nbsp;Di Yan,&nbsp;Chen Zhang,&nbsp;Qinyi Zhang,&nbsp;Ping Jiang,&nbsp;Jun Qiu,&nbsp;Jie Wen,&nbsp;Bo Xu,&nbsp;Shun Bai,&nbsp;Xiaohua Jiang","doi":"10.1155/humu/7635300","DOIUrl":"10.1155/humu/7635300","url":null,"abstract":"<p>Primary ciliary dyskinesia (PCD) and multiple morphological abnormalities of the sperm flagella (MMAF) frequently co-occur in male infertility. However, the genetic basis of this syndromic presentation remains unclear. Using whole-exome sequencing, we identified a novel homozygous <i>ARL2BP</i> splice-site mutation (c.294-2A&gt;G) in a 23-year-old infertile male from a consanguineous family who presented with syndromic PCD and MMAF. This variant causes aberrant pre-mRNA splicing and triggers nonsense-mediated mRNA decay, resulting in the complete absence of ARL2BP protein expression. Transmission electron microscopy revealed extensive disorganization of flagellar axonemes with consistent central pair (CP) microtubule depletion and disorganization of peripheral doublets. Immunofluorescence confirmed a severe deficiency of the CP protein SPAG6 in the sperm flagella. Notably, the patient presented without retinal symptoms. Given that <i>ARL2BP</i>-related retinitis pigmentosa generally emerges during the third decade, long-term ophthalmological follow-up is essential to detect delayed-onset retinal degeneration. In conclusion, these findings confirm <i>ARL2BP</i> as a causative gene for both PCD and MMAF, expanding the genotypic and phenotypic spectrum of ciliopathies.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817435","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":"CDKN3, PKP2, ADM, MS4A1, FAM83A, and DKK1 Define a Posttranslational Modification (PTM)–Associated Prognostic Model for Lung Adenocarcinoma","authors":"Zhi Liu,&nbsp;Gang Li,&nbsp;Ling Lin","doi":"10.1155/humu/3201577","DOIUrl":"10.1155/humu/3201577","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Introduction&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Posttranslational modification (PTM) plays an important role in protein regulation and may influence tumor initiation and progression. However, the role of PTM-related programs in lung adenocarcinoma (LUAD) remains incompletely understood.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Materials and Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Single-cell RNA sequencing (scRNA-seq) data were analyzed to quantify the activity of PTM-related gene set using the AUCell algorithm and to characterize intercellular communication using CellChat. Molecular subtypes and differentially expressed genes (DEGs) were identified using ConsensusClusterPlus and limma packages, respectively, followed by functional enrichment analysis. Univariate Cox regression, LASSO regression with 10-fold cross-validation, and stepwise multivariable Cox regression based on the Akaike information criterion (AIC) were used to construct a prognostic model. Immune infiltration was evaluated using ESTIMATE, CIBERSORT, MCP-counter, and TIMER algorithms, and drug sensitivity was predicted using oncoPredict package. The IMvigor210 cohort was used for exploratory assessment of immunotherapy response. Quantitative real-time reverse transcription PCR (qRT-PCR) was used to measure the expressions of the model genes. CCK-8, wound-healing, and Transwell assays were performed to evaluate the effects of &lt;i&gt;CDKN3&lt;/i&gt; knockdown on LUAD cells.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Comparison between two PTM groups revealed that receptor ligands such as MIF-(CD74+CXCR4) and MIF-(CD74+CD44) had higher communication probabilities in the high–PTM-score group. Two molecular subtypes were identified, and a six-gene risk model for LUAD was established based on &lt;i&gt;CDKN3&lt;/i&gt;, &lt;i&gt;PKP2&lt;/i&gt;, &lt;i&gt;ADM&lt;/i&gt;, &lt;i&gt;MS4A1&lt;/i&gt;, &lt;i&gt;FAM83A&lt;/i&gt;, and &lt;i&gt;DKK1&lt;/i&gt;. The high-risk group showed a lower immune score, and drugs such as Docetaxel_1007 may have therapeutic potential for LUAD. Immunotherapy response prediction further demonstrated that the low-risk group may be more likely to benefit from immunotherapy. In vitro experiments demonstrated that &lt;i&gt;CDKN3&lt;/i&gt;, &lt;i&gt;PKP2&lt;/i&gt;, &lt;i&gt;ADM&lt;/i&gt;, &lt;i&gt;FAM83A&lt;/i&gt;, and &lt;i&gt;DKK1&lt;/i&gt; were upregulated, whereas &lt;i&gt;MS4A1&lt;/i&gt; was downregulated in A549 cells compared with BEAS-2B cells. Additionally, knockdown of &lt;i&gt;CDKN3&lt;/i&gt; significantly suppressed the viability, migration, and invasion of LUAD cells.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The PTM-related six-gene model showed potential for prognostic stratification and characterization of immune-related features in LUAD. However, further prospe","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812870","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":"Bridging the Gap: High-Resolution RHCE Genotyping by Third-Generation Sequencing Enhances Serological Interpretation of Weak Variants","authors":"Fan Wu,&nbsp;Li-Yan Sun,&nbsp;Shuang Liang","doi":"10.1155/humu/8527062","DOIUrl":"https://doi.org/10.1155/humu/8527062","url":null,"abstract":"<p>From January 2022 to June 2023, this study enrolled 124 healthy blood donors. Column agglutination and third-generation sequencing (TGS) were used for <i>RHCE</i> genotyping and RhCE antigen typing. Additional serological screening was performed using conventional tube and column agglutination methods. Sanger sequencing was performed on 22 specimens with abnormal RhCE expression. Among the 124 samples, 102 exhibited normal RhCE expression whereas 22 showed abnormal expression; TGS-predicted phenotypes disagreed with serological results in eight of the 102 normal-expression samples and in seven of the 22 abnormal-expression samples, with discrepancies attributed to reagent limitations and the presence of novel alleles. Indeed, six novel <i>RHCE</i> alleles were identified by TGS and their potential phenotypes inferred based on serological findings, demonstrating that conventional tube and column agglutination methods are effective in determining serological phenotypes, especially in cases of weak RhCE antigen expression, whereas TGS proves valuable for genotyping and elucidating the underlying causes of weakened expression.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/8527062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784706","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":"Multiomic Investigation of Shared Genetic Pathways in Paediatric Congenital Heart Disease and Neurodevelopmental Disorders","authors":"Jamie-Lee M. Thompson,&nbsp;Yunkai Gao,&nbsp;Eri Iwasawa,&nbsp;Debjani Das,&nbsp;Emma Rath,&nbsp;Michael Troup,&nbsp;David T. Humphreys,&nbsp;Haleh Heydarian,&nbsp;Julia Anixt,&nbsp;Nadine A. Kasparian,&nbsp;Tanya E. Froehlich,&nbsp;Jason Tchieu,&nbsp;K. Nicole Weaver,&nbsp; Congenital Heart Disease Synergy Study Group,&nbsp;Edwin P. Kirk,&nbsp;Russell Dale,&nbsp;Sally L. Dunwoodie,&nbsp;David S. Winlaw,&nbsp;Eleni Giannoulatou","doi":"10.1155/humu/7869246","DOIUrl":"https://doi.org/10.1155/humu/7869246","url":null,"abstract":"<p>Recent medical advances have significantly improved the life expectancy of individuals with congenital heart disease (CHD); however, these children remain at increased risk of co-occurring neurodevelopmental disorders (NDD), such as attention-deficit/hyperactivity disorder and autism spectrum disorder. Although prenatal environmental factors, including placental dysfunction and altered oxygen levels in utero, as well as postnatal events such as cardiac surgery, may contribute to this increased risk, shared genetic factors may also underlie both conditions. Therefore, this study is aimed at investigating genomic, transcriptomic and epigenomic findings in patients with NDD and/or CHD using an integrative multiomic approach. A cohort of 14 trios and one duo was recruited: Two probands had both NDD and CHD, two had CHD only and 11 had NDD only. Blood samples were analysed using whole-genome sequencing, RNA sequencing and DNA methylation profiling. We identified one large deletion (~2.5 Mb) and seven likely pathogenic/pathogenic (LP/P) variants, including two in autosomal dominant genes relevant to the patients′ phenotypes and five in autosomal recessive genes consistent with carrier status. This included a likely pathogenic de novo splice-disrupting variant in the chromatin remodelling gene <i>ARID1B</i>, validated by RNA sequencing. DNA methylation analysis revealed epigenetic differences between CHD and NDD patients, with CHD patients showing elevated biological age acceleration. Comparison with a reference cohort of 178 controls identified four probands with extreme methylation dysregulation, including the individual with the <i>ARID1B</i> variant. Overall, these findings highlight the diagnostic and mechanistic value of integrative multiomic profiling in paediatric developmental disease cohorts.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7869246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784712","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":"Type III Osteogenesis Imperfecta and COL1A1 Pathological Variants Are Associated With Higher Incidence and Progression of Hearing Loss","authors":"Julie A. Christensen,&nbsp;Anne Tran,&nbsp;Hui Cheng,&nbsp;Sara Talvacchio,&nbsp;Carmen C. Brewer,&nbsp;Christopher Zalewski,&nbsp;Jennifer Chisholm,&nbsp;Talah T. Wafa,&nbsp;L. Noelle Allemang,&nbsp;Elena F. Evans,&nbsp;Alberta Derkyi,&nbsp;Joan C. Marini,&nbsp;Gayla L. Poling","doi":"10.1155/humu/6245371","DOIUrl":"https://doi.org/10.1155/humu/6245371","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>This study interrogates longitudinal natural history data to determine whether hearing loss (HL) incidence, onset, degree, and type in osteogenesis imperfecta (OI) caused by heterozygous collagen missense variants are associated with a specific gene or combinations of causal gene and OI type.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Audiological evaluation was conducted in 73 children with Type III or IV OI carrying <i>COL1A1</i> or <i>COL1A2</i> missense, exon-skipping, or small deletion variants, with adult follow-up.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 71% of Type III OI participants experienced HL, compared with 39% of those with Type IV OI. Conductive HL persisted (33%) or transitioned to mixed conductive/sensorineural (67%) with progression. While HL was predominantly mild in most participants, six Type III participants (25%) but only one Type IV OI participant (7%) progressed to more severe loss. Most Type III and IV OI participants had HL onset in the first decade of life, with 46% and 33% of onsets, respectively, occurring before school age. More than half of participants with <i>COL1A1</i> or <i>COL1A2</i> variants had HL. Interfamilial and intrafamilial variability in HL was noted. Statistical interaction between genotype and phenotype indicated the greatest HL progression among Type III OI with <i>COL1A1</i> variants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our data reveal significant HL onset in the first decade, and an interaction of Type III OI and COL1A1 variants among those with HL progression. These findings will guide clinical management, facilitating early monitoring tailored to genotype and phenotype.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6245371","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784710","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 Variants in PET Complex Encoding Genes TDRD12 and EXD1 Impair piRNA Biogenesis and Cause Male Infertility","authors":"Beibei Zhang,&nbsp;Ao Ma,&nbsp;Hongyi Wang,&nbsp;Chong Xie,&nbsp;Shengwei Ke,&nbsp;Ziqi Yu,&nbsp;Haoran Xu,&nbsp;Zhipeng Xu,&nbsp;Zhiran Li,&nbsp;Xun Wang,&nbsp;Lv Yao,&nbsp;Fuxing Zhang,&nbsp;Lingying Jiang,&nbsp;Xiaozhi Zhao,&nbsp;Fei Sun","doi":"10.1155/humu/7629729","DOIUrl":"https://doi.org/10.1155/humu/7629729","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Nonobstructive azoospermia (NOA), the most severe form of male infertility, has approximately 30% of its cases attributed to genetic factors. However, current genetic research only explains a small fraction of NOA cases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, 156 infertile Chinese patients diagnosed with idiopathic male infertility were recruited. Whole exome sequencing and subsequent bioinformatic analysis were performed to find candidate pathogenic variants. Sanger sequencing was used to validate the candidate variants. Quantitative reverse-transcript PCR (RT-qPCR) was performed to detect the mRNA expression of <i>TDRD12</i> and related piRNA genes. Hematoxylin and eosin staining and immunofluorescence staining were performed on testicular sections obtained from patients′ biopsies. Intracytoplasmic sperm injection (ICSI) was applied for assisted fertilization. Additionally, small RNA sequencing was performed to identify the abnormalities of piRNA biogenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified eight variants in PET (PIWI-EXD1-TDRD12) complex encoding genes <i>TDRD12</i> and <i>EXD1</i> from three NOA patients and one oligoasthenozoospermia patient. These variants, which were rare or absent in public human databases, were predicted to be deleterious. Notably, <i>TDRD12</i> mRNA was absent in three NOA patients. Testicular histopathological analyses revealed that spermatogenesis was arrested at zygotene stage in patients carrying biallelic <i>TDRD12</i> variants. Further immunofluorescence staining of L1ORF1p and small RNA sequencing revealed disruptions in piRNA biogenesis and subsequent derepression of retrotransposons. Further assisted reproduction outcomes showed that one of the individuals conceived successfully after ICSI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Overall, this study significantly expands the mutational phenotype of PET complex-encoding genes and significantly advances our understanding of spermatogenic failure and male infertility. Our findings provide direct clinical and functional evidence that the function of the PET complex and piRNA biogenesis is highly conserved between humans and mice.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7629729","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784588","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 Study on the Clinical Phenotypes and Genetic Analysis of ENG Variants in Four Hereditary Hemorrhagic Telangiectasia Type 1 Families","authors":"Yujing Gong,&nbsp;Tingmin Zhou,&nbsp;Xinru Fu,&nbsp;Yiyi Jiang,&nbsp;Danping Wang,&nbsp;Chuangjie Gu,&nbsp;Ruiting Wu,&nbsp;Dan Wang,&nbsp;Chang Yu","doi":"10.1155/humu/8307860","DOIUrl":"https://doi.org/10.1155/humu/8307860","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder primarily caused by pathogenic variants in the <i>ENG</i> gene, leading to clinical manifestations including pulmonary arteriovenous malformation (PAVM), recurrent spontaneous nosebleeds, and other related symptoms. This study is aimed at investigating the clinical manifestations of members in four HHT1 families with PAVMs and analyze novel <i>ENG</i> variants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Clinical evaluations, whole exome sequencing (WES), and Sanger sequencing were performed on the probands and their family members from Families 1 to 4. Bioinformatics programs were utilized to assess the pathogenicity of the candidate variants. Additionally, an in vitro minigene assay was conducted to examine the impact of the variant in Family 2 on RNA splicing, and Western blot was employed to validate the impact of the variant on protein expression and modification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Four <i>ENG</i> variants were identified: c.613del (exon 5), c.1428 + 2 T &gt; C (intron 11), c.1498dup (exon 12), and c.322del (exon 3). The splice-site variant c.1428 + 2 T &gt; C, which has been reported as pathogenic in ClinVar, leads to aberrant <i>ENG</i> mRNA splicing with exon 11 skipping, resulting in a shorter protein (p.Lys438_Gln476del) with impaired glycosylation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The splice-site variant c.1428 + 2 T &gt; C caused aberrant ENG mRNA splicing, leading to exon 11 skipping and producing a shorter protein with abnormal glycosylation (p.Lys438_Gln476del). The variants identified in Families 1, 3, and 4 (c.613delC, c.1498dupC, and c.322delG) are all frameshift variants that lead to premature termination of translation. This study expands the spectrum of <i>ENG</i> variants and provides insights into the pathogenesis of HHT1. These findings offer guidance for the early diagnosis for families affected by HHT1.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/8307860","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784711","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":"From Germline Variants to Tumor Outcome: GWAS-Based Functional Genomics Prioritizes Colorectal Cancer Susceptibility Genes and Links SMAD9 to Prognosis","authors":"Chengguang Hu,&nbsp;Guang Yang,&nbsp;Han Xiong,&nbsp;Yetong Xie,&nbsp;Zhao Yuan,&nbsp;Jiani Liu,&nbsp;Peiying Wang,&nbsp;Meng Li,&nbsp;Jiabao Xu,&nbsp;Qingyun Li,&nbsp;Chulan Li,&nbsp;Wenlin Han,&nbsp;Xin Peng,&nbsp;Li Zhang,&nbsp;Shanshan Cai,&nbsp;Fei Zhong,&nbsp;Lin Dai,&nbsp;Side Liu","doi":"10.1155/humu/5617762","DOIUrl":"https://doi.org/10.1155/humu/5617762","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Introduction&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Genome-wide association studies (GWAS) have identified over 200 germline risk loci for colorectal cancer (CRC), yet the causal variants and genes behind most GWAS signals remain unknown and the link between inherited risk and tumor outcome is largely unexplored. Connecting germline single nucleotide polymorphisms (SNPs) to gene expression through expression quantitative trait loci (eQTL) and to clinical outcome is needed to interpret this inherited risk.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We combined CRC GWAS summary data (73,149 cases and 112,467 controls of European ancestry) with GTEx v8 eQTL from colon sigmoid, colon transverse, small intestine terminal ileum, and whole blood, integrating causal transcriptome-wide association study (cTWAS) with SuSiE fine-mapping, Bayesian colocalization, MAGMA SNP-to-gene analysis, and AlphaGenome variant-effect prediction. Prioritized proteins were assessed by western blot. Four experimentally selected regulatory variants were genotyped in HCT116, SW480, RKO, and NCM460 cells; genotype-protein associations were tested across cell-line means, and cis-regulatory effects were assessed by allele-specific expression (ASE) and reference-versus-alternate dual-luciferase assays. Prognostic relevance was evaluated in TCGA colorectal tumors.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;cTWAS identified seven genes with posterior inclusion probability (PIP) &gt; 0.50, and colocalization across 78 gene-tissue pairs revealed 20 associations with PP.H4 &gt; 0.80. Four genes showed convergent evidence: SMAD9 (PIP = 0.916, PP.H4 = 0.981), MAP3K2 (PIP = 0.762, PP.H4 = 0.827), FADS1 (PIP = 0.632, PP.H4 = 0.942), and ACTR1B (PIP = 0.566, PP.H4 = 0.994). All four proteins were reduced in CRC cells. Alt-allele dosage was inversely associated with SMAD9 (Pearson r = −0.985, BH-adjusted &lt;i&gt;p&lt;/i&gt; = 0.029) and FADS1 protein abundance (&lt;i&gt;r&lt;/i&gt; = −0.995, BH-adjusted &lt;i&gt;p&lt;/i&gt; = 0.020), but not with MAP3K2 or ACTR1B. Reporter and ASE assays detected the clearest allele-specific effects at SMAD9 and FADS1, whereas MAP3K2 and ACTR1B were null in the tested systems. Lower SMAD9 expression was nominally associated with poorer survival (log − rank &lt;i&gt;p&lt;/i&gt; = 0.022 to 0.050), but these associations did not survive Benjamini–Hochberg correction across 12 tests.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Integrating statistical genetics, regulatory prediction, and locus-directed experiments prioritized SMAD9, MAP3K2, FADS1, and ACTR1B as CRC susceptibility genes. Functional evidence was strongest ","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/5617762","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784735","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":"Mutation-Immune Crosstalk Contextualizes CAF-Associated ARPC1A Programs and Cisplatin Response in Gastric Cancer","authors":"Deyi Lu,&nbsp;Fanlai Meng,&nbsp;Weiying Zhou,&nbsp;Yifei Hu,&nbsp;Gaosha Li,&nbsp;Jiahao Ge,&nbsp;Qing Zhang,&nbsp;Qi Min","doi":"10.1155/humu/9607360","DOIUrl":"https://doi.org/10.1155/humu/9607360","url":null,"abstract":"<p>Cisplatin response in gastric cancer is shaped by malignant cell programs, stromal states, and mutation-immune crosstalk, but the CAF subtypes linked to platinum tolerance and their epithelial effectors remain incompletely defined. We integrated single-cell RNA sequencing, epithelial CNV-like inference, fibroblast reclustering, CellChat analysis, signature scoring, hdWGCNA, CAF-epithelial coupling, exploratory GSE14209 evaluation, TCGA-STAD mutation/copy-number contextualization, and DepMap CRISPR virtual knockout analysis, followed by experimental validation in AGS and HGC-27 cells. IGF1+ CXCL12+ CAFs showed resistance-supportive stromal features, and CAF-epithelial coupling prioritized ARPC1A as a tumor epithelial candidate associated with this stromal program. In TCGA-STAD, ARPC1A mutations were rare and consisted of three missense and two frameshift variants without a recurrent hotspot; the mutant tumors were confined to the MSI subtype and showed an immune-activated, high TMB/MSI context, indicating mutation-immune crosstalk rather than a clear mutation-specific CAF, EMT, drug resistance, or cisplatin response phenotype. By contrast, ARPC1A copy-number gain/amplification was more frequent and tracked with ARPC1A expression, CIN enrichment, aneuploidy, and fraction of genome altered. DepMap CRISPR data indicated mostly weak-to-mild baseline ARPC1A dependency in upper GI and gastric/GEJ models. Experimentally, ARPC1A knockdown increased cisplatin sensitivity, promoted cisplatin-induced apoptosis, and suppressed migration and invasion. These findings identify a CAF-associated ARPC1A epithelial program linked to cisplatin response and support a mutation-immune/copy-number framework in which ARPC1A is interpreted mainly through immune-contextual mutation patterns and expression dosage rather than recurrent gain-of-function mutation.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9607360","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784879","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":"Identification of Novel Pathogenic Variants in Familial Adenomatous Polyposis Through Whole Genome Sequencing","authors":"Sung-Ryung Choi,&nbsp;Min Jung Kim,&nbsp;Ja-Lok Ku,&nbsp;Seung-Yong Jeong,&nbsp;Murim Choi,&nbsp;Ji Won Park","doi":"10.1155/humu/1896928","DOIUrl":"https://doi.org/10.1155/humu/1896928","url":null,"abstract":"<p>Familial adenomatous polyposis (FAP) is an autosomal dominant colorectal cancer predisposition syndrome most commonly caused by pathogenic variants in the <i>APC</i> gene. Although targeted gene panel sequencing is routinely used, some FAP cases remain genetically unresolved due to limitations in detecting structural and deep intronic variants. We investigated two unrelated kindreds with clinically evident but genetically unexplained FAP using targeted panel sequencing and whole exome sequencing. Pedigree-based whole genome sequencing (WGS) was performed to detect cryptic variants, with in silico splice prediction and transcript-level validation using RT-PCR, Sanger sequencing, and RT-qPCR of blood-derived RNA. WGS uncovered two novel pathogenic <i>APC</i> variants missed by prior testing. In Kindred 1, a heterozygous large deletion encompassing exon 10 was detected and confirmed to cause exon skipping, resulting in a frameshift and premature termination codon. In Kindred 2, a deep intronic complex deletion-insertion variant was identified between exons 11 and 12, predicted to create novel splice sites. Transcript analysis demonstrated aberrant pseudoexon activation with a 2-base-pair deletion, leading to a frameshift and premature termination. Both variants segregated with disease within the respective families and were classified as pathogenic according to ACMG guidelines based on loss-of-function effects and functional RNA evidence. Our findings demonstrate that cryptic pathogenic <i>APC</i> variants beyond the detection limits of routine genetic testing can be resolved through WGS combined with transcript-level validation. This study highlights the importance of transcript-aware variant interpretation and supports the integration of genome-wide sequencing and RNA-based analyses into the diagnostic evaluation of genetically unexplained FAP.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/1896928","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784246","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}