Human Mutation最新文献

{"title":"Patient-Derived iPSC-Cardiomyocytes Reveal Subclinical Cardiomyocyte Dysfunction Associated With the CAV3 N-Terminal Variant p.Ala46Thr","authors":"Junyi Wang,&nbsp;Xintong Zhu,&nbsp;Yaqiong Li,&nbsp;Limeng Dai,&nbsp;Xiaoyin Tan,&nbsp;Jia Li,&nbsp;Hong Guo","doi":"10.1155/humu/4061668","DOIUrl":"10.1155/humu/4061668","url":null,"abstract":"<p>The <i>CAV3</i> p.Ala46Thr mutation is previously associated with skeletal muscle damage only, with its myocardial impact and long-term cardiac risks unclear. This study is aimed at investigating whether it induces subclinical myocardial damage at the cellular level and explore its mechanism using a patient-specific iPSC-CMs model. To achieve this, peripheral blood from a proband carrying the <i>CAV3</i> c.136G&gt;A (p.Ala46Thr) mutation but only clinical manifestations of skeletal muscle damage was collected. Subsequently, a patient-derived iPSC line was established and directionally differentiated into iPSC-CMs. IF and TEM were then conducted to observe the structure of cardiomyocytes, the arrangement of sarcomeres, and the subcellular localization of CAV3 protein. Additionally, laser confocal calcium imaging technology was used to analyze the basic electrophysiological rhythm of cardiomyocytes and their response to fenoterol. As a result, the mutant iPSC-CMs model was successfully constructed. Compared with controls, mutant iPSC-CMs exhibited a normal cellular structure, but notably, the CAV3 protein exhibited abnormal aggregation around and inside the nucleus, resulting in a loss of membrane localization. Furthermore, functional assays showed that the mutant iPSC-CMs had a significant decrease in basic beating frequency and an irregular rhythm. After stimulation with fenoterol, the increases in beating frequency and rhythm regularity were significantly less pronounced than those in controls. In conclusion, this study is the first to demonstrate that human cardiomyocytes from carriers of the <i>CAV3</i> p.Ala46Thr mutation without any cardiac symptoms clinically exhibit an abnormal localization of CAV3 protein and definite altered spontaneous activity and calcium-handling behavior. This suggests that the mutation can induce subclinical myocardial damage, and the carriers should be considered as a group with potential risk of heart disease. Overall, this study provides a novel experimental basis for the early warning and accurate treatment of <i>CAV3</i>-related diseases on the site of clinics.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024757","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":"Uncovering the Novel Genetic Determinants of Primary Congenital Glaucoma in Pakistani Families","authors":"Hamza Khan,&nbsp;Sadia Bukhari,&nbsp;Nauman Ahmad,&nbsp;Israr Ahmed Bhutto,&nbsp;Yousaf Jamal Mahsood,&nbsp;Mohsin Iqbal Haroon,&nbsp;Muhammad Moeez Uddin,&nbsp;Amal Shabir Memon,&nbsp;Atta Ur Rehman,&nbsp;Shah Zainab,&nbsp;Asad Munir,&nbsp;Syeda Hafiza Benish Ali,&nbsp;Muhammad Ajmal,&nbsp;Raheel Qamar,&nbsp;Jibril Hirbo,&nbsp;Maleeha Azam,&nbsp;Humaira Ayub","doi":"10.1155/humu/1806353","DOIUrl":"https://doi.org/10.1155/humu/1806353","url":null,"abstract":"<p>Primary congenital glaucoma (PCG) is an early-onset eye disorder, particularly prevalent in populations with high consanguinity rates. In Pakistan, approximately 63% of marriages are reported to be consanguineous, contributing to an increased burden of autosomal-recessive disorders. The genetic basis of PCG in the highly consanguineous Pakistani population is largely unexplored. This study was conducted to broaden the genetic landscape of PCG in families of Pakistani origin. PCG families identified through clinical characterization were recruited in the study. All probands were initially investigated for <i>CYP1B1</i> mutations by targeted Sanger sequencing, followed by segregation analysis of the identified variants. Moreover, one family (PCG02) not linked to <i>CYP1B1</i> was further subjected to a 250K SNP microarray and whole-exome sequencing (WES). The study participants comprised nine large, unrelated consanguineous and three PCG trio families collected from Pakistan. Nine identified variants were recurrent, whereas one previously unreported variant, <i>CYP1B1</i> (NM_000104.4: c.1390T&gt;C; p.Ser464Pro), was not found in any of the online databases such as gnomAD, ClinVar, and dbSNP, and was predicted to be deleterious by all the pathogenicity predicting tools. Furthermore, a plausible 2-Mb novel locus was identified on Chromosome 7q34 (139,681,371-141,507,822) (GRCh38/hg38) in family PCG02. The current study expands the mutation spectrum of <i>CYP1B1</i> in the Pakistani population and highlights the genetic heterogeneity of the disease in this population.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/1806353","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148994346","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":"Zygosity-Dependent Phenotypic Spectrum of RELN-Related Disorders: 10 New Patients and Genotype–Phenotype Correlations Across 48 Kindreds","authors":"Sajjad Biglari,&nbsp;Halimeh Rezaei,&nbsp;Elnaz Asadollahzadeh,&nbsp;Mohammad Salimi Asl,&nbsp;Hamid Galehdari,&nbsp;Masoud Garshasbi,&nbsp;Emran Esmaeilzadeh,&nbsp;Raziyeh Khalesi,&nbsp;Payman Jamali,&nbsp;Farshid Parvini,&nbsp;Gholamreza Shariati,&nbsp;Niloofar Chamanrou,&nbsp;Reza Saligheh,&nbsp;Atefeh Sohanforooshan Moghaddam,&nbsp;Hamid Reza Khorram Khorshid,&nbsp;Sepideh Shohani,&nbsp;Samira Nafar,&nbsp;Atieh Eslahi,&nbsp;Mojtaba Lotfi,&nbsp;Behnoosh Bakhshoodeh,&nbsp;Fatemeh Hajizadeh,&nbsp;Saeed Abtahi,&nbsp;Reza Gharaei Jomehei,&nbsp;Hassan Vahidnezhad,&nbsp;Mehran Beiraghi Toosi,&nbsp;Morteza Heidari,&nbsp;Hanieh Mirzadeh,&nbsp;Majid Mojarrad,&nbsp;Mina Mohammadi Sarband,&nbsp;Ehsan Ghayoor Karimiani","doi":"10.1155/humu/9993570","DOIUrl":"https://doi.org/10.1155/humu/9993570","url":null,"abstract":"<p>Variants in <i>RELN</i> lead to a range of neurodevelopmental phenotypes, from autosomal recessive lissencephaly with cerebellar hypoplasia (LCH) (LIS2) to autosomal dominant focal epilepsies. We carried out exome sequencing (ES) on 10 affected individuals from eight unrelated Iranian families with consanguinity. Nine distinct variants were identified: Four are novel; four had been deposited in ClinVar without a reported affected individual; and the ninth, c.2015C&gt;T, p.(Pro672Leu), had been reported only in heterozygous carriers with dominant epilepsy. In this study, we report the variant for the first time in the homozygous state, in a patient with the full recessive phenotype. The patients were pooled in a systematic review following PRISMA, updated to July 2026, with 28 papers, and all variants were reannotated against NM_005045.4, under a single ACMG/AMP framework. The primary cohort comprised 80 individuals from 48 kindreds (70 previously reported, 10 new) with 48 distinctive variants, of which 41 (85%) were pathogenic or likely pathogenic and five were variants of uncertain significance; two balanced rearrangements were not in either the sequence-variant or copy-number frameworks; and 16 individuals from nine kindreds with monoallelic candidate or susceptibility variants were analyzed separately. The age of onset was not continuous with no reports of onsets between 2.4 and 8 years. Zygosity did not account for this separation because monoallelic individuals occurred in both onset groups; in contrast, malformations of cortical development were documented in all 32 early-onset individuals and in none of the 23 later onset individuals with evaluable neuroimaging. ES was the diagnostic method in 65% of individuals. Thus, zygosity contributes to the phenotypic severity in a broad spectrum of RELNopathies and supports carrier testing and reproductive counseling in consanguineous families.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9993570","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148994599","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":"Biallelic WDR19 Variants: Systematic Analysis of Genotype–Phenotype Correlations","authors":"Zoe Webster,&nbsp;Lisa Woods,&nbsp;Robert Dalziel,&nbsp;Kylie Drake,&nbsp;Guillem de Valles-Ibáñez,&nbsp;Gemma Poke","doi":"10.1155/humu/9449547","DOIUrl":"10.1155/humu/9449547","url":null,"abstract":"<p>Ciliopathies represent a diverse group of inherited disorders resulting from dysfunctional cilia. A rare subset is associated with biallelic variants in <i>WDR19</i>, with fewer than 100 affected individuals reported worldwide. This study is aimed at reviewing the clinical and molecular spectrum of <i>WDR19</i>-associated ciliopathies, with a particular focus on genotype–phenotype correlations. We report a 32-year-old woman with renal, ocular and hepatic manifestations attributed to compound heterozygous variants in <i>WDR19</i>, and reviewed available data from 93 previously published cases. Missense, truncating, splice-site and copy number variants have all been reported, with renal, ocular, skeletal and hepatic involvement most frequently observed. Genotype–phenotype analyses indicated that the presence of a truncating variant was associated with increased likelihood of skeletal involvement and reduced likelihood of hepatobiliary disease compared with individuals harbouring only missense variants. Amongst individuals with only missense variants, variants located outside repeat protein domains were associated with early symptom onset (before 16 years of age) and with ocular manifestations. Notably, recurrent variants demonstrated considerable phenotypic variability. This study represents the largest review of <i>WDR19</i> variants to date and contributes to current understanding of <i>WDR19</i>-related disease.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13583927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148989814","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":"CBX3 as a Prognostic Biomarker and Therapeutic Target in Colorectal Carcinoma","authors":"Tao Hu,&nbsp;Wenbin Song,&nbsp;Zhaoyi Liu,&nbsp;Cangchang Shi,&nbsp;Xiaoyan Hu,&nbsp;Shengxuan Wang,&nbsp;Zhikai Cao,&nbsp;Keyun Zhu,&nbsp;Yao Tian,&nbsp;Yingxi Li","doi":"10.1155/humu/9582961","DOIUrl":"https://doi.org/10.1155/humu/9582961","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Colorectal cancer (CRC) is a common and lethal disease worldwide. The chromobox (CBX) protein family, integral to the Polycomb repressive complex 1 (PRC1), plays a crucial role in epigenetic regulation and the progression of cancer. The expression profiles, clinical importance, and roles of various CBX family members in CRC remain unclear, especially concerning nonepigenetic functions and roles in the tumor microenvironment.&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;The transcriptional profiles of the entire CBX family, consisting of eight members, were systematically analyzed using multiple public databases. Genomic alterations, prognostic data, and GSEA identified CBX3 as an important oncogenic gene. To explore CBX3 expression patterns and their association with immune cell infiltration in the tumor microenvironment, single-cell RNA sequencing was employed. Through experimental validation, cell proliferation, migration, apoptosis, and cell cycle analysis, the oncogenic role of CBX3 was confirmed. Experiments involving coimmunoprecipitation and immunofluorescence colocalization were performed to confirm protein–protein interactions and subcellular localization of the protein. The screening of the CMap was executed to find potential therapeutic compounds, sorted by CBX3 expression levels.&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;The integrated analysis revealed a complicated expression pattern of CBX family members in CRC, with notable increases in CBX2, CBX3, CBX4, and CBX8, whereas CBX6 and CBX7 were decreased in tumor tissues. The prognostic analysis revealed that higher levels of CBX3, CBX4, CBX6, CBX7, and CBX8 were connected to lower overall survival rates, whereas increased CBX5 expression was associated with improved prognosis. Among all members, CBX3 was noted for having the highest frequency of alterations and the most frequent copy number gain, establishing it as a leading oncogenic driver. Single-cell analysis showed that CBX3 expression was predominantly found in malignant cells, and higher CBX3 levels were associated with increased infiltration of immunosuppressive regulatory T cells. CMap screening revealed that epidermal growth factor receptor (EGFR) inhibitors were the most significantly enriched compounds in the high CBX3 expression group. In vitro, reducing CBX3 expression decreased cell proliferation and migration, promoted apoptosis, and caused G2/M phase arrest in CRC cells. CBX3 interacts with EGFR, activating the PI3K/AKT signaling pathway and promoting epithelial–mesenchymal transition (EMT).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9582961","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148994580","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":"Infantile Epileptic Spasm Syndrome Caused by TAF1 Missense Variants: Expanding the Epileptic Phenotype and Revealing Underlying Impairments in Neuronal Excitability and Development","authors":"Hui Xiao,&nbsp;Changning Xie,&nbsp;Pan Peng,&nbsp;Xiaoyuan Ni,&nbsp;Leilei Mao,&nbsp;Jing Peng","doi":"10.1155/humu/4104648","DOIUrl":"10.1155/humu/4104648","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pathogenic variants in <i>TAF1</i> have previously been associated with X-linked intellectual disability and X-linked dystonia-parkinsonism. Epilepsy is observed in approximately 24.4% of affected individuals, ranging from focal seizures to generalized seizures including either tonic-clonic, tonic, myoclonic, atonic or absences. To date, no cases of infantile epileptic spasm syndrome (IESS) have been associated with this neurogenetic condition. In this study, we are aimed at investigating the association between <i>TAF1</i> and IESS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed whole-exome sequencing in two unrelated Chinese patients with IESS. Functional consequences were assessed using in vitro overexpression assays, transcriptome profiling of Neuro-2a cells with stable <i>TAF1</i> knockdown, morphological, and electrophysiological analyses in primary mouse cortical neurons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified two novel <i>TAF1</i> missense variants (c.236C &gt; A, p.T79N; c.4771G &gt; A, p.D1591N) in the two patients. Both novel <i>TAF1</i> missense variants led to reduced TAF1 protein expression, suggesting a loss-of-function mechanism. Transcriptome analysis revealed that <i>TAF1</i> deficiency resulted in significant downregulation of key neuronal genes involved in axon guidance and epileptogenesis, including <i>Kcnn2</i>, <i>Kcna4</i>, <i>Draxin</i>, and <i>Lgi1</i>. In primary mouse cortical neurons, <i>TAF1</i> knockdown markedly impaired neurite outgrowth and increased neuronal excitability.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings establish <i>TAF1</i> missense variants as a novel cause of IESS—a previously unrecognized phenotype—thereby expanding the epileptic phenotype of <i>TAF1</i>-related disorders. Furthermore, we demonstrate that <i>TAF1</i> deficiency contributes to disease pathogenesis by impairing neuronal development and increasing neuronal excitability, likely through the downregulation of <i>Kcnn2</i>, <i>Kcna4</i>, <i>Draxin</i>, and <i>Lgi1</i>.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13583436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148989836","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":"Conventional and Shared Genetic Association Analysis Between Diabetes Mellitus and Sensorineural Hearing Loss","authors":"Xiaoyu Wang,&nbsp;Ziyan Zhang,&nbsp;Ke Qiu,&nbsp;Yaxin Luo,&nbsp;Xiaowei Yi,&nbsp;Wendu Pang,&nbsp;Dan Jiang,&nbsp;Jianjun Ren,&nbsp;Yu Zhao","doi":"10.1155/humu/5099141","DOIUrl":"10.1155/humu/5099141","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>This study aims to investigate the epidemiological and genetic associations between diabetes mellitus (DM) and sensorineural hearing loss (SNHL) across different subtypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed 502,490 participants from the UK Biobank using multivariate logistic regression to examine the association between DM and SNHL, considering gender, age, and HbA1c levels. Genetic correlations and causality were examined by linkage disequilibrium score regression and bidirectional Mendelian randomization. Cross-trait meta-analyses identified shared loci between DM and SNHL, followed by gene annotation, functional analysis, and drug candidate exploration for the shared traits.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Observational analysis revealed significant associations between DM and SNHL, consistent in subgroups based on age, sex, and certain HbA1c levels. A positive genetic correlation was found between type 2 diabetes mellitus (T2D) and SNHL (Rg = 0.0982, <i>p</i> = 0.0095) between T2D and SNHL, and four loci were identified, with <i>ARHGEF28</i> and <i>TCF7L2</i> prioritized as credible pleiotropic genes. Enrichment was indicated in glucose metabolism and organogenesis, with shared heritability in metabolic tissues and outer hair cells. Metformin was identified as potential drug candidates for the T2D-SNHL comorbidity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings progress our understanding of the epidemiological association, shared genetic basis, and potential therapeutic targets between T2D and SNHL, which might contribute to the management of their comorbidity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13576905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976593","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":"Clinical and Genetic Spectrum of Large AIP Deletions","authors":"Tea Shehu Kolnikaj,&nbsp;Maren Ruka,&nbsp;Artur Xhumari,&nbsp;Anila Babameto-Laku,&nbsp;Athanasios Siolos,&nbsp;Panagiotis Alexandros Drakos,&nbsp;Kesson Magid,&nbsp;Thomas O. Millner,&nbsp;Robert D. Murray,&nbsp;Marinella Tzanela,&nbsp;Dragana Miljić,&nbsp;Arlinda Ramaj,&nbsp;Paul Benjamin Loughrey,&nbsp;Stelios Tigas,&nbsp;Márta Korbonits","doi":"10.1155/humu/4212742","DOIUrl":"https://doi.org/10.1155/humu/4212742","url":null,"abstract":"<p>Familial isolated pituitary adenoma (FIPA) accounts for approximately 2%–5% of all pituitary adenomas, with inactivating variants of the aryl hydrocarbon receptor-interacting protein (<i>AIP</i>) gene representing the most frequent known genetic cause. Clinically, patients with <i>AIP</i> variants often have young-onset macroadenomas with growth hormone hypersecretion, although disease severity and penetrance are variable. Most reported <i>AIP</i> variants are point mutations, whereas large deletions are rare and potentially underdiagnosed. Accurate detection of <i>AIP</i> copy-number variants requires methods such as multiplex ligation-dependent probe amplification or validated copy-number analysis of next-generation sequencing data, as Sanger sequencing alone may fail to identify these alterations. Due to the rarity of the disease, it is unknown whether large deletions in the ubiquitously expressed <i>AIP</i> gene are associated with potentially more severe phenotype. Available data suggest that large deletions may occur in 8%–10% of <i>AIP</i> mutation-positive pedigrees, highlighting the importance of incorporating copy-number variant detection into <i>AIP</i> testing workflows. We analysed data from all published patients with large <i>AIP</i> deletions (<i>n</i> = 25) and report here two novel large <i>AIP</i> deletions (Exons 3–4 and Exons 2–6 deletions) and three additional three families, including an Albanian kindred associated with metastatic Hürthle cell thyroid carcinoma. No major differences compared with other <i>AIP</i> variants were found in age at diagnosis, tumour size, hormonal profile, sex distribution or presence of other tumours. A role for <i>AIP</i> variants in thyroid carcinogenesis is unlikely.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/4212742","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943296","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 Novel Technique for Validating Copy Number Variants and Its Application in Familial Exudative Vitreoretinopathy","authors":"Li-li Zhang,&nbsp;Zi-jia Zhao,&nbsp;Kai-xin Chen,&nbsp;Yu-qiao Ju,&nbsp;Feng-juan Gao,&nbsp;Yuan Zong,&nbsp;Qing Chang,&nbsp;Xin Huang,&nbsp;Ting Zhang,&nbsp;Ge-zhi Xu","doi":"10.1155/humu/9556416","DOIUrl":"https://doi.org/10.1155/humu/9556416","url":null,"abstract":"<p>Inherited diseases have a strong genetic basis, with copy number variants (CNVs) playing a crucial role in their pathogenesis. However, the detection and validation of CNVs remain challenging. In this study, we introduce target enrichment polymerase chain reaction (tecPCR), a novel technique that integrates multiplex polymerase chain reaction (PCR) with next-generation sequencing (NGS) for enhanced CNV validation, and applied it in familial exudative vitreoretinopathy (FEVR). Using NGS, 97 variants linked to FEVR were identified, including 91 SNVs and 6 CNVs. Of the CNVs, 66.67% (4/6) were validated both by quantitative PCR and tecPCR, yielding a positive predictive value of 100% (95% confidence intervals: 39.8%–100%) and negative predictive value of 100% (95% confidence intervals: 15.8%–100%) for tecPCR in this pilot validation. The validated FEVR genetic test showed a positivity rate of 53.07% (95/179). Moreover, the demographic and ocular features of the FEVR patients with CNVs were comparable to those with SNVs. This study broadens the mutation spectrum of FEVR and demonstrates that tecPCR provides exceptional specificity and sensitivity, making it a promising tool for genetic diagnostics.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9556416","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943294","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 COPZ1 as a Shared Candidate Ferroptosis-Related Hub Gene in Periodontitis and Inflammatory Bowel Disease","authors":"Xin Yu,&nbsp;Yun Ruan,&nbsp;Zongying Zhang,&nbsp;Jiyuan Shi,&nbsp;Xinyu Gu,&nbsp;Yuyi Chen,&nbsp;Mengmeng Sang,&nbsp;Xiaorong Zhou,&nbsp;Yan Zhou,&nbsp;Liming Mao","doi":"10.1155/humu/6316527","DOIUrl":"https://doi.org/10.1155/humu/6316527","url":null,"abstract":"<p>Clinical and epidemiological evidence demonstrates a robust bidirectional link between inflammatory bowel disease (IBD) and periodontitis, with IBD patients having a significantly elevated risk of periodontitis. Although this association is well established, the shared molecular mechanisms remain unclear. Both IBD, including Crohn′s disease (CD) and ulcerative colitis (UC), and periodontitis feature aberrant ferroptosis activation, which drives oxidative damage and tissue breakdown. We therefore hypothesized that ferroptosis is a core pathogenic mechanism common to all three conditions. Using GEO transcriptomic data, we identified 116, 134, and 255 exploratory candidate ferroptosis-related differentially expressed genes in CD, UC, and periodontitis, respectively, with 55 candidate genes overlapping across all three conditions. Four machine learning–based feature selection algorithms consistently ranked COPZ1 as the top hub gene. In animal models of colitis and periodontitis, COPZ1 showed markedly elevated protein levels in inflamed intestinal and gingival tissues. In vitro experiments demonstrated that COPZ1 knockdown upregulated the expression of ferroptosis-inhibitory genes (Gpx4, Slc7a11, and Fth1) in RAW264.7-ASC macrophages under both basal and LPS-induced inflammatory conditions, and reversed LPS-mediated downregulation of Gpx4, suggesting that COPZ1 is involved in the regulation of ferroptosis in macrophages. Immune infiltration analysis revealed correlations between COPZ1 expression and the abundance of macrophages, neutrophils, B cell subsets, and T cell subsets, suggesting its association with differences in estimated immune cell composition. Single-cell RNA sequencing from CD patient biopsies further demonstrated heterogeneous COPZ1 expression across diverse intestinal immune cell types (including neutrophils, CD8⁺ T cells, CD4⁺ T cells, and macrophages) and linked to ferroptosis-associated intercellular signaling. In silico drug prediction identified nine small-molecule compounds that stably bound to COPZ1 through hydrogen bonds. Molecular dynamics simulations subsequently ranked BRD-K66453893 as the compound exhibiting the greatest structural stability among the tested candidates. Collectively, our findings identify COPZ1 as a shared candidate ferroptosis-related hub gene for CD, UC, and periodontitis, and highlight its association with the inflammatory immune microenvironment, thereby providing a promising therapeutic target for these interrelated chronic inflammatory disorders.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6316527","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148943549","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}