Molecular Genetics & Genomic Medicine最新文献

{"title":"Yield of Genetic Testing in Pediatric Cardiomyopathies: Implications for Novel Therapeutic Options.","authors":"Adelaide Ballerini, Francesca Girolami, Alessia Gozzini, Silvia Passantino, Mattia Zampieri, Alberto Marchi, Alessia Tomberli, Giovanni B Calabri, Gaia Spaziani, Giulio Porcedda, Elena Bennati, Silvia Favilli, Iacopo Olivotto","doi":"10.1002/mgg3.70119","DOIUrl":"10.1002/mgg3.70119","url":null,"abstract":"<p><p>Pediatric cardiomyopathies are rare, heterogeneous, and challenging conditions, often with a genetic etiology. We estimated the yield of genetic testing in a pediatric cohort with cardiomyopathies and evaluated the potential candidacy to current or emerging treatments based on genetic results. Over one-third had a conclusive genetic test, including 25% of potential candidates for emerging precision therapies or developing pharmacological options.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 7","pages":"e70119"},"PeriodicalIF":1.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12246793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of Variants of Uncertain Significance in ACADVL Gene From a Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency Patient.","authors":"Qin Wang, Jingxin Yang, Yong Xu, Xingping Li, Nan Jiang, Jiansheng Xie","doi":"10.1002/mgg3.70120","DOIUrl":"10.1002/mgg3.70120","url":null,"abstract":"<p><strong>Background: </strong>Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare disorder of long-chain mitochondrial fatty acid oxidation (FAO) caused by biallelic mutations in the acyl-CoA dehydrogenase very-long-chain (ACADVL) gene with autosomal recessive (AR) inheritance. Currently, the ACADVL gene has over 350 VUSs in the ClinVar database that require characterization to determine potential pathogenicity.</p><p><strong>Methods: </strong>In this study, we performed functional studies and three-dimensional protein structure analysis to identify the pathogenicity of two ACADVL VUSs in a Chinese VLCADD patient with severe clinical symptoms.</p><p><strong>Results: </strong>Biallelic variants in ACADVL gene c.1055T>C (p.Met352Thr) and c.1269G>A (p.Ser423=) were identified by whole-genome sequencing (WGS) and confirmed using Sanger sequencing. Both variants were recorded in ClinVar database with \"conflicting interpretation of its pathogenicity\" and need appropriate evidence for reclassification to guide family reproductive planning. Synonymous variant p.Ser423= could result in skipping of exon 12 through mini-gene splicing experiment testing. Further functional studies reveal that both variants yield a mild-to-severe decrease in ACADVL mRNA and protein expression in vitro.</p><p><strong>Conclusion: </strong>In this study, we determined the pathogenicity of ACADVL variants c.1055T>C (p.Met352Thr) and c.1269G>A (p.Ser423=) via experimental and in silico analysis. The findings contribute to expanding the variant spectrum in the ACADVL gene, and exploring the pathogenicity of VUS may provide us with further understanding of the disease.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 7","pages":"e70120"},"PeriodicalIF":1.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12272298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic Mutations in the Otogelin-Like Gene (OTOGL) Associated With Congenital Non-Syndromic Sensorineural Hearing Loss in a Chinese Family.","authors":"Xiang Dai, Jun Li, Xijiang Hu, Wenqian Cai","doi":"10.1002/mgg3.70122","DOIUrl":"10.1002/mgg3.70122","url":null,"abstract":"<p><strong>Background: </strong>Hearing loss, characterized by significant genetic heterogeneity, is a widespread global disorder. Mutations in the OTOG and OTOGL genes have recently been implicated in non-syndromic sensorineural hearing loss. However, the mutation spectrum of OTOGL and its functional relevance remain incompletely understood.</p><p><strong>Methods: </strong>We investigated a Chinese family with unexplained hearing loss using whole-exome sequencing. Compound heterozygous mutations in the OTOGL gene were identified and validated through Sanger sequencing. The proband's clinical features were assessed through audiological evaluations, and genotype-phenotype correlation analysis was conducted. Additionally, single-cell RNA sequencing analysis of the inner ear was performed to explore OTOGL's expression profile in auditory-related cell types.</p><p><strong>Results: </strong>Two compound heterozygous mutations in the OTOGL gene (p.Ile34Val and p.Phe319del) were identified in the proband, a 6-year-old boy with moderate congenital hearing loss. These mutations are predicted to be pathogenic and may explain the observed phenotype. Single-cell RNA sequencing revealed specific OTOGL expression in key auditory-related cell types, providing insights into its developmental and functional roles in the inner ear.</p><p><strong>Conclusion: </strong>The findings have marked implications for molecular diagnosis and genetic counseling, potentially guiding more personalized treatment and intervention strategies in clinical practice.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 7","pages":"e70122"},"PeriodicalIF":1.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electronic Patient Portals as a Modality for Returning Reclassified Genetic Test Results.","authors":"Sukh Makhnoon, MinJae Lee, Mujeeb Basit, Cindy Kao, Sun Won Min, Christine Mai, Alexa Badalamenti, Jacqueline Mersch","doi":"10.1002/mgg3.70123","DOIUrl":"10.1002/mgg3.70123","url":null,"abstract":"<p><strong>Background: </strong>Most reclassified genetic test results are clinically inactionable and burdensome for healthcare providers to return to patients. The feasibility of using electronic patient portals (e.g., MyChart) to return reclassified results remains unclear.</p><p><strong>Methods: </strong>Patient and provider initiated MyChart actions were obtained from MyChart data and matched to patient demographic and clinical information using unique patient medical record numbers. Data on who (patient or provider) sent and read these messages and when (date and time) were collected for clinically actionable and inactionable reclassifications.</p><p><strong>Results: </strong>Among 801 patients with 828 reclassified variants in cancer susceptibility genes, 551 had an active MyChart account at the time of reclassification. Patients with active MyChart accounts were less likely to be Hispanic (p < 0.001) compared to other ethnic groups. Of these, 302 (55%) were notified about 308 reclassified results (307 inactionable and 1 actionable) via MyChart messages, and 80% (244/302) read the message within a median time of 3.6 h.</p><p><strong>Conclusion: </strong>We find that it is feasible to return reclassified results via electronic patient portals for most patients, but alternative modalities are still necessary. Unidirectional, low-touch modalities of recontact can be used to efficiently return the increasing number of inactionable reclassified results.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 7","pages":"e70123"},"PeriodicalIF":1.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12277930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Loss of Function Variant in SOST From Chinese Family Results in Sclerosteosis 1.","authors":"Yufan Guo, Xintao Wu, Yuting Jin, Yu Gu, Yuting Lou, Pu Miao, Ye Wang, Bijun Zhang, Xueting Lin, Chudi Zhang, Jianhua Feng","doi":"10.1002/mgg3.70109","DOIUrl":"10.1002/mgg3.70109","url":null,"abstract":"<p><strong>Background: </strong>SOST encodes a secreted glycoprotein that is similar in sequence to the differential screening-selected gene aberrative in neuroblastoma (DAN) family of bone morphogenetic protein (BMP) antagonists. Pathogenic variants in the SOST gene result in sclerosteosis, van Buchem disease (VBD), or craniodiaphyseal dysplasia. SOST-related genetic disorders are very rare, and limited studies have reported variants associated with sclerosteosis.</p><p><strong>Methods: </strong>Clinical tests such as magnetic resonance imaging (MRI), computed tomography (CT), emission computed tomography (ECT), electromyogram (EMG), routine blood tests, and physical examinations were conducted for the proband. Trio-whole exome sequencing (Trio-WES) was performed, and the rare variants (allele frequency < 0.01) in the exon and splicing regions were selected for further pathogenic evaluation. Candidate pathogenic variants were validated through Sanger sequencing. The wild and mutant SOST sequences were cloned into the pcDNA3.1 expression vector, and the RNA and protein expression levels were investigated in the HEK293T cell line.</p><p><strong>Results: </strong>In this study, we present a case study of a proband who displays abnormal facial expressions accompanied by numbness. The results of the brain MRI show thickening of the skull and disappearance of the diplopia signal. The temporal bone CT scan indicates diffuse osteosclerosis affecting the bilateral ossicular chains and internal auditory meatus, as well as stenosis of the bilateral internal auditory meatus. Trio-WES sequencing detected a novel homozygous variant in the proband: NM_025237.3(SOST): c.327C>A (p.Cys109*), which was also validated in his sister from the same family. According to the ACMG guidelines, the variant is classified as \"likely pathogenic.\" The in vitro experiments demonstrated that the variant caused a decrease in SOST expression at RNA and protein level and produced a truncated protein.</p><p><strong>Conclusion: </strong>The report presents new evidence for the clinical diagnosis of SOST-related facial numbness and expands the variant spectrum of SOST.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 7","pages":"e70109"},"PeriodicalIF":1.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 Intronic Mutation in MBD5 Results in Autosomal Dominant Intellectual Disability Type 1 due to Abnormal Splicing.","authors":"Heng Jiang, Jingjing Mou, Qiwei Zhao, Long Ding, Yu Wang, Xiaohong Guo, Guohua Yang","doi":"10.1002/mgg3.70121","DOIUrl":"10.1002/mgg3.70121","url":null,"abstract":"<p><strong>Background: </strong>We identified a novel variant in MBD5 located within intron 6: c.114-13A>G (NM_018328.5) in a family with a patient presenting intellectual disability. This variant is hypothesized to be the etiological agent underlying the patient's condition.</p><p><strong>Methods: </strong>We conducted an analysis of mRNA splicing within the patient and their relatives' blood samples via reverse transcription polymerase chain reaction (RT-PCR) to assess intronic mRNA splicing. Additionally, we employed a minigene vector construction approach to verify in vitro the splicing of mRNA containing the mutated fragment. Protein structure prediction analysis of the aberrant mRNA was performed using PyMOL software.</p><p><strong>Results: </strong>The patient harbors a novel mutation in the MBD5 gene: c.114-13A>G. Analysis of the patient's blood sample revealed the presence of aberrantly sized mRNA molecules. Utilizing a minigene approach, we discovered that this mutation results in the generation of two types of abnormally sized mRNAs. The first type of abnormal splicing leads to a 12-base pair retention at the 3' end of intron 6, and the second type of abnormal splicing causes exon 7 skipping.</p><p><strong>Conclusion: </strong>In accordance with the \"Standards and Guidelines for the Interpretation of Sequence Variants\" established by the American College of Medical Genetics and Genomics (ACMG), the novel mutation c.114-13A>G in the MBD5 gene meets the criteria for PS2 (the variant is de novo and not inherited from either parent) and PS3 (the variant affects mRNA splicing, resulting in aberrant transcripts). We propose that the c.114-13A>G variant, located within intron 6 of the MBD5 gene, is pathogenic. This discovery not only expands the repository of pathogenic variants for MBD5 but also provides additional insights into intronic mutations of the MBD5 gene, thereby offering significant information for the genetic diagnosis of Autosomal Dominant Intellectual Disability Type 1.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 7","pages":"e70121"},"PeriodicalIF":1.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three Siblings With an Attenuated Presentation of Perlman Syndrome: A Case Report and Literature Review.","authors":"Alayne P Meyer, Daniel C Koboldt, Swetha Ramadesikan, Kristin Zajo, Maria E Hernandez Gonzalez, Anthony R Miller, Douglas Depoorter, Catherine P Comer, James I Geller, Katherine Somers, Nilay Shah, Marco L Leung","doi":"10.1002/mgg3.70124","DOIUrl":"10.1002/mgg3.70124","url":null,"abstract":"<p><strong>Introduction: </strong>Perlman syndrome is a rare autosomal recessive overgrowth disorder with a predisposition to Wilms tumor, caused by biallelic variants in DIS3L2. The majority of patients die in infancy due to respiratory and/or renal failure, limiting the reports of patients surviving into childhood.</p><p><strong>Methods: </strong>Exome sequencing was performed in the proband and her older brother. A younger sibling subsequently underwent targeted variant analysis. RNA sequencing was utilized to investigate the functional impact of the missense variant.</p><p><strong>Results: </strong>Three siblings presented at birth with fetal macrosomia, dysmorphic facial features, and facial hypotonia. The proband had early speech delay and was diagnosed with Wilms tumor at 3 years old. Her brothers both had developmental delay presenting within the first year of life. Genetic testing identified compound heterozygous variants in DIS3L2 (NM_152383.5): c.127C>T (p.Arg43Ter) (paternal)/c.2381G>A (p.Arg794His) (maternal).</p><p><strong>Conclusion: </strong>Our findings expand the genetic and clinical spectrums associated with Perlman syndrome and increase the understanding of the phenotype observed in childhood. They also support consideration of genetic testing for Perlman syndrome in individuals and sibships with macrosomia, developmental delay, and characteristic facial dysmorphisms, with or without the presence of Wilms tumor.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 7","pages":"e70124"},"PeriodicalIF":1.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Synonymous Variant of PAX2 in Monochorionic Diamniotic Twins With Bilateral Renal Agenesis: A Case Report and Literature Review.","authors":"Wencong Yao, Bocheng Xu, Hao Wang, Shanling Liu, He Wang, Jingqun Mai, Xihan Wang, Xin Chen, Zhu Zhang","doi":"10.1002/mgg3.70113","DOIUrl":"10.1002/mgg3.70113","url":null,"abstract":"<p><strong>Background: </strong>Paired Box 2 (PAX2, NM_000278.5) encodes paired box gene 2, one of many human homologs of the Drosophila melanogaster gene prd. PAX2-related disorder is an autosomal dominant disorder associated with renal and eye abnormalities.</p><p><strong>Methods: </strong>In this study, both monochorionic diamniotic twins presenting bilateral renal agenesis were subjected to investigation. The pregnancy was terminated and muscular tissue of the fetus was analyzed by trio whole exome sequencing (WES). The target sequence was verified by Sanger sequencing at the genome level. In vitro Minigene model was constructed and the transcribed cDNA was subjected to Sanger sequencing to explore the splicing effect of the suspected mutation.</p><p><strong>Results: </strong>The synonymous mutation PAX2 c.792G>A was detected in both twins, but not in the parents or the family's firstborn. Although this mutation did not alter the amin acid sequence, minigene splice analysis confirmed that c.792G>A resulted in exon 6 skipping, leading to aberrant mRNA splicing.</p><p><strong>Conclusion: </strong>PAX2 c.792G>A is the first pathogenic synonymous mutation ever documented. It has a significant impact on mRNA splicing and leads to developmental abnormalities. This case highlights the importance of clinical phenotyping as well as comprehensive genetic analysis during genetic testing, including evaluation of synonymous mutations.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70113"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying a Novel Causal FAM83H Variant for Autosomal Dominant Amelogenesis Imperfecta Using Exome-Sequencing.","authors":"Rick Kamps, Herm Martens, Bart de Koning, Bert Smeets, Michel van Geel","doi":"10.1002/mgg3.70108","DOIUrl":"10.1002/mgg3.70108","url":null,"abstract":"<p><strong>Background: </strong>Amelogenesis imperfecta (AI) is a rare genetic disorder causing tooth enamel defects. AI has been classified into 14 different clinical subtypes with different modes of inheritance. In this study, we performed whole-exome sequencing to identify the causative gene defect in a large Dutch family with autosomal dominant hypocalcified AI (ADHCAI).</p><p><strong>Methods: </strong>Whole-exome sequencing (WES) was performed on genomic DNA of the proband with AI. We focused on eight candidate genes known to be involved in inherited autosomal dominant AI. Sanger sequencing was used to confirm the selected exome candidate variant. Additionally, genotype and phenotype analyses were performed in the selected affected and non-affected individuals and compared according to previously listed literature for this candidate gene of the proband.</p><p><strong>Results: </strong>The clinical phenotype of the affected individuals showed a generalized and extensive enamel defect of all teeth. In the exome dataset of the proband, a novel nonsense variant in FAM83H, c.1055C>A p.(Ser352*) was detected, which was verified by conventional Sanger sequencing. Co-segregation analysis confirmed that the variant was present in all affected individuals and not in unaffected individuals.</p><p><strong>Conclusion: </strong>A novel pathogenic, protein-truncating variant was detected in FAM83H, a gene with similar truncating variants known to be associated with ADHCAI.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70108"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole Exome Sequencing Identifies a Novel Frameshift Mutation of the WRN Gene in a Werner Syndrome Family and Functional Analysis.","authors":"Hao Xiong, Haiqing Gao, Jianji Wan, Jieping Xiao, Xiaoqun Luo, Xiuqin Dong, Yueheng Wu, Tao Liu","doi":"10.1002/mgg3.70118","DOIUrl":"10.1002/mgg3.70118","url":null,"abstract":"<p><strong>Introduction: </strong>Werner syndrome (WS) is a rare recessive disorder characterized by premature aging and metabolic abnormalities. WS is caused by mutations in the WS RecQ-like helicase gene (WRN), which encodes the WRN RecQ-like helicase protein. This study aimed to identify the deletion mutation in the WRN gene within the WS family and comprehensively analyze its regulatory role.</p><p><strong>Methods: </strong>We utilized whole exome sequencing to assess gene mutations in non-close relatives of two patients with WS. The mutation was further verified using Sanger sequencing. Subsequently, the pathophysiological characteristics of the mutation were examined using Western blotting, subcellular localization determination, conservative analysis, and three-dimensional (3D) protein structure prediction.</p><p><strong>Results: </strong>Whole exome sequencing revealed a previously unreported homozygous mutation c.3244delG (p.Val1082Tyrfs*17) within exon 27 of the WRN gene. Sanger sequencing confirmed the presence of a homozygous mutation in the two patients, while a heterozygous mutation was identified in the other six family members. Western blotting revealed that the c.3244delG mutation in the WRN gene resulted in a reduced molecular weight of the mutated WRN protein. Furthermore, subcellular localization experiments revealed that the mutant WRN protein could not be effectively transported to the nucleus. Some studies reported that the mutation exhibits a high conservation rate across various species. The three-dimensional structure prediction indicates that the mutant WRN protein exhibits a distinct structure compared to the wild-type protein.</p><p><strong>Conclusions: </strong>This study identified a frameshift mutation in the WRN gene, which was associated with WS. The subsequent functional analysis revealed the inefficiency of the mutated protein. This study broadens the spectrum of known WRN mutations and enhances the comprehension of WS pathogenesis.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70118"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12175019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}