Molecular Genetics & Genomic Medicine最新文献

{"title":"Unraveling the Genetic Landscape of Hearing Loss: A Comprehensive Study of Azeri Families in Ardabil, Iran.","authors":"Marzieh Mohseni, Farzane Zare Ashrafi, Ehsan Abbaspour Rodbaneh, Haleh Mokabber, Maryam Vafaei, Ramiz Nobakht, Fatemeh Keshavarzi, Sanaz Arzhangi, Sara Arish, Zahra Nematollahi Azar, Kimia Kahrizi, Hossein Najmabadi, Behzad Davarnia","doi":"10.1002/mgg3.70080","DOIUrl":"10.1002/mgg3.70080","url":null,"abstract":"<p><strong>Background: </strong>Hereditary hearing loss (HHL) is a clinically and genetically heterogeneous sensorineural disorder that presents challenges for diagnosis. Next-generation sequencing (NGS) approaches have facilitated a more cost-effective, streamlined diagnostic process. This study aimed to identify HHL variants using NGS in Iranian Azeri families in Ardabil Province, establishing a suitable framework for screening programs tailored to the local population.</p><p><strong>Methods: </strong>Seventy-four GJB2-negative Azeri families with HHL from Ardabil Province of Iran were studied using the OtoSCOPE panel and/or exome sequencing over 15-years from 2008 to 2023.</p><p><strong>Results: </strong>Data analysis revealed 53 HHL variants in 52 of the 74 most consanguineous families (70%), including 34 pathogenic/likely pathogenic variants and 19 variants of uncertain significance. Seventeen of the detected variants were novel. SLC26A4, MYO7A, USH2A, and TMPRSS3 were the most prevalent mutated genes for non-syndromic hearing loss (NSHL) and syndromic hearing loss (SHL) in this study.</p><p><strong>Conclusion: </strong>Our results are comparable to those of previous studies, indicating that SLC26A4 is the second most common cause of HHL, after GJB2. Moreover, our study emphasizes the significance of understanding the genetic basis of HL for early diagnosis and the implementation of suitable screening programs for various ethnicities in Iran.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70080"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11836346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449564","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":"Correction to \"Influence of the Sex of Translocation Carrier on Clinical Outcomes of Couples Undergoing Preimplantation Genetic Testing\".","authors":"","doi":"10.1002/mgg3.70071","DOIUrl":"10.1002/mgg3.70071","url":null,"abstract":"","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70071"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365153","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 Compound Heterozygous Variant in the ABHD12 Gene Cause PHARC Syndrome in a Chinese Family: The Proband Presenting New Genotype and Phenotype.","authors":"Meijiao Ma, Jinhai Ma, Yuanyuan Lian, Xueli Wu, Wenming Wang, Weining Rong, Xunlun Sheng","doi":"10.1002/mgg3.70055","DOIUrl":"10.1002/mgg3.70055","url":null,"abstract":"<p><strong>Background: </strong>PHARC syndrome, a rare autosomal recessive neurodegenerative disorder caused by mutations in the ABHD12 gene, is characterized by demyelinating polyneuropathy, hearing loss, ataxia, retinitis pigmentosa (RP), and early-onset cataracts. If patients are first diagnosed in the ophthalmology department, they are easily misdiagnosed as having RP or Usher syndrome. This study aimed to identify the genetic etiology and determine the clinical diagnosis of a Chinese family with suspected PHARC syndrome.</p><p><strong>Method: </strong>Comprehensive ophthalmic examinations and systemic evaluations were conducted to confirm the phenotype. The genotype was identified through Whole Exome Sequencing (WES), and the current literature was reviewed understand better manifestations of PHARC syndrome related to pathogenic variants.</p><p><strong>Results: </strong>The principal symptoms of the proband comprised profound sensorineural hearing loss since childhood, severe visual impairment, congenital cataracts, cone-rod dystrophy, and ataxia. WES revealed that the proband carried a compound heterozygous variant in the ABHD12 gene: M1, a known nonsense variation c.477G > A (p.Trp159Ter); and M2, a novel copy number variant with a deletion of approximately 18.10 Kbp in chromosome 20p11.21 (seq[GRCh38]del(20) (p11.21)chr20:g. 25302218_25320318del), covering exons 4-12 of the ABHD12 gene. The literature review indicated that there were 65 patients with PHARC from 30 different families. All clinical information of the described patients with PHARC syndrome and all known mutations associated with the disease to date were compiled.</p><p><strong>Conclusion: </strong>This study expands the spectrum of pathogenic variants and phenotype for PHARC syndrome and suggests genetic testing is necessary for a definitive diagnosis of PHARC syndrome.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70055"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256263","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":"Trichothiodystrophy due to ERCC2 Variants: Uncommon Contributor to Progressive Hypomyelinating Leukodystrophy.","authors":"Ali Reza Tavasoli, Arastoo Kaki, Maedeh Ganji, Seyyed Mohammad Kahani, Foozhan Radmehr, Pouria Mohammadi, Morteza Heidari, Mahmoud Reza Ashrafi, Kara S Lewis","doi":"10.1002/mgg3.70067","DOIUrl":"10.1002/mgg3.70067","url":null,"abstract":"<p><strong>Background: </strong>Trichothiodystrophy (TTD) is caused by homozygous or compound heterozygous variants in genes associated with DNA repair. The ERCC2 gene encoded a protein, XPD, that is a subunit of the general transcription factor TFIIH and important in both DNA repair and transcription. Disease-causing variants in ERCC2 can partially inactivate these activities, giving rise to symptoms seen in TTD, Cockayne syndrome (CS) and xeroderma pigmentosa (XP). Although generalized cerebral white matter abnormalities is reported in TTD, myelination disorders specifically linked to ERCC2 gene variants are exceptionally uncommon. Here, we introduce a thorough investigation of a patient exhibiting classic TTD symptoms alongside progressive cerebral hypomyelination with ERCC2 variants.</p><p><strong>Methods: </strong>In a non-consanguineous family, we conducted Autism/ID gene Panel on a 5-year-old affected child who presented with microcephaly, failure to thrive, developmental delay, and progressive hypomyelination on three serial brain imaging over 5-years follow-up. Our investigation aimed to elucidate the genetic underpinnings of the observed phenotype. We also conducted a comprehensive review of the genetic profiles of all documented ERCC2-related patients exhibiting myelination disorders.</p><p><strong>Results: </strong>Autism/ID gene Panel identified a compound heterozygous variant in ERCC2 gene causing TTD. Clinical and paraclinical findings enabled differentiation of TTD from Cockayne syndrome and XP. Segregation analysis revealed that, the variation in the paternal allele was a splice junction loss (c.2190 + 1delG), and the other alteration in the maternal allele was a pathogenic variant (c.1479 + 2dupT). It has been noted that these variants were reported in previous studies in homozygous or compound heterozygous form in patients with TTD, but none of them exhibited hypomyelinating leukodystrophy.</p><p><strong>Conclusion: </strong>The identification of hypomyelination in TTD due to ERCC2 sheds a light on the molecular diagnosis and contributing to the limited literature on ERCC2 variants and associated hypomyelinating leukodystrophy in patients with TTD.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70067"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458659","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":"Saliva Sample-Based Non-Invasive Carrier Screening for Spinal Muscular Atrophy, Hereditary Hearing Loss, and Thalassemia in 13,926 Women of Reproductive Age From South Zhejiang.","authors":"Chenyang Xu, Yanbao Xiang, Xiaoling Lin, Qifan Ma, Yunzhi Xu, Huanzheng Li, Shaohua Tang, Xueqin Xu","doi":"10.1002/mgg3.70064","DOIUrl":"10.1002/mgg3.70064","url":null,"abstract":"<p><strong>Background: </strong>Although spinal muscular atrophy (SMA), hereditary hearing loss (HL), and thalassemia are common monogenic genetic diseases, the carrier frequencies and variant spectrums of these diseases show regional differences, even within China. Their carrier frequencies and variant spectrums in Southern Zhejiang, China are unclear.</p><p><strong>Methods: </strong>Saliva was collected for carrier screening and amniotic fluid, villi, and peripheral blood were collected for prenatal diagnosis. Real-time quantitative polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification (MLPA) were used to detect the copy number of SMN1 exon 7. PCR coupled with flow-through hybridization, MLPA, and Sanger sequencing were used to detect common genes for HL and thalassemia.</p><p><strong>Results: </strong>Common variants were detected in 15.14% (2109/13926) of the 13,926 women of reproductive age from South Zhejiang who participated in this study. The carrier frequencies of SMA, HL, and thalassemia were 2.11% (294/13926), 4.87% (678/13926), and 8.82% (1228/13926), respectively. In total, 56.47% (1117/1978) of husbands were successfully recalled. The total number of at-risk couples was 111 (111/13926, 0.80%). Further, 47 families underwent prenatal diagnosis. A total of 13 (13/13926; 0.93‰) affected pregnancies were identified.</p><p><strong>Conclusion: </strong>Our findings confirm that SMA, HL, and thalassemia are highly prevalent in Southern Zhejiang, with some regional specificity, as compared with recent large population-based surveys in China. Further, a rapid saliva sample-based non-invasive screening method was established, and its feasibility was demonstrated.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70064"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11847965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483687","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":"Unmasking a Recessive Allele by a Rare Interstitial Deletion at 10q26.13q26.2: Prenatal Diagnosis of MMP21 -Related Disorder and Further Refine INSYN2A Involvement in the Postnatal Cognitive Phenotype.","authors":"Jiasun Su, Shujie Zhang, Wei Li, Yuan Wei, Fei Lin, Chaofan Zhou, Xianglian Tang, Yueyun Lan, Minpan Huang, Qiang Zhang, Shang Yi, Qi Yang, Sheng Yi, Xunzhao Zhou, Zailong Qin, Peng Huang","doi":"10.1002/mgg3.70082","DOIUrl":"10.1002/mgg3.70082","url":null,"abstract":"<p><strong>Background: </strong>The 10q26 microdeletion syndrome (OMIM #609625) is a distinct genomic disorder characterized by a spectrum of clinical features including craniofacial anomalies, developmental delay (DD)/intellectual disability (ID), hypotonia, cardiovascular, and urogenital malformations. Despite the identification of critical regions within 10q26 linked to the syndrome's phenotype, the specific genes responsible for the associated facial characteristics, microcephaly, cognitive issues, and growth deficiencies remain elusive. Interstitial deletions at 10q25.3-q26.3 are rare, and their contributions to 10q26 microdeletion syndrome remain unknown.</p><p><strong>Methods: </strong>We conducted trio-whole-exome sequencing (WES) on a fetus presenting with ventricular septal defect (VSD), aortic span, intrauterine growth retardation (IUGR), and microcephaly. Variant classification was assessed according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, and the causative gene associated with cognitive phenotype was refined by means of smallest regions of overlap (SRO).</p><p><strong>Results: </strong>A homozygous variant c.1544A>G (p.Tyr515Cys) in MMP21 and a large deletion at 10q26.13-q26.2 which unmasked the homozygous mutation were identified in the proband. The maternally inherited 10q26.13q26.2 deletion was classified as likely pathogenic, while the variant c.1544A>G was of uncertain significance (VUS) based on ACMG/AMP criteria. A critical interval of approximately ~500 kb implicating the involving genes DOCK1 and INSYN2A (inhibitory synaptic factor 2A) in the cognitive phenotype of 10q26 microdeletion syndrome was refined.</p><p><strong>Conclusion: </strong>This study introduces a recessive MMP21 mutation unmasked by a rare 10q26.13q26.2 deletion via WES in a Chinese fetus with congenital heart disease (CHD), IUGR, and microcephaly. We further refine INSYN2A as a potential candidate gene for cognitive phenotype in 10q26.1-q26.3 region. Our study also highlights the utility of WES for its advantage in simultaneously analyzing both single nucleotide variants (SNVs) and copy number variants (CNVs) and provide a reference for prenatal diagnosis and genetic counseling in patients with similar conditions.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70082"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458677","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":"The Functions and Implications of MicroRNAs in Premature Ovarian Insufficiency.","authors":"Hui Gao, Xi-Xia Cao, Hua Hua, Hui Zhu","doi":"10.1002/mgg3.70074","DOIUrl":"10.1002/mgg3.70074","url":null,"abstract":"<p><strong>Background: </strong>Premature ovarian insufficiency (POI) is a condition in women characterized by the premature decline of ovarian function before age 40, evident through menstrual irregularities such as amenorrhea or oligomenorrhea, elevated FSH levels exceeding 25 U/L, and a progressive decrease in estrogen levels. Despite considerable research, the exact pathogenic mechanisms underlying POI remain unclear. This study focuses on the role of microRNAs (miRNAs) in the development of POI. As critical regulators of gene expression, miRNAs may play significant roles in diagnosis and the development of innovative therapeutic approaches for POI.</p><p><strong>Methods: </strong>A comprehensive literature search was conducted on PubMed for this review. We included studies published in English up to September 2024. Our search utilized a combination of the following keywords: microRNA, premature ovarian insufficiency (POI), and premature ovarian failure (POF). Articles were filtered by title and subsequently through full-text review, selecting only those pertinent to our topics of interest and their related areas.</p><p><strong>Results: </strong>miRNAs have emerged as critical regulators in POI, mediating a range of biological processes that contribute to the disease's progression. Their involvement offers promising insights for early diagnosis, prognostic assessments, and therapeutic interventions, highlighting their potential as biomarkers and therapeutic targets.</p><p><strong>Conclusion: </strong>Elucidating miRNAs' roles in POI opens new avenues for managing the disease. By understanding how miRNAs influence the molecular mechanisms of POI, innovative strategies can be developed for diagnosis and treatment, potentially improving patient outcomes.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70074"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440917","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":"Loss-of-Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype.","authors":"Christina Del Greco, Molly E Kuo, Desiree E C Smith, Marisa I Mendes, Gajja S Salamons, Marek Nemcovic, Rebeka Kodrikova, Sergej Sestak, Malina Stancheva, Anthony Antonellis","doi":"10.1002/mgg3.70078","DOIUrl":"10.1002/mgg3.70078","url":null,"abstract":"<p><strong>Background: </strong>Mutations in cysteinyl-tRNA synthetase (CARS1) have been implicated in a multisystem disease including microcephaly, developmental delay, and brittle hair and nail phenotypes.</p><p><strong>Methods: </strong>Here, we present a patient with hepatopathy, hypothyroidism, short stature, developmental delay, microcephaly, muscular hypotonia, brittle hair, and ataxia. The patient underwent exome sequencing to identify potentially pathogenic genetic variants. In addition, identified variants were assessed using yeast complementation assays to determine functional consequences.</p><p><strong>Results: </strong>Exome sequencing determined that the patient is compound heterozygous for p.Arg341His and p.Arg370Trp CARS1. Yeast complementation assays showed that the p.Arg341His variant has a hypomorphic effect and that the p.Arg370Trp variant causes a complete loss-of-function effect.</p><p><strong>Conclusion: </strong>This study is the second report of pathogenic CARS1 variants and expands the allelic and phenotypic heterogeneity of CARS1-associated disease.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70078"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440901","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":"Identification and Validation of Biomarkers in Metabolic Dysfunction-Associated Steatohepatitis Using Machine Learning and Bioinformatics.","authors":"Yu-Ying Zhang, Jin-E Li, Hai-Xia Zeng, Shuang Liu, Yun-Fei Luo, Peng Yu, Jian-Ping Liu","doi":"10.1002/mgg3.70063","DOIUrl":"10.1002/mgg3.70063","url":null,"abstract":"<p><strong>Background: </strong>The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing annually. MASH can progress to cirrhosis and hepatocellular carcinoma. However, the early diagnosis of MASH is challenging.</p><p><strong>Aim: </strong>To screen prospective biomarkers for MASH and verify their effectiveness through in vitro and in vivo experiments.</p><p><strong>Methods: </strong>Microarray datasets (GSE89632, GSE48452, and GSE63067) from the Gene Expression Omnibus database were used to identify differentially expressed genes (DEGs) between patients with MASH and healthy controls. Machine learning methods such as support vector machine recursive feature elimination and least absolute shrinkage and selection operator were utilized to identify optimum feature genes (OFGs). OFGs were validated using the GSE66676 dataset. CIBERSORT was utilized to illustrate the variations in immune cell abundance between patients with MASH and healthy controls. The correlation between OFGs and immune cell populations was evaluated. The OFGs were validated at both transcriptional and protein levels.</p><p><strong>Results: </strong>Initially, 37 DEGs were identified in patients with MASH compared with healthy controls. In the enrichment analysis, the DEGs were mainly related to inflammatory responses and immune signal-related pathways. Subsequently, using machine learning algorithms, five genes (FMO1, PEG10, TP53I3, ME1, and TRHDE) were identified as OFGs. The candidate biomarkers were validated in the testing dataset and through experiments with animal and cell models. The malic enzyme (ME1) gene (HGNC:6983) expression was significantly upregulated in MASH samples compared to controls (0.4353 ± 0.2262 vs. -0.06968 ± 0.3222, p = 0.00076). Immune infiltration analysis revealed a negative correlation between ME1 expression and plasma cells (R = -0.77, p = 0.0033).</p><p><strong>Conclusion: </strong>This study found that ME1 plays a regulatory role in early MASH, which may affect disease progression by mediating plasma cells and T cells gamma delta to regulate immune microenvironment. This finding provides a new idea for the early diagnosis, monitoring and potential therapeutic intervention of MASH.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70063"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492983","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":"Effects of a Novel COL4A3 Homozygous/Heterozygous Splicing Mutation on the Mild Phenotype in a Family With Autosomal Recessive Alport Syndrome and a Literature Review.","authors":"Dan Chen, Li Zhang, Jing Rao, Yan Zhou, Lujun Dai, Songsong Huang, Chunxia Yang, Qiuhan Bian, Tao Zhang, Xiaoyan Yang","doi":"10.1002/mgg3.70053","DOIUrl":"10.1002/mgg3.70053","url":null,"abstract":"<p><strong>Background: </strong>Alport syndrome involves chronic progressive kidney failure and extrarenal organ damage caused by COL4A3, COL4A4, and COL4A5 mutations.</p><p><strong>Methods: </strong>We initially discerned a COL4A3 splicing mutation via next-generation sequencing. Next, we used bioinformatics, renal biopsy pathology, and an in vitro minigene experiment. Complementary analysis of clinical data was carried out, and we explored the expression and function of the variants to verify their pathogenicity.</p><p><strong>Results: </strong>A splicing mutation (c.687 + 1G > T) in COL4A3 was found in a Chinese family. Bioinformatics analysis revealed its impact on splicing, causing a translational frameshift, which was confirmed by an in vitro minigene assay. The proband's glomerular basement membrane displayed reduced type IV collagen α3, α4, and α5 chains, with some absent, suggesting disruption of collagen IV trimers in the glomerular basement membrane, potentially damaging the glomerular filtration barrier.</p><p><strong>Conclusion: </strong>We present a novel finding of a previously unreported c.687 + 1G > T mutation in COL4A3 that disrupts transcription and translation, impairing α3α4α5 (IV) chain formation, altering the integrity of the glomerular basement membrane, causing hereditary Alport syndrome. This discovery enriches the genetic map of Alport syndrome, aiding in clinical genetic guidance, and enhancing the efficacy of prenatal testing.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70053"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11807844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382836","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}