Human Gene最新文献

{"title":"Dual high expression of epithelial-mesenchymal transcription factors ZEB1 and ELF3 was inversely correlated with survival of liver cancer patients","authors":"İrem Yalim-Camci ,&nbsp;Pelin Balcik-Ercin","doi":"10.1016/j.humgen.2025.201395","DOIUrl":"10.1016/j.humgen.2025.201395","url":null,"abstract":"<div><div>Liver cancer represents the sixth most prevalent form of cancer globally, with a markedly elevated mortality rate. Despite advancements in molecular diagnostics and therapies, only a few molecular markers are currently utilized in liver cancer diagnosis and treatment. The epithelial-mesenchymal transition (EMT) is a pivotal process during embryonic development and is also observed in pathological contexts such as cancer progression. Mesenchymal- epithelial transition (MET) represents the reverse process of EMT. Recent studies have demonstrated that cancer cells exhibit heightened aggressiveness when they acquire a hybrid epithelial/mesenchymal phenotype. Major transcription factors regulate EMT and MET processes. This study examined the expression of EMT-inducing transcription factors (ZEB1, TWIST, SNAI1) and MET-inducing transcription factors (GRHL2, ELF3, OVOL1) to gain insight into hybrid epithelial/mesenchymal states in liver cancer. A strong positive correlation was observed between <em>ZEB1</em> and <em>ELF3</em>, as well as <em>SNAI1</em> and <em>GRHL2</em> gene expressions. Protein analyses revealed the highest correlation between ZEB1 and ELF3. Furthermore, high- expression groups of <em>ZEB1</em> and <em>ELF3</em> were associated with significantly lower survival rates compared to low-expression groups. These findings suggest that dual expression of ZEB1 and ELF3 could serve as a potential diagnostic marker in liver cancer.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"44 ","pages":"Article 201395"},"PeriodicalIF":0.5,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143534367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PLA2G6 and NOTCH3 variants associated with familial Parkinson's disease in two suspected families based on whole genome sequencing","authors":"Shima Abbasnejad,&nbsp;Zahra Rezvani","doi":"10.1016/j.humgen.2025.201393","DOIUrl":"10.1016/j.humgen.2025.201393","url":null,"abstract":"<div><h3>Introduction</h3><div>Parkinson's disease is a progressive, destructive, and long-term disorder of the central nervous system that mainly disrupts the movement system of the body. In the advanced stages of Parkinson's disease, sometimes dementia is also common. In the present study, two patients from two families of five suspected to have Parkinson's disease were investigated to identify pathogenic variants.</div></div><div><h3>Methods and materials</h3><div>After confirmation by a neurologist and a geneticist, blood samples were taken. Then DNA was extracted from the target sample and analyzed by exome sequencing. The VCF file of WES was extracted using the databases 1000 Genomes, EXAC, NHLBI Sequencing project, GMA variom, HIX (Healthy Exoues), CAD and also with the help of bioinformatics analysis using the HGMD site, all the genes and mutations of this disease were extracted. Then, using the POLY PHEN and SIFT sites, the effect of mutations in causing the disease was investigated separately.</div></div><div><h3>Results</h3><div>In total, we obtained 3420 variants. After several stages of filtering, 181 variants were reported in 11 genes related to Parkinson's disease, of which 4 variants were new. Two variants related to the PLA2G6 gene and 2 variants related to the NOTCH3 gene, were introduced as pathogenic variants after data analysis using Finch TV software with the help of trench sequencing of NOTCH3 and PLA2G6 gene variants.</div></div><div><h3>Conclusion</h3><div>It was conducted that the variant reported as heterozygous mutations in NOTCH3 and PLA2G6 genes can be related to the occurrence of Parkinson's disease.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"44 ","pages":"Article 201393"},"PeriodicalIF":0.5,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential Anticancer Effect of Thymoquinone on Glioblastoma Cancer Cells through Alteration in CTSB and CTSD Gene Expression Level","authors":"Omid Hosseini ,&nbsp;Fatemeh Ataellahi ,&nbsp;Raheleh Masoudi","doi":"10.1016/j.humgen.2024.201374","DOIUrl":"10.1016/j.humgen.2024.201374","url":null,"abstract":"<div><h3>Background</h3><div>Glioblastoma is one of the most aggressive and rapidly growing brain tumors. Current therapeutic approaches have proven largely ineffective in treating this malignancy, resulting in a very low survival rate. Accordingly, finding new therapeutic strategies seems inevitable. Recently, some molecular mechanisms that help cancer cells survive, and grow have been elucidated, and targeting critical molecules involved in these processes brings new hopes to cancer treatment. CTSB and CTSD are two important proteins associated with invasion, angiogenesis, and metastasis, which are overexpressed in glioblastoma. A considerable body of evidence demonstrated that Thymoquinone, the main bioactive component of black seeds, has anticancer power against a range of various cancers. The current experiment was designed to determine whether TQ can modulate the mRNA expression level of <em>CTSB</em> and <em>CTSD</em> in glioblastoma cells.</div></div><div><h3>Methods</h3><div>An in vitro study was conducted and relative mRNA level of <em>CTSB</em> and <em>CTSD</em> were assessed using quantitative real-time RT-RCR in U87MG cells treated with 30 or 60 μM concentrations of TQ at two time points; 12 and 24 h post-exposure to capture dynamic changes in gene expression at early and mid-phase intervals.</div></div><div><h3>Results</h3><div>Although there was no reduction in the relative expression of <em>CTSB</em> and <em>CTSD</em> in cells exposed to TQ for 12 h, the mRNA level of both genes significantly decreased at 60 μM of TQ after 24 h exposure.</div></div><div><h3>Conclusion</h3><div>The data presented revealed that at certain concentration and time point, TQ effectively targets two key genes involved in metastasis. Thus, it can be concluded that TQ holds potential as a promising candidate for glioblastoma treatment.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"43 ","pages":"Article 201374"},"PeriodicalIF":0.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143143810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on doi.org/10.1016/j.humgen.2024.201316 publication entitled “Germline mutations of the putative tumor suppressor gene PTEN/MMAC1 as molecular biomarker in prostate cancer”","authors":"Thomas Pepper ,&nbsp;Madhuri Hegde","doi":"10.1016/j.humgen.2024.201369","DOIUrl":"10.1016/j.humgen.2024.201369","url":null,"abstract":"","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"43 ","pages":"Article 201369"},"PeriodicalIF":0.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143144020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-oxidant and anti-inflammatory action of calorie restriction and quercetin in two age groups of rats: Involvement of thioredoxin and heme oxygenase-1","authors":"Nima Mahdei Nasirmahalleh ,&nbsp;Mina Hemmati ,&nbsp;Fereshteh Ghorbani","doi":"10.1016/j.humgen.2024.201363","DOIUrl":"10.1016/j.humgen.2024.201363","url":null,"abstract":"<div><h3>Background</h3><div>Aging associated with an increase in free radicals, inflammatory factors and oxidative stress. This study aimed to investigate potential of calorie restriction (CR) and quercetin (QUER) in alleviating oxidative stress and inflammation in aging.</div></div><div><h3>Methods</h3><div>Two age groups of male Wistar rats (8 and 20 weeks) were included in the study and subdivided to normal diet (ND), ND with QUER (15 mg Kg⁻¹, IP), ND with CR, and ND with QUER and CR groups.</div></div><div><h3>Results</h3><div>We showed higher expression of Tumor Necrosis Factor alpha (TNF-α) in 20-week-old rats compared with 8-week-old rats, and the administration of QUER and CR for 4 weeks restored this value to the normal range. The expression of heme oxygenase-1 (HO-1) and thioredoxin (TXN) are also affected by CR and QUER. CR alone and in combination with QUER significantly raised the expression of the TXN and HO-1 genes. Also, CR alone and in combination with QUER significantly reduced thioredoxin-interacting protein (TXNIP) gene expression.</div></div><div><h3>Conclusions</h3><div>QUER and CR jointly improved the adverse impacts of aging through the regulation of antioxidant signaling pathways, indicating the potential of this blend as a supplementary therapeutic approach for aging and age-related ailments.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"43 ","pages":"Article 201363"},"PeriodicalIF":0.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143143785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidation of potential miRNAs as prognostic biomarkers for coronary artery disease","authors":"Summan Thahiem ,&nbsp;Malik Faisal Iftekhar ,&nbsp;Muhammad Faheem ,&nbsp;Ayesha Ishtiaq ,&nbsp;Muhammad Ishtiaq Jan ,&nbsp;Riaz Anwar Khan ,&nbsp;Iram Murtaza","doi":"10.1016/j.humgen.2025.201385","DOIUrl":"10.1016/j.humgen.2025.201385","url":null,"abstract":"<div><div>Coronary Artery Disease (CAD) is a cardiovascular disorder characterized by narrowing of arteries due to metabolic dysregulations, which severely impedes blood flow through cardiac tissues. Genetic factors significantly contribute to the susceptibility of CAD and miRNAs play a crucial role in gene expression and regulation. In this study, we aim to identify highly specific miRNA-mRNA interactions and gene targets by employing machine learning approaches such as association rules mining (ARM) and singular value decomposition (SVD), followed by differential expression analysis of microarray datasets. For this, genes associated to CAD and its lethal sequelae (valvular heart disease, fibrosis, atherosclerosis, hyperlipidemia, oxidative stress and inflammation) were obtained from databases i-e., <em>National Center for Biotechnology Information</em>, Genetic Testing Registry (GTR). Highly conserved miRNAs were selected using bioinformatics repositories TargetScan, miRBase, and miRanda. Furthermore, ARM and SVD were utilized to discover significant association patterns and frequently occurring miRNAs. For the validation of hub miRNAs, differential expression analysis was carried out on two independent cohorts of miRNA expression datasets of cardiac patients. This integrated approach identified 3 hub miRNAs (miR-200a-3p, miR-32-5p and miR-92-3p). Functional enrichment analysis revealed their involvement in diabetes, cholesterol metabolism, inflammation, and atherosclerosis. Moreover, disease enrichment analysis showed their association with heart diseases, vascular diseases, and endothelial dysfunction. Conclusively, this is the first study that employed ARM and SVD approaches to identify hub miRNAs and novel gene targets involved in CAD. The identification of these miRNAs as putative biomarkers may lead to a more accurate prognostic score for early detection of CAD.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"43 ","pages":"Article 201385"},"PeriodicalIF":0.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143264831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LDLR variants and structure-function predictions of protein models related to familial hypercholesterolemia in Vietnam","authors":"Ngoc-Thanh Kim ,&nbsp;Doan-Loi Do ,&nbsp;Mai-Ngoc Thi Nguyen ,&nbsp;Hong-An Le ,&nbsp;Thanh-Tung Le ,&nbsp;Thanh-Huong Truong","doi":"10.1016/j.humgen.2025.201381","DOIUrl":"10.1016/j.humgen.2025.201381","url":null,"abstract":"<div><div>Here, we explore familial hypercholesterolemia (FH) in the Vietnamese population which is an understudied FH ethnicity, addressing genetic and clinical variability to improve personalized healthcare. Utilizing next-generation sequencing (NGS), Multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, 103 FH cases from the Vietnam Familial Hypercholesterolemia (VINAFH) Program were analyzed, identifying 21 low-density lipoprotein receptor (LDLR) variants in 39.8 % of the patients, including 3 novel variants. Advanced computational modeling was used to obtain insights into the biological impact of these mutations. Most variants (81 %) were located in ligand-binding and Epidermal growth factor (EGF) homology domains, critical for LDLR-LDL binding and subsequent clearance. Disruptive mutations in these domains (<em>e.g.</em>, Gln660Ter, Cys104Tyr, Cys318Arg), impaired LDLR function by destabilizing protein structure, reducing solvent-accessible surface area, and increasing root-mean-square deviation (RMSD) values, which weakened receptor-ligand interactions, leading to elevated plasma LDL-C levels. Notably, Asp227Glu enhanced stability without functional impairment, indicating mutation-specific effects. Mutations in transmembrane and cytoplasmic domains, such as Val797Met and Gly844Ser, disrupted intracellular signaling and receptor recycling, further compromising LDL clearance. Molecular dynamics simulations revealed dynamic instabilities in mutants carrying Ser586Pro and His583Tyr, linking structural flexibility and misfolding to impaired LDLR-LDL binding and trafficking (critical processes in cholesterol homeostasis). We established genotype-phenotype relationships, with homozygous FH (HoFH) and compound heterozygous FH (cHeFH) patients exhibiting more severe symptoms, including significantly higher LDL-C levels and premature atherosclerotic cardiovascular disease (ASCVD), compared to heterozygous FH (HeFH) patients. HoFH patients showed average LDL-Cholesterol (LDL-C) levels (14.83 mmol/L), consistent with severe receptor dysfunction. Variability in plasma LDL-C levels among mutation carriers and non-carriers highlights population-specific clinical diversity and suggests influence of genetic and non-genetic factors.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"43 ","pages":"Article 201381"},"PeriodicalIF":0.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143144836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential modifier genes for cystic fibrosis disease","authors":"Hajra Aqeel ,&nbsp;Muhammad Usman Ghani ,&nbsp;Zartashay Naeem ,&nbsp;Farheena Iqbal Awan ,&nbsp;Muhammad Umer Khan ,&nbsp;Shazia Tanveer ,&nbsp;Nauman Chaudary ,&nbsp;Rehan Sadiq Shaikh","doi":"10.1016/j.humgen.2025.201377","DOIUrl":"10.1016/j.humgen.2025.201377","url":null,"abstract":"<div><h3>Background</h3><div>Cystic Fibrosis (CF) is a genetic disease caused primarily by mutations in the <em>CFTR</em> gene. However, CF patients with the same mutations in the CFTR gene can manifest the disease with varying severity, likely due to the role of modifier genes.</div></div><div><h3>Methodology</h3><div>To uncover the underlying non-<em>CFTR</em> genetic factors, we compiled a list of CF modifier genes through an extensive literature review and conducted pathway enrichment analysis using ENRICHR and DAVID tools to understand their biological significance and functional roles in CF disease. We also used the STRING tool to explore the protein-protein interaction of genes identified by pathway enrichment analysis with the CFTR gene.</div></div><div><h3>Results</h3><div>The literature review identified 36 CF modifier genes: <em>GSTM1, IL10, SLC26A9, IL1B, MUC6, CLC-2, CXCL8/IL8, EDNRA, DCTN4, SLC9A3, ADRB2, AGER, EZR, HLAII, HFE, CFTR, IFRD1, CAV1, PRKAR2B, PPP2R4, MBL2, EHF, SCNN1A, SERPINA1, AHSAI, SNAP23, SCNN1B, SCNN1G, PRSS8, SLC9A3R1/NHERF1, KRT19, Nedd4L, TGFB1, CALR, SLC6A14, MMP9 and MIF.</em> Pathway enrichment analysis predicted three key pathways linked to CF and enriched with 13 modifier genes. Furthermore, the STRING tool predicted that six out of the thirteen modifier genes (SLC9A3R1, EZR, ADRB2, SERPINA1, IL1B, and IFRD1<em>)</em> interact with <em>CFTR</em>, indicating a complex network of functional relationships supported by various evidence.</div></div><div><h3>Conclusion</h3><div>This research identified 36 modifier genes associated with cystic fibrosis, alongwith three key pathways enriched with 13 of these genes. Six of these genes were found to have a complex network of interactions with CFTR genes, highlighting their probable role as CF modifier genes.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"43 ","pages":"Article 201377"},"PeriodicalIF":0.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143143789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulation of miR-1269a pronounces breast cancer bone metastasis","authors":"Smit Patel ,&nbsp;Ishita Agarwal ,&nbsp;Nishita Adnani ,&nbsp;Deepshikha Rathore ,&nbsp;Nandani Dharwal ,&nbsp;Nirali Shukla ,&nbsp;Heena V. Dave","doi":"10.1016/j.humgen.2025.201380","DOIUrl":"10.1016/j.humgen.2025.201380","url":null,"abstract":"<div><div>Breast cancer (BC) is the most prevalent cancer among women globally. Metastasis poses a significant challenge for BC patients and its complete mechanism is yet to be discovered. Bone is one of the most common sites for metastasis in BC patients, making early diagnosis of bone metastasis necessary. To identify potential biomarkers for early diagnosis, we analyzed transcriptomic data from The Cancer Genome Atlas (TCGA) database, focusing on differentially expressed microRNAs. Among the screened miRNAs, miR-1269a was significantly downregulated based on log2 FC ±2 and adjusted <em>p</em>-value ≤0.05. Receiver operating curve (ROC) analysis revealed that miR-1269a could effectively distinguish between bone-metastatic and primary breast cancer patients. Additionally, we found a significant downregulation of miR-1269a in metastatic breast cancer cells (MDA-MB-231) compared to non-metastatic breast cancer cells (MCF-7). TargetScan and miRDB were used to identify targets of miR-1269a, leading to a focus on cyclin D1 (CCND1), a cell cycle regulator gene, significantly overexpressed in primary breast cancer patients. Overall, this study uncovers the unique role of hsa-miR-1269a as a biomarker associated with the biological and transcriptional processes in bone metastasis in breast cancer. The study also identifies a novel miRNA-mRNA axis, miR-1269a-CCND1, which possesses a potential biomarker role in BC patients with Bone metastasis.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"43 ","pages":"Article 201380"},"PeriodicalIF":0.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143144019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and functional characterization of two novel SRD5A2 variants in Iranian siblings with 5α-reductase type 2 deficiency: Expanding the mutational spectrum and implications for genetic diagnosis","authors":"Mahtab Ordooei ,&nbsp;Nasrin Zamani ,&nbsp;Bahareh Rabbani ,&nbsp;Nejat Mahdieh","doi":"10.1016/j.humgen.2025.201389","DOIUrl":"10.1016/j.humgen.2025.201389","url":null,"abstract":"<div><div>Disorders of sex development (DSD) represent a diverse group of congenital conditions that disrupt the typical development of sexual tissues due to various genetic anomalies. Among these, 5α-reductase type 2 deficiency, caused by mutations in the <em>SRD5A2</em> gene, impairs the conversion of testosterone to dihydrotestosterone (DHT), essential for male genital differentiation. In this study, we describe two sisters from an Iranian consanguineous family, both presenting with 46,XY DSD due to two novel variants in <em>SRD5A2</em> gene.</div><div>Clinical evaluations, biochemical testing, and karyotyping were conducted for the patients. Clinical evaluations, including karyotyping and biochemical analyses, revealed a 46,XY karyotype and significantly elevated testosterone-to-DHT ratios in both patients, raising suspicion of 5α-reductase deficiency. The coding regions of the <em>SRD5A2</em> gene were sequenced for the affected siblings and their parents, and a thorough search using targeted keywords was conducted to identify previously reported intronic variants in this gene.</div><div>Molecular genetic testing identified two novel homozygous variants in the <em>SRD5A2</em> gene: c.314G&gt;C, p.(Arg105Thr) and c.445+5G&gt;C. Segregation analysis confirmed that the parents were heterozygous carriers for these variants. In silico predictions and bioinformatics analyses suggest that the p.(Arg105Thr) variant destabilizes the protein structure, alters its charge, and increases its molecular flexibility, likely contributing to the disease phenotype. Additionally, the c.445+5G&gt;C variant, located within a splice motif, may disrupt normal splicing, further implicating it in the pathogenesis of the disorder. To date, twelve intronic variants have been reported in <em>SRD5A2</em>, suggesting that intronic mutations may significantly impact its function.</div><div>This study underscores the importance of early genetic diagnosis in DSD, particularly in populations with high rates of consanguinity, to enable timely intervention. The novel variants reported here expand the mutational spectrum of <em>SRD5A2</em> and highlight the utility of comprehensive genetic and bioinformatic analyses in understanding the molecular underpinnings of DSD.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"43 ","pages":"Article 201389"},"PeriodicalIF":0.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143377829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}