BMC Medical Genomics最新文献

{"title":"The prognostic significance and Immunomodulatory role of SCGB3A1 expression in stage I lung adenocarcinoma.","authors":"Xin Zhang, ShiNing Li, Yujin Lv, XinYu Liu, Yong Ao, LeQi Zhong, Yi Hu","doi":"10.1186/s12920-025-02192-7","DOIUrl":"10.1186/s12920-025-02192-7","url":null,"abstract":"<p><strong>Background: </strong>Many early-stage lung adenocarcinoma patients experience recurrence or metastasis after surgery, and the efficacy of targeted therapies remains suboptimal, significantly impacting the prognosis of these patients. Our study aims to investigate the impact of SCGB3A1 on the prognosis of lung adenocarcinoma patients and its role in immunity. We propose that SCGB3A1 may offer a novel treatment approach for lung adenocarcinoma patients who do not respond well to targeted therapies.</p><p><strong>Methods: </strong>We obtained RNA sequencing data from 539 lung adenocarcinoma samples, 59 normal tissues, and 2 metastatic cancer tissues from The Cancer Genome Atlas database. Using Venn diagrams, we analyzed the expression of SCGB3A1 and other differentially expressed genes (DEGs) in different patient groups. Additionally, we performed another Venn diagram analysis to explore the association between SCGB3A1 and immune-related genes. We investigated the relationship between SCGB3A1 expression and patient clinical-pathological data and prognosis. Furthermore, through GO, KEGG, and GSEA enrichment analyses, we explored the functional roles of SCGB3A1 and its association with immune cell infiltration and immune checkpoint genes. The role of SCGB3A1 in LUAD was investigated by cytological experiments.</p><p><strong>Results: </strong>The results indicated that SCGB3A1 is associated with both prognosis and immunity. In lung adenocarcinoma, SCGB3A1 may function as a tumor suppressor gene. The high-expression group of SCGB3A1 exhibited a better prognosis and more pronounced immune cell infiltration. Additionally, SCGB3A1 was associated with smoking status and tumor size. A multivariate Cox regression model suggested that SCGB3A1 expression, pathological type, and ethnicity independently impact patient prognosis. Functional enrichment analysis indicated that SCGB3A1 was related to tumor progression, cell proliferation, and immune suppression. Furthermore, ssGSEA analysis revealed that SCGB3A1 expression is associated with immune cell infiltration and tumor-related immune genes. Experimental validation suggested that the overexpression of SCGB3A1 suppressed cell proliferation, migration, and invasion of LUAD.</p><p><strong>Conclusions: </strong>In summary, this study investigated the association between SCGB3A1 and the prognosis of early-stage lung adenocarcinoma. The findings revealed that SCGB3A1 is related to immune cell infiltration and tumor-related immune gene expression, which may provide insights into the role of SCGB3A1 in immunotherapy. The cytological experiments indicate that SCGB3A1 is a potential therapeutic target for LUAD.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"119"},"PeriodicalIF":2.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681891","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 recurrent ABCC2 c.2439 + 5G > A variant disturbs mRNA splicing and causes Dubin-Johnson syndrome.","authors":"Rongyue Sun, Ting Zhu, Tingmin Zhou, Yanzhao Luo, Tiantian Jiang, Chuangjie Gu, Ruiting Wu, Yue Wang, Fengzhen Xu, Shikang Fan, Dan Wang, Yiming Chen","doi":"10.1186/s12920-025-02187-4","DOIUrl":"10.1186/s12920-025-02187-4","url":null,"abstract":"<p><strong>Background: </strong>Hyperbilirubinemia is the main clinical manifestation of Dubin-Johnson syndrome (DJS), of which most cases can be attributed to the variants in the ABCC2 gene. This study aimed to characterize the mechanism of a splicing variant of the ABCC2 gene and interrogate the variant pathogenicity.</p><p><strong>Methods: </strong>Whole exome sequencing (WES) was performed to identify potential genetic causes. Bioinformatics analysis was performed to predict the variant pathogenicity. Minigene assays were performed to investigate the effects of the identified variant on mRNA splicing. Western blot (WB) experiments were performed to verify the impact of the variant on protein expression. Protein subcellular localization was analyzed by indirect immunofluorescence (IF).</p><p><strong>Results: </strong>Genetic analysis revealed compound heterozygous variants in ABCC2 gene: the splice-site variant c.2439 + 5G > A inherited from the mother and the nonsense variant c.3825 C > G (p.Y1275X) inherited from the father. The recurrent ABCC2 c.2439 + 5G > A variant can affect mRNA splicing which leads to the skipping of exon 18 and induces the loss of 56 native amino acids, resulting in a shortened MRP2 protein (p.Gly758_Lys813del). The c.2439 + 5G > A variant may cause mislocalization of the mutant protein and significantly reduces its expression.</p><p><strong>Conclusion: </strong>Our study identifies c.2439 + 5G > A in ABCC2 as a pathogenic variant underlying DJS through aberrant splicing. Critically, the proband's phenotype resulted from compound heterozygous variants leading to biallelic loss of functional protein. These findings highlight the necessity of comprehensive ABCC2 genetic testing for DJS, facilitating accurate diagnosis and personalized patient management.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"118"},"PeriodicalIF":2.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666997","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":"Genetic etiology of 283 Chinese individuals with epilepsy using copy number variation sequencing and whole exome sequencing: a single-center cohort study.","authors":"Junji Hu, Min Xin, Jinxiu Liu, Hongxing Li, Xuemei Li, Longchang Chen, Ping Yang, Haiyan Zhao, Pengfei Sun, Guodong Gao, Hu Feng, Zhongxia Li, Guang Xiao, Yu Li, Kun Li, Xinsheng Xu","doi":"10.1186/s12920-025-02184-7","DOIUrl":"10.1186/s12920-025-02184-7","url":null,"abstract":"<p><strong>Background: </strong>The genetic etiology of epilepsy is highly heterogeneous and complex. Copy number variation sequencing (CNV-seq) and whole exome sequencing (WES) have emerged as effective tools for identifying genetic causes in patients with unexplained epilepsy. This study aimed to investigate the genetic etiology, evaluate the diagnostic utility of concurrent CNV-seq and WES, and provide evidence for precision medicine and genetic counseling.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study of 283 patients with unexplained epilepsy undergoing WES and 228 patients undergoing CNV-seq, with partial cohort overlap (n = 228). The diagnostic efficiency, its correlation with demographic information, and the clinical impacts of gene diagnostic results on clinical decision-making were assessed.</p><p><strong>Results: </strong>A genetic diagnosis was obtained in 81 patients (28.6%). Among these, 67 (23.7%) had SNVs/Indels, 13 (4.6%) exhibited CNVs, and one (0.3%) displayed dual molecular findings of pathogenic SNV and CNV. The combined approach increased diagnostic yield to 30.7% (70/228) compared to standalone WES (27.9%, 79/283) or CNV-seq (6.1%, 14/228). Trio-based whole exome sequencing (trio-WES) demonstrated a higher diagnostic rate (33.3%, 7/21 vs. 27.5%, 72/262 proband-only WES). The predominant pathogenic genes identified were SCN1A (n = 14), PRRT2 (n = 5), GABRG2 (n = 4), and TSC1 (n = 4). Twenty-four novel SNVs/Indels were identified. Diagnostic yield correlated significantly with early seizure onset [< 3 year: 41.5% vs. ≥3 year: 20.9%; OR (95%CI): 2.685 (1.581-4.560), p = 2.569 × 10^- 4] and the presence of other comorbidities [45.9% vs. 17.4%; OR (95%CI): 4.023 (2.338-6.922), p = 4.950 × 10^- 7]. Genetic findings directly informed anti-seizure medication optimization in 42.0% (34/81) of diagnosed cases.</p><p><strong>Conclusions: </strong>This dual sequencing approach enhances diagnostic yield in unexplained epilepsy, with trio-WES providing incremental yield. The strong genotype-phenotype correlations underscore the prognostic value of molecular diagnosis, while the 42% clinical utility rate highlights its translational relevance. Our findings expand the epilepsy mutational spectrum and enhance genetic understanding of epilepsy.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"117"},"PeriodicalIF":2.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641708","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":"Hereditary kidney disease with auditory abnormalities: analysis of mutations and clinical phenotypes.","authors":"Jingru Bi, Wenkai Guo, Pengcheng Ji, Yuansheng Xie","doi":"10.1186/s12920-025-02178-5","DOIUrl":"10.1186/s12920-025-02178-5","url":null,"abstract":"","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"116"},"PeriodicalIF":2.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636029","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":"Integrated analysis reveals key circRNA-mediated regulatory axes related to prognosis and immune infiltration in lung adenocarcinoma.","authors":"Yan Pei, Kang Lin","doi":"10.1186/s12920-025-02182-9","DOIUrl":"10.1186/s12920-025-02182-9","url":null,"abstract":"<p><strong>Background: </strong>For lung adenocarcinoma (LUAD), the competitive endogenous RNA (ceRNA) networks mediated by circular RNAs (circRNAs) have been partially constructed. However, a mass of networks still need to be thoroughly investigated to uncover novel regulatory axes in LUAD.</p><p><strong>Methods: </strong>Clinical information along with transcriptome data were obtained from open databases. The circRNA-mediated ceRNA subnetworks and a risk score were constructed through layer-by-layer screening and validating. Immune infiltration analysis was performed by CIBERSORT. Quantitative real-time PCR, immunohistochemical analysis, and dual-luciferase reporter assays confirmed the expression and relationships of hub genes.</p><p><strong>Results: </strong>The expression of 9 circRNAs, 81 miRNAs, and 952 mRNAs significantly varied in LUAD tissues. Subsequently, 63 miRNA-mRNA interactions and 3 circRNA-miRNA interactions were employed to generate a ceRNA network. Two prognostic subnetworks mediated by hsa_circ_0072088 and hsa_circ_0049271 were obtained following hub genes screening and survival analysis. Then, a risk score consisting of MMP14 and DCN was successfully constructed and verified using a different dataset. Among the high-risk group, more deaths and poor prognosis occurred. The distribution of immune infiltrating cells varied between high- and low-risk groups, and they were correlated with both the expression of DCN and MMP14 and the risk score.</p><p><strong>Conclusions: </strong>The two key regulatory axes, hsa_circ_0072088/hsa-miR-532-3p/MMP14 and hsa_circ_0049271/hsa-miR-224-5p/DCN, might be involved in carcinogenesis, prognosis and immune infiltration of LUAD.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"115"},"PeriodicalIF":2.1,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12247359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607192","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":"Epidemiological factors associated with the prevalence of mobile genetic elements, and antimicrobial resistance patterns in Klebsiella pneumoniae of farm environments in Bangladesh.","authors":"Md Hafizur Rahman, Sonia Akther, Shihab Ahmed, Md Niamul Shahadat, Md Nuruzzaman Munsi, Abu Bakkar Siddique","doi":"10.1186/s12920-025-02181-w","DOIUrl":"10.1186/s12920-025-02181-w","url":null,"abstract":"<p><p>Farm environments serve as reservoirs for antibiotic-resistant bacteria and mobile genetic elements (MGEs), spreading resistance genes. Klebsiella pneumoniae, a nosocomial opportunistic pathogen, often acquires resistance through MGEs. This study examined the prevalence, resistance patterns, and factors associated with MGEs in K. pneumoniae isolates, focusing on environmental and management practices. 48 pooled samples were collected from environmental niches in three major districts of Bangladesh including Dhaka, Barisal, and Sylhet and analyzed using standard microbiological techniques and PCR. Antibiotic susceptibility was assessed per CLSI (2020) guidelines, and multidrug-resistant (MDR) strains were identified. Genotypic resistance patterns and mobile genetic elements (MGEs), including class 1 integrons and plasmids, were detected via PCR. Fisher's exact test evaluated factors associated with MGEs. Overall, 66.66% tested positive for K. pneumoniae. Regarding resistance patterns, the highest resistance was observed to ertapenem (90.6%) and ampicillin (84%), while complete sensitivity was noted to several antibiotics, including amikacin and tigecycline. Among the tested isolates, 53.12% were identified as MDR. Genotypic analysis revealed that bla_CTX-M, bla_NDM-5,bla_Oxa-1 and bla_Oxa-48 were the most prevalent. Additionally, the presence of MGEs including class 1 integron and IncQ type plasmid were significantly associated with factors such as poor sanitation, antibiotic misuse, and high cattle density, highlighting critical areas for intervention. This study revealed that MDR K. pneumoniae circulates in food animals' farm environments in Bangladesh, with environmental factors strongly linked to the presence of MGEs. Farm niches, particularly soil, act as key reservoirs of MGEs and resistance genes. Importantly, these also carry serious implications for human health, as resistance genes may transfer to clinical settings, exacerbating the burden of AMR. Strengthening environmental and agricultural policies through a One Health approach is essential to mitigate the public health threat posed by antimicrobial resistance.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"114"},"PeriodicalIF":2.1,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574780","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":"Antibiotic resistance genes circulating in Nigeria: a systematic review and meta-analysis from the One Health perspective.","authors":"Emmanuel N Ugbo, Fleischer C N Kotey, Eric S Donkor","doi":"10.1186/s12920-025-02163-y","DOIUrl":"10.1186/s12920-025-02163-y","url":null,"abstract":"","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"113"},"PeriodicalIF":2.1,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574779","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":"Driver mutations and malignant pleural effusion in non-small cell lung cancer.","authors":"Ugur Temel, Onur Derdiyok","doi":"10.1186/s12920-025-02180-x","DOIUrl":"10.1186/s12920-025-02180-x","url":null,"abstract":"<p><strong>Background: </strong>Malignant pleural effusion (MPE) complicates approximately 50% of non-small cell lung cancer (NSCLC) cases, signaling advanced disease and poor patient outcomes. While molecular alterations such as ALK, ROS1, and T790M mutations, as well as PD-L1 expression, are critical in NSCLC progression, their relationship with MPE development remains inadequately characterized.</p><p><strong>Methods: </strong>This retrospective cohort study examined 130 NSCLC patients (52 with MPE, 78 without MPE). Clinical characteristics and comprehensive molecular profiles were analyzed using next-generation sequencing. Statistical comparisons were performed, and a Least Absolute Shrinkage and Selection Operator (LASSO) regularized logistic regression model identified independent predictors of MPE. Model performance was evaluated using receiver operating characteristic (ROC) analysis.</p><p><strong>Results: </strong>PD-L1 expression demonstrated a significant association with MPE development (Odds ratio = 2.78, p < 0.01), nearly tripling the likelihood of effusion. The presence of ALK, ROS1, and T790M mutations (combined OR = 2.41, p < 0.05) also showed predictive value for MPE formation. Several clinical factors independently correlated with MPE, including advanced age, heavy smoking history (> 50 pack-years), and right inferior lobe tumor location (all p < 0.05). The predictive model demonstrated robust performance with an area under the curve of 0.80.</p><p><strong>Conclusions: </strong>These findings establish important associations between specific driver mutations and PD-L1 expression in relation to MPE development in NSCLC patients. Identifying these genetic and clinical predictors may enhance risk stratification approaches and guide personalized treatment strategies, especially for those with advanced disease. Further prospective validation studies are needed to confirm these associations and explore their therapeutic implications.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"112"},"PeriodicalIF":2.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144538016","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 of mitophagy-related biomarkers with immune cell infiltration in psoriasis.","authors":"Shanshan Yu, Fangyuan Long, Hui Yan, Yongfang Xu, Jun Li, Zhimin Hao","doi":"10.1186/s12920-025-02176-7","DOIUrl":"10.1186/s12920-025-02176-7","url":null,"abstract":"<p><strong>Background: </strong>Psoriasis is an inflammatory disorder characterized by scaly erythematous plaques and significant comorbidities. Recent studies have suggested that impaired mitophagy, the cellular mechanism for removing dysfunctional mitochondria, may contribute to the pathogenesis of psoriasis.</p><p><strong>Methods: </strong>In this study, we analyzed bulk RNA sequencing data from 167 healthy individuals and 177 patients with psoriasis obtained from the Gene Expression Omnibus database (GSE30999 and GSE54456). Mitophagy-related genes were isolated using weighted gene co-expression network analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed and protein-protein interaction networks were constructed for the functional enrichment of genes associated with mitophagy. The correlations between genes associated with mitophagy, signaling pathways, and immune cell infiltration were analyzed. The potential diagnostic value of genes associated with mitophagy was evaluated using receiver operating characteristic (ROC) curves, which were validated in imiquimod-induced psoriatic skin lesions in mice.</p><p><strong>Results: </strong>We identified 3,839 differentially expressed genes between healthy individuals and patients with psoriasis, and 23 genes were selected as hub genes showing a high correlation with mitophagy in psoriasis. GO and KEGG analyses revealed that hub and associated genes were significantly correlated with skin functions, such as epidermal development and keratinocyte differentiation. In addition, mitophagy-related genes were negatively associated with pro-inflammatory and pro-proliferation pathways in psoriasis. Among the immune cells, CD4⁺ T cells were most significantly affected by mitophagy-related genes. ROC analysis demonstrated that mitophagy-related genes, especially ACER1, C1ORF68, CST6, FLG2, GJB3, GJB5, GPRIN2, KRT2, and SPRR4 were potential biomarkers of psoriasis for use in diagnosis or treatment.</p><p><strong>Conclusions: </strong>Mitophagy-related genes play crucial roles in psoriasis and have potential use as biomarkers, providing insights into disease mechanisms and therapeutic targets. Further research may lead to the development of new strategies for psoriasis management.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"110"},"PeriodicalIF":2.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144538019","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":"Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene.","authors":"Imad M Dweikat, Hamza A Abdul-Hafez, Alaa Zayed, Moien Kanaan, Hanin Kasem, Rami Bzour","doi":"10.1186/s12920-025-02175-8","DOIUrl":"10.1186/s12920-025-02175-8","url":null,"abstract":"<p><strong>Background: </strong>Beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency (OMIM #203750, *607809) is an autosomal recessive disorder of isoleucine catabolism and ketone body utilization. It is caused by mutations in the ACAT1 gene and characterized by intermittent ketoacidosis episodes triggered by ketogenic stresses, with no clinical symptoms between the episodes. Neurological complications, particularly extrapyramidal signs may occur as sequelae of the ketoacidosis episodes but may also occur without or before any apparent metabolic crisis. T2 deficiency is characterized by the accumulation of isoleucine metabolites, 2methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine, detected in urine organic acids and blood acylcarnitines with or without hypoglycemia.</p><p><strong>Methods: </strong>This study presents data from twelve patients with T2 deficiency, diagnosed between 7 months and 22 months of age at two tertiary care centers in Palestine. The clinical, biochemical, molecular genetic data, and neurological outcomes are reviewed.</p><p><strong>Results: </strong>We report on twelve patients (6 females and 6 males) from eight families in four different regions of the West Bank and Gaza Strip. All patients were offspring of consanguineous marriages. Ketoacidotic episodes were the predominant manifestations in all patients, and each episode was triggered by either acute gastroenteritis or upper respiratory infections. One patient initially presented with hypotonia and psychomotor delay, later developing a ketoacidotic episode a few months afterward. The characteristic laboratory finding in all patients was the increased urinary excretion of 2-methyl-3-hydroxybutyrate and tiglylglycine. Ten of the twelve patients had favorable outcomes, while two unfortunately passed away at the time of the study. Molecular genetic analysis of the ACAT1 gene was conducted on nine patients from six families, revealing four different variants, two of which were novel. Additionally, a founder mutation was identified in six patients from three families.</p><p><strong>Conclusions: </strong>The study underscores the critical role of genetic research in unraveling the complexities of beta-ketothiolase deficiency and related disorders. By identifying haplotype blocks, founder mutations, and novel pathogenic variants, researchers can significantly improve diagnostic precision, enhance genetic counseling, and lay the groundwork for developing targeted therapies. We identified two novel variants and a founder mutation, thereby broadening the genetic spectrum of this rare disease.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"106"},"PeriodicalIF":2.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144538030","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}