BMC Medical Genomics最新文献

{"title":"Identification and growth features of developmental delay with macrocephaly caused by a novel TRIO variant affecting the second SH3 domain.","authors":"Si-Yuan Zhang, Jie-Yuan Jin, Lei Zeng, Rui-Chao Niu, Xia Wang","doi":"10.1186/s12920-026-02422-6","DOIUrl":"https://doi.org/10.1186/s12920-026-02422-6","url":null,"abstract":"<p><strong>Background: </strong>Trio Rho guanine nucleotide exchange factor (TRIO) encodes the guanine nucleotide exchange factor (GEF) for RHOA and RAC1 GTPases, which plays a critical role in neurodevelopment. Pathogenic variants in the TRIO gene are predominantly associated with two autosomal dominant neurodevelopmental disorders: intellectual developmental disorder 44 with microcephaly (MRD44) and intellectual developmental disorder 63 with macrocephaly (MRD63). However, the genotype-phenotype correlation of TRIO-related disorders and the impacts of TRIO variants on early-life disease progression remain unclear.</p><p><strong>Methods: </strong>In this study, we recruited a male infant with developmental delay and macrocephaly and chronologically detailed his growth from birth. Whole-exome sequencing was performed to identify genetic variants; three-dimensional protein modeling was employed to assess the pathogenicity of these variants, and previously reported TRIO variants were summarized.</p><p><strong>Result: </strong>We identified a novel TRIO missense variant (NM_007118.4: c.7738 A > T, p.I2580F; chr5:14492781 A > T/hg19) in the patient, and the variant was positioned in the second Src homology 3 (SH3) domain. Bioinformatic and three-dimensional protein modeling evidence all support the p.I2580F variant as likely pathogenic. Additionally, we systematically collated and summarized previously reported TRIO gene variants.</p><p><strong>Conclusion: </strong>Our findings broaden the variant landscape of TRIO, establish a correlation between macrocephaly and TRIO variants within the second SH3 domain, provide the first detailed growth chart for a patient with TRIO-associated macrocephaly, and deepen our understanding of developmental impairments attributed to TRIO variants.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410177","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":"Whole exome sequencing uncovers genetic syndromes and putative candidate genes underlying orofacial clefts presenting with limb abnormalities in a Sub-Saharan African cohort.","authors":"Edna Tackie, Solomon Obiri-Yeboah, Gideon Okyere Mensah, Tamara D Busch, Bruce Tsri, Daniel Kwesi Sabbah, Christian Opoku Asamoah, Alexander Acheampong Oti, Gyikua Plange-Rhule, Adebowale A Adeyemo, Peter Donkor, Azeez Butali, Lord Jephthah Joojo Gowans","doi":"10.1186/s12920-026-02426-2","DOIUrl":"10.1186/s12920-026-02426-2","url":null,"abstract":"<p><strong>Background: </strong>Orofacial clefts (OFCs) are the most frequent congenital craniofacial anomalies that occur during embryonic development. The incidence is ~ 1 in 700 live births, and it may occur in isolation or with other abnormalities, such as limb deformities. Congenital limb malformations are the second most prevalent birth defect, affecting 1 per 500 to 1000 live births. It can also occur in isolation or as part of a syndrome. This study investigated the genetic etiology of OFCs co-occurring with limb abnormalities in a Sub-Saharan African cohort.</p><p><strong>Methods: </strong>Nine unrelated probands with concurrent OFC and limb anomalies were recruited, including one multiplex family involving an affected mother and proband. Whole exome sequencing (WES) was performed at 100X on DNA samples from affected families, utilising a paired-end configuration on the Illumina HiSeq platform. Variant calling utilized the Sentieon workflow. Rare, deleterious variants were identified in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines on variant classification. De novo and other variants predicted as pathogenic were prioritized based on all possible Mendelian inheritance patterns, including variable penetrance and expressivity. Pathway enrichment analysis, protein-protein interactions, and gene expression analysis were undertaken to decipher the biological functions of implicated genes.</p><p><strong>Results: </strong>All cases were syndromic, presenting with preaxial and postaxial limb anomalies along with other craniofacial features. WES revealed plausible pathogenic variants in pleiotropic genes (TP63, NIPBL, MYH3, and FGFR2) in four simplex cases. In four other simplex probands, multiple rare variants were identified in developmentally relevant genes (e.g., RGPD5, FAM90A26, FOXD4L1, FAM170A, TRIM74, TRIM73, and PRDM9) necessary for normal craniofacial and limb development. The multiplex family had two affected individuals (the mother and the proband), both carrying a TP63 variant, consistent with autosomal dominant inheritance with variable expressivity. Most of the observed variants were de novo, with some being novel. Functional genomic analysis supported the craniofacial relevance of the implicated genes.</p><p><strong>Conclusion: </strong>While some cases can be attributed to single-gene syndromes (e.g., NIPBL-associated Cornelia de Lange Syndrome), others may result from multiple co-occurring syndromes. These findings may inform recurrence risk estimates, genetic counselling, and clinical management if validated across multiple populations.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403536","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":"Integrated transcriptomic and metabolomic analysis identifies a core gene-metabolite network linking lysine degradation and propanoate metabolism to psoriasis pathogenesis.","authors":"Hongkai Zheng, Rujun Xue, Wei Li, Xiaonan Sima, Jingyao Liang, Sanquan Zhang","doi":"10.1186/s12920-026-02420-8","DOIUrl":"https://doi.org/10.1186/s12920-026-02420-8","url":null,"abstract":"<p><strong>Background: </strong>Psoriasis is a complex chronic inflammatory disease with cutaneous manifestations, driven by intricate interactions between genetic, immunological, and metabolic dysregulations. However, the integrated molecular networks connecting transcriptional alterations to metabolic reprogramming remain incompletely elucidated.</p><p><strong>Methods: </strong>We performed a comprehensive integrated analysis of transcriptomics and targeted metabolomics using serum samples from 11 psoriasis vulgaris patients and 11 healthy controls to dissect the core gene-metabolite regulatory axes underlying psoriasis.</p><p><strong>Results: </strong>RNA sequencing identified 5,186 differentially expressed genes (DEGs), with a striking predominance of downregulation (5,147 DEGs), and targeted metabolomic profiling detected 208 significantly altered metabolites, including upregulated propanoic acid and downregulated L-allysine. KEGG pathway enrichment analysis revealed six dysregulated metabolic pathways shared by DEGs and altered metabolites, notably lysine degradation, propanoate metabolism, and central carbon metabolism in cancer-with the latter identified as a novel pathogenic pathway in psoriasis vulgaris. Weighted Gene Co-expression Network Analysis (WGCNA) further delineated strong correlations between core genes (TP53, MTOR, AKT3) and key metabolites (propanoic acid, L-allysine), forming a functional network that links cellular energy metabolism to immune-inflammatory responses. Protein-protein interaction network analysis confirmed these core genes as hub regulators within the dysregulated pathways.</p><p><strong>Conclusion: </strong>In this exploratory pilot study, integrated transcriptomic and metabolomic profiling revealed preliminary associations between lysine degradation, propanoate metabolism, and psoriasis status. The observed crosstalk with central carbon metabolism, potentially involving TP53, MTOR, and AKT3, generates hypotheses that require validation in independent, larger cohorts before any clinical or mechanistic inferences can be drawn.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403480","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":"Construction and validation of a lncRNA/circRNA-miRNA-mRNA ceRNA network in allergic rhinitis pathogenesis.","authors":"Shaojie Zhang, Molu Ban, Rong Wang, Min Li, Min Shi, Jingjin Weng, Shenhong Qu","doi":"10.1186/s12920-026-02423-5","DOIUrl":"https://doi.org/10.1186/s12920-026-02423-5","url":null,"abstract":"<p><strong>Background: </strong>The lncRNA/circRNA-miRNA-mRNA interaction constructs a competing endogenous RNAs (ceRNAs) network, which is closely related to inflammation. However, their roles in allergic rhinitis (AR) remain unclear. In this study, we investigated the regulatory role of ceRNA networks in AR pathogenesis by analyzing long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), then constructing a lncRNA/circRNA-miRNA-mRNA interaction network.</p><p><strong>Methods: </strong>An AR mouse model was established using ovalbumin (OVA). Pathological examination was performed on the nasal mucosa of the mice, and ELISA was conducted on the mouse serum. High-throughput sequencing was used to analyze the expression profiles of lncRNAs, circRNAs, miRNAs, and mRNAs in the nasal mucosa of AR mice. A fold change > 2 and a q-value < 0.05 were used to identify the significantly differentially expressed (DE) lncRNAs, circRNAs, miRNAs, and mRNAs in AR. Then, bioinformatics and statistical methods were used to construct ceRNA networks, while RT-PCR was employed to validate RNA seq results.</p><p><strong>Results: </strong>A total of 216 mRNAs, 241 lncRNAs, 659 circRNAs, and 19 miRNAs were identified as significantly differentially expressed. Among them, 145 mRNAs were up-regulated and 71 were down-regulated; 138 lncRNAs were up-regulated and 103 were down-regulated; 304 circRNAs were up-regulated and 355 were down-regulated; 16 miRNAs were up-regulated and 3 were down-regulated. Additionally, 223 miRNA -mRNA pairs, 50 miRNA-lncRNA pairs, and 17 circRNA-miRNA pairs were obtained, and a network diagram of lncRNA/circRNA-miRNA-mRNA pairs was drawn. Functional enrichment analysis based on the ceRNA network confirmed that lncRNAs are involved in the regulation of the Wnt signaling pathway, ECM-receptor interaction, and the PI3K-Akt signaling pathway. In contrast, circRNAs are implicated in the modulation of adipocyte lipolysis, as well as ECM-receptor interactions and protein digestion and absorption. Some DE-lncRNAs and DE-mRNAs determined by RNA sequencing were verified by RT-PCR, and their trends were similar to those observed in RNA seq.</p><p><strong>Conclusion: </strong>We established a ceRNA network based on lncRNA/circRNA-miRNA-mRNA interactions for AR, providing a solid foundation for future investigations into its underlying molecular mechanisms and the identification of novel drug targets.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395794","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":"Genetic architecture of patients with autism spectrum disorder - data analysis based on the literature review.","authors":"Gabriela Ręka, Katarzyna Wojciechowska, Monika Lejman","doi":"10.1186/s12920-026-02424-4","DOIUrl":"https://doi.org/10.1186/s12920-026-02424-4","url":null,"abstract":"<p><strong>Background: </strong>Autism spectrum disorder (ASD) is a neurodevelopmental condition including incorrect functioning in communication, social interaction, and repetitive behavior. Global prevalence is estimated as 1-2%, with a predominance of men. Different pre- and perinatal, environmental, immunological, neurobiological, genetic, and epigenetic factors are involved in the etiology of ASD. The study aims to analyze genetic abnormalities in patients with ASD according to data from the current literature.</p><p><strong>Materials and methods: </strong>Studies available in the PubMed and Google Scholar databases were chosen through a literature search. Only papers published from 2020, available as full-text publications in English, with studies conducted on humans, original papers, or meta-analyses were included.</p><p><strong>Results and discussion: </strong>The following types of genetic variation were identified: copy number variants, larger insertions, inversions, uniparental disomies, tandem repeat expansions, common single nucleotide polymorphisms, single nucleotide variants, short insertions/deletions, and mitochondrial variants. Epigenetic factors, like histone modifications, deoxyribonucleic acid (DNA) methylation, and micro ribonucleic acid might play an important role in ASD predisposition. Genes identified in the review were mainly involved in neurodevelopment, synaptic formation, neuronal migration, neurotransmission, glial proliferation, ubiquitination, chromatin remodeling, or transcription. ASD is described as a component of the phenotype in fragile X syndrome, tuberous sclerosis complex, neurofibromatosis type 1, Angelman, Phelan-McDermid, Smith-Lemli-Opitz syndromes, and chromosome trisomies. Current guidelines for genetic diagnosis of ASD recommend performing directed genetic studies in the first line (like multiplex ligation-dependent probe amplification - MLPA, analysis of FMR1 gene), in case of a negative result, chromosomal microarray as a routine method, then next-generation sequencing (NGS) panel testing, WES (whole exome sequencing), or even WGS (whole genome sequencing) as the last test.</p><p><strong>Conclusions: </strong>Wider access to modern diagnostic methods has increased the number of ASD patients in whom the genetic etiology of the disorder has been uncovered. Knowledge of the genetic background would be applicable in the diagnosis, prevention, prognosis, and individualized treatment.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387196","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":"Elective genomic sequencing for adults in research, clinical and commercial contexts.","authors":"Michael D Linderman, Sophia M Adelson, Tala M Berro, Jennifer L Anderson, Scott D Crawford, Tshaka J Cunningham, Edward D Esplin, Altovise T Ewing-Crawford, Daiva E Nielsen, Stacey Pereira, Tara Schmidlen, Heather Andrighetti, Steven B Bleyl, George M Church, Eden V Haverfield, Madhuri Hegde, Lazaridis N Konstantinos, Paul Kruszka, Debra Leonard, Thomas May, Molly McGinniss, Vaibhav Pandya, Eric E Schadt, Bastian Greshake Tzovaras, Bethany Zettler, Amy L McGuire, Robert C Green","doi":"10.1186/s12920-026-02414-6","DOIUrl":"10.1186/s12920-026-02414-6","url":null,"abstract":"<p><strong>Purpose: </strong>Elective genomic sequencing (EGS) returns monogenic disease findings in multiple genes, including potentially novel variants, and may also provide participants with carrier status, pharmacogenomic and other health-related information. The PeopleSeq Study assessed participants' motivations for and concerns about EGS and the associated clinical and psychosocial outcomes across diverse EGS providers.</p><p><strong>Methods: </strong>We administered a shared questionnaire to participants who chose to undergo EGS via 18 academic, clinical, or commercial EGS platforms.</p><p><strong>Results: </strong>We enrolled 1575 participants, of whom 1147 (72.8%) completed a questionnaire after receiving their EGS results. A majority (60.3%) of the participants who completed a post-result questionnaire self-reported receiving results they assessed as important, including negative findings, and 75.9% reported a form of health-related utility. Among a subset (19.4%) who shared their EGS reports, 16.6% (37 of n = 223) received a monogenic finding and self-reported results deemed \"important\" were consistent with EGS reports. Most participants (74.1%) discussed their results with their family, but fewer discussed their results with a healthcare provider other than the site team (41.7%) or had one or more medical visits as a direct result of their EGS testing (23.1%). Participants expressed diverse motivations for EGS, with 91.4% expressing interest in their personal disease risk and 54% who expressed quasi-indication-based motivations related to family medical history. Individuals motivated by family history reported important results at a significantly higher rate.</p><p><strong>Conclusions: </strong>Early adopters of EGS are motivated by general interest in their health as well as quasi-indication-based considerations such as family history. A majority of participants learned results they considered medically important, but a much smaller segment engaged healthcare providers with their results.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381415","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":"Role of the PTPN22 C1858T (R263Q) variant in tuberculosis susceptibility: genetic and functional evidence from a South Asian cohort.","authors":"Fasihat Ul Ain, Faheem Shahzad, Shah Jahan, Khursheed Javed, Romeeza Tahir, Hasnain Javed, Rabia Siddiqua","doi":"10.1186/s12920-026-02409-3","DOIUrl":"https://doi.org/10.1186/s12920-026-02409-3","url":null,"abstract":"<p><strong>Background: </strong>The PTPN22 gene encodes Lyp, a phosphatase involved in downregulating T-cell receptor signaling and modulating immune homeostasis. Although PTPN22 polymorphisms rs2476601 (R620W) and rs33996649 (R263Q) are associated with autoimmune diseases, their role in infectious diseases such as tuberculosis susceptibility remains unclear.</p><p><strong>Objective: </strong>To evaluate the association of PTPN22 polymorphisms with TB susceptibility and assess their functional relevance through gene expression profiling in a South Asian cohort.</p><p><strong>Methodology: </strong>PTPN22 polymorphisms and expression in 111 TB patients and 85 controls were analyzed by ARMS-PCR and RT-qPCR, with association and predictive analyses performed using logistic regression, ROC, LD (Haploview), and SPSS v26.</p><p><strong>Results: </strong>A significant association was observed between the rs33996649 C/T genotype and increased TB susceptibility (p < 0.008; OR = 5.87), while no significant association was found for rs2476601. Logistic regression indicating a stronger contribution to TB risk for rs33996649 (1.1279) compared to rs2476601 (0.2276). ROC curve analysis yielded an area under the curve (AUC) of 0.63, suggesting good predictive power for the combined genetic model. Linkage disequilibrium analysis demonstrated low correlation between the SNPs (D' ≈ 0.40, r2 ≈ 0), indicating independent inheritance. PTPN22 expression was modestly upregulated in TB patients (mean fold change = 1.2 vs. 1.0 in controls), though the difference was not statistically significant (p > 0.05), possibly reflecting compensatory immune regulation in variant carriers.</p><p><strong>Conclusion: </strong>The PTPN22 rs33996649 (R263Q) variant shows a significant independent association with TB susceptibility, highlighting its role as a genetic risk factor and potential target for immunogenetic research.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381391","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":"Targeting acetylcholine: a novel strategy for treating lung adenocarcinoma.","authors":"Suoni Li, Yuxin Song, Hui Wang, Jiequn Ma, Jie Bai, Xinming Xie, Bo Guo, Zhao Wei, Yu Yao","doi":"10.1186/s12920-026-02412-8","DOIUrl":"https://doi.org/10.1186/s12920-026-02412-8","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer remains one of the deadliest cancers, both in terms of the incidence and mortality rates. Although a combination therapy comprising immune checkpoint inhibitors and chemotherapy has become the standard therapy for driver gene-negative lung adenocarcinoma, its efficacy is yet to be further improved. Additionally, new treatment methods still need to be developed. Acetylcholinesterase (AChE) has emerged as a potential therapeutic target in various cancers. However, its role in lung adenocarcinoma remains poorly understood.</p><p><strong>Objective: </strong>This study aims to investigate the role of AChE in the progression of lung adenocarcinoma and to design and synthesize small-molecule compounds targeting AChE for exploring their potential as novel therapeutic agents.</p><p><strong>Methods: </strong>AChE is significantly overexpressed in lung adenocarcinoma. Therefore, we synthesized two novel AChE inhibitors and characterized them by nuclear magnetic resonance and high-resolution mass spectrometry. Subsequently, two inhibitors were added to lung adenocarcinoma A549 and H1975 cells to detect changes in their biological behaviors such as cell proliferation, apoptosis, cell cycle, and colony-formation ability. Simultaneously, a mouse transplant tumor model was constructed and an AChE inhibitor was injected intraperitoneally to observe changes in the volume and weight of the mouse transplant tumor.</p><p><strong>Result: </strong>Our AChE inhibitors showed significant cytotoxicity against A549 and H1975 cells. They can effectively inhibit cell proliferation, induce apoptosis, prevent cell cycle progression, and reduce colony-formation ability. The mouse transplant tumor model confirmed that they can inhibit cell proliferation. The tumor volume and weight were significantly reduced in the intraperitoneal injection inhibitor group. Notably, the inhibitor did not cause pathological damage to normal organs.</p><p><strong>Conclusion: </strong>Our novel AChE inhibitors can potentially be used to treat lung adenocarcinoma and to develop a promising new direction for future lung adenocarcinoma treatments.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381397","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":"Improved prognostic survival models for pediatric medulloblastoma using high dimensional gene expression data.","authors":"Elizabeth B Amona, Mst Sharmin Akter Sumy, Tyler Jones, Shuoyang Wang, Akshitkumar M Mistry, Ashok Raj, Howard Donninger, Kavitha Yaddanapudi, Maiying Kong","doi":"10.1186/s12920-026-02418-2","DOIUrl":"https://doi.org/10.1186/s12920-026-02418-2","url":null,"abstract":"<p><p>Genetic, epigenetic, and transcriptomic analyses have stratified medulloblastoma (MB) into four canonical subgroups of Wingless Type (WNT), Sonic Hedgehog (SHH), and Group 3 and Group 4, with distinct patient profiles and prognoses. Recent classification strategies have also considered combining Group 3 and Group 4 tumors into a Non-WNT/Non-SHH subgroup to account for biological overlap and heterogeneity. Using high-dimensional gene expression data from 487 pediatric and young adult patients and over twenty-one thousand transcripts, this study explores which genes can improve prognostic accuracy for survival while accounting for molecular stratification, histological subtype, key oncogenic drivers (MYC and MYCN amplification), and established clinical covariates, including age group (< 3 vs. 3-21 years) and metastatic status. We then develop a multi-stage framework for identifying prognostic genes and evaluating modern survival modeling strategies. In the first stage, gene screening was performed using Benjamini-Hochberg adjusted Cox regression across false discovery rate (FDR) thresholds from 1% to 6%, with the number of retained genes increasing from 15 at 1% to 146 at 6% FDR. In the second stage, multiple survival models were evaluated, including LASSO, Elastic Net, Ridge regression, SCAD, MCP, PCA-Cox, and Random Survival Forests, using ten-fold cross-validation with the Integrated Brier Score as the primary calibration metric and the concordance index as a secondary discrimination measure. Although Ridge regression achieved the lowest prediction error at higher FDR thresholds, it did not perform variable selection and retained large gene sets, limiting interpretability. In contrast, the 6% FDR Elastic Net model provided an optimal balance between predictive accuracy and model sparsity while reducing the gene set from 146 to 49 genes, yielding an interpretable final multivariable model. Gene-level effects from the final Elastic Net-penalized Cox model revealed a clear prognostic gradient. Genes associated with poorer survival included FKBP4, CSNK2A2, GPC4, GATA3, NPY, LYPD1, CLCA4, and BNC2, which have been implicated in tumor progression, signaling pathways, and immune-related processes, whereas genes associated with improved survival included ZNF774, COX10, FBLIM1, and UNC13C, reflecting roles in cellular regulation and protective biological processes. These findings demonstrate that combining FDR-based screening with Elastic Net-penalized Cox modeling yields a robust, parsimonious, and biologically meaningful prognostic framework for medulloblastoma, achieving strong predictive performance while maintaining interpretability in high-dimensional genomic settings.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366754","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":"Identification of a novel pathogenic variant in MYLK in an Iranian family with non-syndromic familial aortic aneurysm and dissection by whole-exome sequencing and literature review.","authors":"Hamide Jafari, Mansoor Salehi, Mohaddeseh Behjati, Mohammad Hashemi Jazi, Masoud Garshasbi","doi":"10.1186/s12920-026-02419-1","DOIUrl":"https://doi.org/10.1186/s12920-026-02419-1","url":null,"abstract":"<p><strong>Background: </strong>Non-syndromic familial thoracic aortic aneurysm and dissection (ns-FTAAD) is an inherited disease that follows an autosomal dominant pattern; however, pinpointing the responsible genes is often complex. The MYLK gene has been identified as one implicated in TAAD, which necessitates careful and specialized clinical oversight. Systematically gathering evidence on the disease-causing potential of rare genetic variants through detailed family studies is crucial for developing more effective treatment protocols for individuals with this life-threatening hereditary condition. This study reports the identification of a novel pathogenic variant causing ns-FTAAD and provides a comprehensive review of all associated TAAD variants.</p><p><strong>Methods: </strong>We report an Iranian family with ns-FTAAD associated with a novel MYLK germline variant. We evaluated all relevant clinical and genetic information. Whole-exome sequencing (WES) was used for variant detection, and Sanger sequencing was performed for validation. A literature search for all TAAD types was conducted on PubMed. The extracted data included the total number of patients studied, the subset with MYLK variants, specific nucleotide and protein changes, patient demographics, pathological features, and clinical symptoms.</p><p><strong>Results: </strong>Exome sequencing led to the identification of a novel variant, NM_053025.4:c.2208_2230dup (p.Ile744Argfs*9), that led to a premature stop codon and nonsense-mediated decay. Five people were variant carriers and three people were non-carriers. A total of 1,440 patients clinically diagnosed with TAAD were recruited in these studies, among whom 59 were carriers of an MYLK variant. Among the 34 variants collected, the distribution was as follows: missense (58.82%), frameshift (14.71%), splicing (5.88%), CNVs (5.88%), and other (14.71%).</p><p><strong>Conclusion: </strong>Our study expands the mutational landscape of MYLK-related ns-FTAAD with a novel pathogenic variant. The aggregation of all reported cases highlights that while missense variants predominate, loss-of-function mechanisms like frameshift variants are a significant cause of disease. These findings are crucial for risk assessment, familial screening, and the clinical management of affected families.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337606","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}