BMC Medical Genomics[JOURNAL]
Sun
200 papers
Improving newborn screening accuracy through genome sequencing, targeted metabolomics, and machine learning.
Xie Y, Peng G, Tikhonova I … +4 more , Enns G, Zhao H, Cowan T, Scharfe C
BMC Med Genomics · 2025 Nov · PMID 41257776 · Full text
BACKGROUND: Newborn screening (NBS) enables early detection of metabolic disorders, but current tandem mass spectrometry (MS/MS) methods often lead to false positives and require confirmatory testing, causing diagnostic...
BACKGROUND: Newborn screening (NBS) enables early detection of metabolic disorders, but current tandem mass spectrometry (MS/MS) methods often lead to false positives and require confirmatory testing, causing diagnostic delays. We evaluated whether integrating genome sequencing, expanded metabolite profiling, and artificial intelligence/machine learning (AI/ML) could improve the accuracy of NBS. METHODS: We analyzed dried blood spots (DBS) from 119 screen-positive cases identified by the California NBS program across four disorders: GA-I, PA/MMA, OTCD, and VLCADD. Genome sequencing was performed to identify variants in condition-related genes using ACMG guidelines, and an AI/ML classifier trained on previously generated metabolomic data was applied to differentiate true and false positives. RESULTS: Genome sequencing confirmed 89% (31/35) of true positives based on the presence of two reportable variants. Among 84 false positives, 74% (62) had no variant, while 26% (22) carried a pathogenic/likely pathogenic variant or rare VUS in a condition-related gene. For VLCADD, half of false positives (15/29) were ACADVL variant carriers (P = 4.66 × 10⁻⁷). VLCADD biomarker levels were highest in patients, intermediate in carriers, and lowest in non-carriers, indicating that ACADVL variants elevate biomarker levels and increase false-positive rates. Metabolomics with AI/ML detected all true positives (100% sensitivity), while genome sequencing reduced false positives by 98.8%. CONCLUSION: Targeted metabolomics with AI/ML showed high sensitivity for identifying true positives, though its ability to reduce false positives varied by condition. Genome sequencing effectively reduced false positives but lacked sufficient sensitivity as a standalone test. The elevated false-positive rate among pathogenic variant carriers underscores the potential value of parental or prenatal carrier screening to improve NBS accuracy. Integrating genomic and metabolomic data may enhance NBS precision and enable earlier diagnosis and intervention for rare diseases.
Serum miR-141-3p serves as a biomarker for early-stage diagnosis of endometriosis.
Tan H, Liu D, Zhang K … +2 more , Li H, Zhou H
BMC Med Genomics · 2025 Nov · PMID 41254724 · Full text
OBJECTIVE: This study is conducted to investigate whether serum microRNA (miR)-141-3p can serve as a biomarker for early-stage diagnosis of endometriosis. METHODS: A total of 246 patients who underwent laparoscopic exami...
OBJECTIVE: This study is conducted to investigate whether serum microRNA (miR)-141-3p can serve as a biomarker for early-stage diagnosis of endometriosis. METHODS: A total of 246 patients who underwent laparoscopic examination and were diagnosed with endometriosis at our hospital between October 2020 and October 2022 were retrospectively enrolled as the Endometriosis group. This group was further allocated into Early-Endometriosis (Stage I-II) and Severe-Endometriosis (Stage III-IV) groups. Additionally, 87 healthy women with normal clinical parameters during the same period were selected as the control group. miR-141-3p expression in the serum of endometriosis patients were detected using RT-qPCR. The relationship of serum miR-141-3p expression with EHP-30 score in endometriosis patients was examined using Spearman. The diagnostic value of serum miR-141-3p for endometriosis was assessed by ROC analysis. Further ROC analysis was conducted to evaluate the diagnostic value of combined serum miR-141-3p and CA125 levels for early-stage endometriosis. RESULTS: Serum miR-141-3p expression was significantly lower in endometriosis patients and was negatively correlated with clinical staging. Serum miR-141-3p demonstrated excellent diagnostic performance for endometriosis (AUC = 0.916) and retained a high diagnostic value for early-stage endometriosis (AUC = 0.858). The diagnostic efficacy was further improved when combined with CA125 (AUC = 0.985). CONCLUSION: Serum miR-141-3p expression decreases with disease progression in endometriosis patients and shows high clinical utility for the early-stage diagnosis of endometriosis. miR-141-3p expression may serve as a potential marker for diagnosis of endometriosis.
Machine learning-based screening and validation of pyroptosis-associated prognostic genes and potential drugs in cervical cancer.
Hou Z, Tang G, Chu H … +2 more , Wang Z, Wang L
BMC Med Genomics · 2025 Nov · PMID 41239481 · Full text
Pyroptosis is a newly discovered form of programmed cell death, but its mechanism in the development of cervical cancer has not been elucidated. Cervical cancer differentially expressed pyroptosis-related genes were iden...
Pyroptosis is a newly discovered form of programmed cell death, but its mechanism in the development of cervical cancer has not been elucidated. Cervical cancer differentially expressed pyroptosis-related genes were identified via bioinformatic analysis Gene Expression Omnibus (GEO) dataset GSE7803, GSE9750, GSE63514 and GSE67522. The correlation between the expression of pyroptosis-related genes in normal cervical tissue and cervical cancer tissue was analyzed through the TCGA database. Using LASSO regression algorithm to establish a prediction model for the obtained genes related to pyroptosis. Exploring the functions of differentially expressed genes through GO and KEGG pathway analysis. Using PPI network analysis to screen hub genes, using CIBERSORT method for immune infiltration analysis of prognostic genes, and finally predicting drug-gene interactions in DGIdb database. A total of 19 pyroptosis-related genes were screened from the GEO dataset of cervical cancer tissues, revealing their regulation of endopeptidase activity, inflammation response, positive regulation of cytokine production and cellular response to environmental stimuli. LASSO regression algorithm was used to establish prediction models for 7 of these genes, and 3 pyroptosis-related genes (SPP1, VEGFA, and CXCL8) closely associated with the prognosis of cervical cancer were identified. qRT-PCR confirmed that compared with normal cervical tissue, the expression of SPP1, VEGFA, and CXCL8 was increased in cervical cancer (P<0.05). SPP1, VEGFA, and CXCL8 are most closely related to macrophages, Th2, and neutrophils, respectively. 148 potential targeted drugs targeting key genes were predicted, providing a possible basis for predicting the prognosis and treatment of cervical cancer. Knocking down SPP1 can inhibit cell proliferation and migration in cervical cancer cells in vitro. In conclusion, our study has identified key genes related to pyroptosis in cervical cancer, which potentially become effective clinical prognostic biomarkers, and further research is needed to explore their underlying mechanisms.
RNA sequencing provides functional insights and diagnostic resolution in previously unsolved rare disease cases.
Lewis RG, O'Shea JM, Pizzo L … +22 more , Wen T, Fulmer ML, Zhao J, Verheijen J, Zhang C, Velinder M, Nicholas TJ, Boyden SE, Ward A, Baldwin EE, Andrews A, Ruiz JH, Marchetti M, Viskochil D, Carey JC, Bleyl SB, Butterfield RJ, Taliercio V, Botto LD, Mao R, Bayrak-Toydemir P, Undiagnosed Diseases Network
BMC Med Genomics · 2025 Nov · PMID 41239373 · Full text
Exome and genome sequencing have greatly improved the diagnosis of rare genetic disorders but remain limited in their ability to identify and classify non-coding variants, including intronic variants, cryptic splice-site...
Exome and genome sequencing have greatly improved the diagnosis of rare genetic disorders but remain limited in their ability to identify and classify non-coding variants, including intronic variants, cryptic splice-site alterations, and disruptions in regulatory regions. RNA sequencing (RNA-seq) has emerged as a powerful tool to bridge this gap by providing functional insights into genomic variants that disrupt splicing or gene expression, thereby aiding in variant interpretation and classification. We retrospectively reviewed 30 cases from the Utah Penelope Program and the Undiagnosed Diseases Network over a three-year period, in which RNA-seq was performed on whole blood and/or fibroblasts following either negative DNA sequencing or the identification of candidate variants requiring functional assessment. In these cases, RNA-seq identified exon skipping, cryptic splice-site activation, and intron retention, leading to transcript disruption. Additionally, positional enrichment analysis clarified X-inactivation patterns and dosage effects, confirming the pathogenicity of copy number variants. By detecting these transcript-level alterations, RNA-seq provided functional evidence supporting the reclassification of multiple variants of uncertain significance, contributing to diagnostic resolution in selected cases. This study underscores the clinical utility of RNA-seq in detecting splicing and regulatory defects that DNA sequencing and predictive tools alone cannot resolve. Integrating RNA-seq into clinical workflows can support variant classification, aid in diagnostic resolution for selected cases, and provide mechanistic insights into genetic disorders, contributing to patient care and genetic counseling.
Epigenetic profiles of response to transcranial magnetic stimulation in treatment resistant depression.
Dahrendorff J, Pages K, Currier G … +5 more , Sarker MH, Graham Z, Louis-Jacques AF, Dagne G, Uddin M
BMC Med Genomics · 2025 Nov · PMID 41225566 · Full text
BACKGROUND: Transcranial magnetic stimulation (TMS) is an established treatment for major depressive disorder (MDD), yet response rates remain suboptimal and biomarkers predictive of treatment outcomes are currently lack...
BACKGROUND: Transcranial magnetic stimulation (TMS) is an established treatment for major depressive disorder (MDD), yet response rates remain suboptimal and biomarkers predictive of treatment outcomes are currently lacking. Recently, DNA methylation (DNAm) has shown promise as an epigenetic predictor of antidepressant and electroconvulsive therapy treatment outcomes but no study to our knowledge has characterized DNAm profiles of treatment outcomes in the context of TMS. Here, we present the first genome-scale DNAm analysis of TMS outcomes in patients with treatment-resistant depression (TRD). METHODS: Peripheral blood samples from 60 TRD patients were collected prior to a standard 36-session TMS course. DNAm was profiled using the Illumina EPIC array and filtered to retain only the top 5% most variable probes for subsequent analysis in relation to three treatment outcomes in an analytic sample of 46 patients: treatment response (> 50% PHQ-9 reduction), symptom trajectory (ΔPHQ-9), and remission (PHQ-9 < 5). RESULTS: Methylated CpG Set Enrichment Analysis (mCSEA) identified 67, 23, and 163 differentially methylated regions (DMRs) associated with treatment response, symptom trajectory, and remission, respectively (FDR < 0.05). Sixteen DMRs were common across all outcomes, implicating genes involved in neurodevelopment (HOXA4, HOXA5), immune signaling (RUNX1, OTUD5), and synaptic function (EFNB1, RAP2C). Targeted analysis of 84 CpGs in the BDNF promoter revealed 10 nominally significant CpGs that differentiated responders from non-responders. Several DMRs showed strong blood-brain methylation concordance (r > 0.5), supporting their potential relevance to central nervous system mechanisms. CONCLUSIONS: Despite the limited sample size, these findings suggest distinct epigenetic signatures prior to treatment that are associated with TMS outcomes, supporting the potential utility of DNAm as a biomarker for response stratification in TRD.
Targeted nanopore long-read sequencing panel for the molecular diagnosis of intronic expansion in familial adult myoclonic epilepsy.
Urabe H, Nakajima T, Mitsuhashi S … +4 more , Ohta K, Fujinaka H, Goto K, Sato A
BMC Med Genomics · 2025 Nov · PMID 41219789 · Full text
BACKGROUND: Familial adult myoclonic epilepsy (FAME), an autosomal dominant disorder, is characterized by cortical myoclonus and occasional generalized tonic-clonic seizures. To date, intronic pentanucleotide repeat expa...
BACKGROUND: Familial adult myoclonic epilepsy (FAME), an autosomal dominant disorder, is characterized by cortical myoclonus and occasional generalized tonic-clonic seizures. To date, intronic pentanucleotide repeat expansions in at least seven genes, including SAMD12, TNRC6A, YEATS2, MARCHF6, STARD7, RAPGEF2, and RAI1, have been reported as causative. Detecting these repeat expansions using conventional sequencing techniques (Sanger or short-read next-generation sequencing) is not feasible as they cannot reliably span or characterize long repetitive elements. Although genetic testing has been performed in some research laboratories, comprehensive long read-based panel is unavailable for clinical application. To address this gap, we developed a targeted long-read sequencing panel and applied it in a clinical diagnostic context for the first time. METHODS: We designed a custom long-read sequencing panel targeting all seven known FAME-associated repeat loci using Oxford Nanopore Cas9-enrichment technology and applied it to a 47-year-old woman with familial cortical myoclonic tremor, clinically suspected to have FAME. RESULTS: The panel functioned as intended, providing robust on-target coverage across all loci, facilitating confident interrogation of each repeat region. At the SAMD12 locus, strand-aware histograms and read-level inspection demonstrated a clear pathogenic expansion, encompassing mixed TTTTA/TTTCA motifs with detectable TTTGA interruptions, consistent with FAME1. Using the crude allele prediction option of tandem-genotypes, the expanded allele contained approximately 689 additional repeats relative to the reference genome. The other six loci showed no pathogenic expansions. CONCLUSIONS: This targeted long-read panel enabled the first clinical molecular diagnosis of FAME using a comprehensive assay, yielding allele-resolved characterization of the pathogenic repeat and its motif composition. With further validation, this approach may serve as a clinically practical tool for reliable detection of FAME1 and for broader screening of other FAME subtypes, potentially reducing reliance on prolonged clinical observation or specialized electrophysiological testing.
Prognostic evaluation of glycolysis markers in hepatocellular carcinoma: insights from meta-analysis and multi-omics approaches.
Li G, Li Y, Zhou J … +3 more , Tang S, Guo H, Lin J
BMC Med Genomics · 2025 Nov · PMID 41206438 · Full text
BACKGROUND: Glycolysis, a central process of cellular energy metabolism, has been shown to be closely associated with the development of hepatocellular carcinoma (HCC). This study aimed to investigate the prognostic valu...
BACKGROUND: Glycolysis, a central process of cellular energy metabolism, has been shown to be closely associated with the development of hepatocellular carcinoma (HCC). This study aimed to investigate the prognostic value of the glycolysis gene set (GGS) in HCC. METHODS: Online databases were searched to identify studies on the correlation between glycolysis-related gene signature score and clinical characteristics in patients with HCC. HR and OR values with 95% CI were calculated. Bioinformatics analysis and in vitro validation were used to validate the results of the meta-analysis and investigate the potential oncogenic mechanisms of GGS. RESULTS: Nineteen studies involving 3,406 patients were included. The pooled analysis showed that a high glycolysis-related gene signature score was associated with poor overall survival (OS) (HR = 1.98, 95% CI 1.59-2.46, P < 0.001), disease-free survival (DFS) (HR = 2.02, 95% CI 1.54-2.64, P < 0.001), and relapse-free survival (RFS) (HR = 2.38, 95% CI 1.39-4.08, P = 0.002). Bioinformatic and in vitro experiments confirmed the prognostic relevance and differential expression of GGS in HCC, and functional assays of ENO1 further demonstrated its role in HCC progression. CONCLUSION: The upregulation of the glycolysis-related gene signature score is predominantly associated with poor prognosis in patients with HCC, suggesting that GGS may serve as a potential prognostic biomarker and therapeutic target for HCC, as exemplified by ENO1 functional validation.
Identification of a VHL germline deletion in a family with Von Hippel-Lindau syndrome using MLPA-NGS.
Yang Y, Ren X, Xia C … +6 more , Zhang Y, Song X, Tang X, Du C, Xu W, Weng W
BMC Med Genomics · 2025 Nov · PMID 41204220 · Full text
Von Hippel-Lindau syndrome (VHL) is an autosomal dominant disorder characterized by the development of tumors and cysts in multiple organs. Pathogenic variants in VHL are known to be associated with the development of th...
Von Hippel-Lindau syndrome (VHL) is an autosomal dominant disorder characterized by the development of tumors and cysts in multiple organs. Pathogenic variants in VHL are known to be associated with the development of this syndrome. Therefore, the present study aimed to investigate VHL rearrangements in a family with VHL syndrome. In the proband, who presented with retinal hemangioma, whole exome sequencing (WES) revealed significant genetic variation. However, WES did not detect germline deletion in VHL in the proband's son. Furthermore, multiplex ligation-dependent probe amplification (MLPA)-next-generation sequencing (NGS) analysis showed that the genomes of the proband and her son encompassed a deletion in VHL, extending from exon 2 to exon 3. Via increasing the probe density to gradually approach the breakpoint and following Sanger sequencing analysis, it was verified that an intermediate fragment of 6,662 bp was lost, with a reconnection occurring between chromosome 3:10145434 and 10,152,097 (GRCh38/hg38). Overall, the present study demonstrated that the application of MLPA-NGS technology combined with Sanger sequencing could be employed to precisely locate deleted DNA fragments.
Unravelling homozygous PLA2G6 variants in Pakistani individuals with diverse clinical manifestations via whole exome sequencing.
Khan H, Zahid M, Shabbir MI … +6 more , Ahmed A, Khan B, Kiyani MM, Abualait T, Bashir S, Li HT
BMC Med Genomics · 2025 Nov · PMID 41204171 · Full text
Whole Exome Sequencing (WES) was performed on 265 Pakistani individuals with suspected neurodevelopmental disorders, revealing that seven of them carried homozygous mutations in the PLA2G6 gene, which is linked to neurod...
Whole Exome Sequencing (WES) was performed on 265 Pakistani individuals with suspected neurodevelopmental disorders, revealing that seven of them carried homozygous mutations in the PLA2G6 gene, which is linked to neurodegenerative diseases such as Infantile Neuroaxonal Dystrophy (INAD) and Parkinson's disease 14 (PD14). These patients presented with a typical cluster of symptoms, including ataxia, gait instability, cognitive decline, motor regression, and psychiatric manifestations like autistic features, impulsive behaviour, and emotional lability. However, the clinical presentation varied across patients, underscoring the phenotypic diversity associated with PLA2G6 mutations. We identified six distinct variants in the PLA2G6 gene (NM_003560.4) across seven affected individuals. These comprised two pathogenic variants (c.2370T > G and c.1427 + 1G > T), three likely pathogenic variants c.929T > A (observed in two patients), c.1591 + 5G > C, and c.2276G > T, and one variant of uncertain significance c.905T > G. All these mutations were predicted to be disease-related by in silico tools, confirming their likely role in disease causation. This study elucidates the variety of clinical features due to PLA2G6 mutations, with manifestations ranging from motor-cognitive to psychiatric features. Our results emphasize the importance of new homozygous variants for the genetic heterogeneity of these diseases. We want to underscore the value of genetic testing in patients with progressive neurodevelopmental signs, like in the case of our patient, which may result in early diagnosis and help in deciding treatment later. Furthermore, this study provides additional insight into genotype-phenotype correlations of PLA2G6-associated diseases and offers directions for future studies to develop tailored therapeutics.
A novel compound heterozygous variant in LAMA2 gene in a family with merosin-deficient congenital muscular dystrophy.
Nejati P, Falsafi N, Alimoradi E … +4 more , Khosravi T, Kamari M, Oladnabi M, Alibakhshi R
BMC Med Genomics · 2025 Nov · PMID 41188926 · Full text
LAMA2 encodes the alpha-2 subunit of a protein called Laminin. It consists of three subunits Y; alpha, beta and gamma. Alpha2 subunit from LAMA2 gene along with beta-2 and gamma-2 forms laminin-2 protein. This protein is...
LAMA2 encodes the alpha-2 subunit of a protein called Laminin. It consists of three subunits Y; alpha, beta and gamma. Alpha2 subunit from LAMA2 gene along with beta-2 and gamma-2 forms laminin-2 protein. This protein is necessary for assembly of basement membrane in skeletal muscle cells, Schwann cells, astrocytes and pericytes. More than 100 LAMA2 variant identified so far which cause recessive form of muscular dystrophy (MD) either a severe form, congenital (CMD) or mild form, limb-girdle (LGMD). Patient with LAMA2 MD suffered from muscle weakness, elevated creatine kinase, facial dysmorphism, peripheral motor neuropathy, epilepsy/seizure, developmental delay, and white matter changes in brain MRI. In this study, we conducted whole exome sequencing (WES) to investigate molecular etiology of patients with CMD in one family with non-consanguineous marriage from Iran. WES has identified a novel compound heterozygous variant, [c.2049_2050del (p.Arg683Serfs*21)]; [c.2857-2 A > G (p.?)], in the proband. The identified variant was confirmed by Sanger sequencing and its segregation within the family was verified. Subsequently, in-silico analysis was performed to map the protein-protein interaction network between LAMA2 and proteins implicated in CMD pathogenesis. Our findings may be considered valuable molecular and clinical insights for improving our understanding of CMD, particularly regarding LAMA2 variants. Furthermore, this finding gives new insights to laboratorians, genetic counselors and clinicians for determining at-risk couples in the prenatal diagnosis (PND) program.
The molecular complexity of deep vein thrombosis was preliminarily explored based on the ceRNA network, scRNA-seq and AlphaFold 2.
Pan BZ, Luo QY, Jiang MJ … +10 more , Ning D, Deng LM, Dai XP, Wu ZX, Deng ZH, Luo DY, Wang YY, Chen J, Xiong GZ, Bi GS
BMC Med Genomics · 2025 Nov · PMID 41188916 · Full text
BACKGROUND: Deep vein thrombosis (DVT) is a prevalent peripheral vascular disease that is frequently accompanied by significant complications. However, the complexity and diversity of its pathogenesis have resulted in a...
BACKGROUND: Deep vein thrombosis (DVT) is a prevalent peripheral vascular disease that is frequently accompanied by significant complications. However, the complexity and diversity of its pathogenesis have resulted in a lack of in-depth understanding of relevant regulatory targets. The objective of this study was to identify the highly distinctive genes associated with DVT, and to investigate their intricacies. METHODS: In this study, a comprehensive transcriptomic analysis was conducted on blood samples from 4 DVT patients and 6 healthy subjects from an internal test set, employing established standard procedures. Differential (diff) circular RNAs (circRNAs), diff microRNAs (miRNAs) and diff messenger RNAs (mRNAs) associated with DVT were identified to construct a competing endogenous RNA (ceRNA) network model, and node mRNAs were identified in an external validation set (n = 14). Furthermore, a topological analysis was conducted by using 7 protein-protein interaction (PPI) network algorithms. Concurrently, AlphaFold 2 was employed for three-dimensional prediction and assessment of the molecular structure. The comparative toxicology genomics database (CTD) was employed to assess the interconnectivity between these genes. Subsequently, single-cell RNA sequencing (scRNA-seq) was conducted on blood samples from 3 DVT patients and 3 healthy subjects, following the standard protocol, to ascertain the cellular localization of gene expression and the role of core pathways. RESULTS: A whole-transcriptome analysis identified a total of 406 diff circRNAs, 29 diff miRNAs and 154 diff mRNAs. Concurrently, a total of 6 circRNAs, 5 miRNAs and 16 mRNAs were incorporated into the ceRNA network models (a total of 6 node mRNAs were identified differentially). A total of 5 hub genes (including JAK2, CD36, TNFSF13B, TLR7 and PARP9) were identified by 7 PPI network algorithms. The structure and function of the above genes are adequately described by the AlphaFold 2 and CTD interference scores. A total of 7 cell types were identified by scRNA-seq, and there were obvious differences in the localization of genes and the role of core pathways in different cells. CONCLUSIONS: JAK2, CD36, TNFSF13B, TLR7 and PARP9 were identified as potential regulatory target genes for the pathophysiological process of DVT. Additionally, hsa_circ_0095124/hsa-miR-3074-5p/TNFSF13B is a potential regulatory pathway for DVT.
Correction: Exploring the prognostic landscape of oral squamous cell carcinoma through mitochondrial damage-related genes.
Wen W, Li R, Wang D … +1 more , Chai L
BMC Med Genomics · 2025 Oct · PMID 41168802 · Full text
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Novel EP300 and NSD1 variants in Chinese pediatric patients with Rubinstein-Taybi syndrome: evidence for oligogenic inheritance and phenotypic expansion.
Ningan X, Yefeng W, Xinghan W … +1 more , Sha Z
BMC Med Genomics · 2025 Oct · PMID 41168794 · Full text
BACKGROUND: Rubinstein–Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disorder caused by heterozygous loss-of-function variants in CREBBP or EP300. EP300-related cases often show milder clinical featur...
BACKGROUND: Rubinstein–Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disorder caused by heterozygous loss-of-function variants in CREBBP or EP300. EP300-related cases often show milder clinical features, but their full phenotypic spectrum and the potential role of oligogenic inheritance remain unclear. METHODS: We retrospectively studied seven Chinese pediatric RSTS patients. Genomic analyses included whole-exome sequencing (WES), chromosomal microarray analysis (CMA) and Sanger validation. Variants were classified by ACMG/AMP guidelines. Protein structural impacts were assessed by homology modeling. Phenotypic frequencies in our EP300-related patients were compared with published European/American cohorts using Fisher’s exact test or χ² test (p < 0.05 as significant). RESULTS: Two de novo EP300 nonsense variants (c.3934 C > T, p.Arg1312Ter; c.2749 C > T, p.Gln917Ter) were identified; one of these patients also harbored a de novo NSD1 missense variant (c.5843G > A, p.Arg1948His). Five other patients carried pathogenic CREBBP variants or deletions. The patient with both EP300 and NSD1 variants exhibited additional anomalies (cryptorchidism, congenital cataracts, strabismus), suggesting synergistic epigenetic dysregulation. Homology models predicted truncation of the EP300 HAT and bromodomain regions and disruption of the NSD1 SET domain. Compared with European/American cohorts, our Chinese EP300-related patients had significantly higher rates of arched eyebrows, downslanting palpebral fissures and low-set ears (p < 0.05). To our knowledge, this is the first clinical evidence of an oligogenic inheritance pattern in RSTS involving both EP300 and NSD1. CONCLUSIONS: Our findings expand the genotypic and phenotypic landscape of RSTS in a Chinese population, delineate distinctions between EP300- and CREBBP-related cases, and underscore the value of comprehensive genomic analysis for accurate diagnosis, genetic counselling and personalized management.
The role of TEAD4 gene in the Hippo signaling pathway in triple-negative breast cancer and targeted therapy strategies.
Zhang X, Wang T, Lian X … +3 more , Wei C, Yan D, Liang Y
BMC Med Genomics · 2025 Oct · PMID 41168787 · Full text
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited targeted therapies. The Hippo signaling pathway, critical in tumor progression, may harbor key genes influencing T...
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited targeted therapies. The Hippo signaling pathway, critical in tumor progression, may harbor key genes influencing TNBC behavior. However, the specific genes and their clinical significance remain unclear. METHODS: We analyzed the GSE45827 dataset from the GEO database using differential gene expression analysis (DEG) and weighted gene co-expression network analysis (WGCNA) to identify TNBC-related genes. We enriched Hippo pathway-related genes from the MsigDB database and literature to identify candidate genes (HRGs) that may affect TNBC progression. The Boruta algorithm further screened for core genes, which were validated by immunohistochemistry in TNBC and other breast cancer tissues. Finally, we explored the biological and pharmacological significance of the target through drug prediction, molecular docking, molecular dynamics simulations, and in vitro experiments. RESULTS: DEG analysis identified 2,888 differentially expressed genes, and WGCNA yielded 276 TNBC-associated genes. Intersection analysis with 70 hypoxia-related genes (HRGs) revealed four key genes: TEAD4, WWTR1, AREG, and SOX11. TEAD4 was confirmed as the central gene influencing TNBC progression. Immunohistochemical results showed strong TEAD4 expression in TNBC tissues, with negligible expression in adjacent normal tissues or other breast cancer subtypes. Drug prediction and molecular docking identified irinotecan as a potential TEAD4-targeting agent. Molecular dynamics simulations confirmed the stable binding and favorable dynamics of the irinotecan-TEAD4 complex. Both TEAD4 knockdown and irinotecan treatment significantly suppressed TNBC cell migration and invasion. The combination of TEAD4 knockout and irinotecan produced a more pronounced inhibitory effect, underscoring the therapeutic potential of targeting TEAD4 in TNBC. CONCLUSIONS: Through comprehensive analysis, we identified TEAD4 as a key gene in TNBC with high expression specificity. Irinotecan may be a potential targeted drug for TEAD4, offering a new therapeutic strategy for TNBC and potentially improving patient outcomes. Further experimental verification is required.
Correction: MEIS1 knockdown upregulates WNT signaling pathway genes in esophageal squamous cell carcinoma.
Hosseini N, Forghanifard MM
BMC Med Genomics · 2025 Oct · PMID 41163203 · Full text
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A novel frameshift variation of PKD1 in familial autosomal dominant polycystic kidney diseases: expanding the clinical phenotype and genetic spectrum of PKD1 disorders.
Chen Q, Shi L, Zhu X
BMC Med Genomics · 2025 Oct · PMID 41163060 · Full text
BACKGROUND: Autosomal dominant polycystic kidney disease is a common monogenic hereditary kidney disorder. Mutations in the PKD1 gene lead to the development of fluid-filled cysts in the kidney, liver, and other organs,...
BACKGROUND: Autosomal dominant polycystic kidney disease is a common monogenic hereditary kidney disorder. Mutations in the PKD1 gene lead to the development of fluid-filled cysts in the kidney, liver, and other organs, which can eventually result in end-stage renal failure. Affected individuals have a 50% chance of passing the mutation to each of their offspring. Families with ADPKD are advised to undergo genetic testing to causative variants and would benefit from genetic counseling to reduce the inherited risk. METHOD: We performed genetic analysis on a family with ADPKD. DNA samples extracted from the peripheral blood of ADPKD patients were subjected to whole exome sequencing (WES) analysis. Variations were assessed in accordance with the American College of Medical Genetics and Genomic (ACMG) guidelines. Moreover, recent literature focusing on newly identified pathogenic PKD1 mutations and their clinical manifestations was summarized in this study. RESULT: A novel heterozygous variant in the PKD1 gene [NM_001009944.2, c. 5733_5751dup GGCTGCCGGCTCAGCTGTC (p.Thr1918Glyfs*78)] was identified. The variant was absent in published database and resulted in a frameshift mutation predicted to lead to premature termination of the protein translation. The comprehensive analysis of population frequency, conservation, structural and pathogenicity prediction suggested that this variant was classified as pathogenic. CONCLUSION: This is the first reported ADPKD case caused by this novel PKD1 variant. This finding expands the known mutation spectrum of the PKD1 genes and provides a foundation for genetic counseling and future preimplantation genetic diagnosis in affected families. Our findings offer valuable genetic and clinical insights for accurate diagnosis and evaluation of disease progression.
Comprehensive analysis of metabolic and molecular alterations in the blood of patients with Sjögren's syndrome based on untargeted metabolomics analysis.
Liu J, Li Q, Sun X … +2 more , Feng X, Xie M
BMC Med Genomics · 2025 Oct · PMID 41162992 · Full text
BACKGROUND: Sjögren's syndrome (SS) is a chronic autoimmune disorder marked by lymphocytic infiltration of exocrine glands, leading to xerostomia, keratoconjunctivitis sicca, and systemic involvement including fatigue, a...
BACKGROUND: Sjögren's syndrome (SS) is a chronic autoimmune disorder marked by lymphocytic infiltration of exocrine glands, leading to xerostomia, keratoconjunctivitis sicca, and systemic involvement including fatigue, arthralgia, and visceral organ impairment. Its pathogenesis reflects a multifactorial interaction of genetic, environmental, and hormonal influences that collectively disrupt immune homeostasis and drive tissue injury. Extensive investigations remain essential to clarify molecular pathways and establish reliable biomarkers that can enable early detection and precision therapy in SS. Detailed characterization of metabolic and molecular disturbances associated with SS is indispensable for advancing both pathophysiological insight and clinical management. MATERIAL AND METHODS: Rigorous quality control, batch adjustment, and data normalization were applied to untargeted metabolomics to ensure consistency and analytical reliability. Serum metabolite profiling in SS was assessed through unsupervised principal component analysis (PCA) to distinguish intergroup variations. Quantitative evaluation of metabolite abundance, machine learning-based metabolite selection, and functional enrichment analyses using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to identify candidate biomarkers. Differential gene expression and enrichment analyses, construction of protein-protein interaction (PPI) networks in the SS group, and orthogonal partial least squares discriminant analysis (OPLS-DA) were subsequently performed to investigate underlying molecular mechanisms. Correlations among metabolites, key genes, and immune cell subsets were also examined. RESULTS: Quality control confirmed the reliability and precision of the untargeted metabolomics data. Differential metabolite analysis highlighted significant alterations, with PC O-36:5, 4-Aminobutyric acid, and PC 16:0_16:1 exhibiting the most marked changes. Machine learning algorithms further identified metabolites including PC O-36:5, Prostaglandin B1, and L-Ergothioneine as candidates with diagnostic potential for SS. Functional enrichment revealed altered KEGG pathways including arginine and proline metabolism, pyrimidine metabolism, and nucleotide metabolism. Sequencing data analysis indicated enriched GO terms related to viral response, KEGG pathways such as Influenza A, and Gene Set Enrichment Analysis (GSEA) pathways including HUNTINGTONS_DISEASE. Two-way orthogonal partial least squares (O2PLS) delineated metabolites central to metabolic networks, such as PC O-36:5, along with genes critical to gene interaction networks, including GZMA. Correlation analysis demonstrated tight associations between metabolites, genes, and immune cell subsets in SS. CONCLUSION: This integrative analysis identified molecular markers with diagnostic relevance for SS and advanced the understanding of metabolic and molecular alterations underlying the disease.
Genomic DNA methylation profile in peripheral blood of children with congenital biliary dilatation.
Wang C, Zheng Y, Wang Y … +1 more , Feng Q
BMC Med Genomics · 2025 Oct · PMID 41131608 · Full text
BACKGROUND: Congenital biliary dilatation (CBD) is a prevalent congenital biliary disease in children, particularly in Asian populations, yet its etiology remains poorly understood. This study aimed to investigate the ge...
BACKGROUND: Congenital biliary dilatation (CBD) is a prevalent congenital biliary disease in children, particularly in Asian populations, yet its etiology remains poorly understood. This study aimed to investigate the genome-wide DNA methylation profile in the peripheral blood of children with CBD to identify potential epigenetic mechanisms involved in its pathogenesis. METHODS: Genome-wide DNA methylation profiles were compared between whole blood samples from 37 children with CBD and 24 healthy controls using the Illumina Infinium Human MethylationEPIC (850 K) BeadChip. Bioinformatic analyses were performed to identify differentially methylated positions (DMPs) and regions (DMRs), and functional enrichment analysis was conducted on associated genes. RESULTS: We identified 24,230 differentially methylated sites associated with 5,863 genes. Among these, 8,313 sites were hypermethylated and 15,917 were hypomethylated in CBD patients compared to controls. 54 significant differentially methylated regions (DMRs) were also detected. Functional enrichment analysis revealed that the differentially methylated genes were significantly enriched in key biological pathways, most notably the T cell receptor signaling pathway. CONCLUSION: This study presents the first comprehensive analysis of genome-wide DNA methylation in CBD, revealing significant epigenetic alterations in peripheral blood. These findings suggest that aberrant DNA methylation, particularly in genes regulating immune pathways, may play a critical role in the development of CBD and could provide valuable insights for identifying novel diagnostic biomarkers.
Immunomodulation and iron dysregulation: exploring their roles in the pathogenesis of osteoarthritis.
Yang D, Ruan Y, Zheng S … +2 more , Xu W, Hao J
BMC Med Genomics · 2025 Oct · PMID 41126243 · Full text
BACKGROUND: The purpose of this study was to explore the role of immune modulation and iron metabolism disorder in the pathogenesis of osteoarthritis. METHODS: We performed a systematic analysis of datasets and immune in...
BACKGROUND: The purpose of this study was to explore the role of immune modulation and iron metabolism disorder in the pathogenesis of osteoarthritis. METHODS: We performed a systematic analysis of datasets and immune infiltration of osteoarthritis and healthy cartilage tissues, to obtain differences in genes expression and immune cell infiltration related to iron metabolism between two samples. The iron metabolism-related genes with prognostic value was screened by Lasso and Cox regression, and validated their expression in knee cartilage samples from normal and osteoarthritis patients by immunohistochemistry. RESULT: We obtained 494 differential genes that meet the criteria and 147 genes related to iron metabolism diseases. Many entries have been found, which Wnt signaling pathway and cholesterol metabolism may play key roles in the degradation of cartilage. The immunohistochemical staining on normal and osteoarthritis cartilage showed that iron metabolism-related genes genes were significantly higher expressed in osteoarthritis cartilage than in normal cartilage. CONCLUSIONS: The iron metabolism imbalance and immune cell subtype infiltration may be associated with the occurrence and progression of osteoarthritis. These results provide a new perspective for understanding the pathophysiology of osteoarthritis, and also offer new ideas for developing more effective treatment strategies.
Expanding the phenotype of CARS1 variants to include congenital hyperinsulinism.
Sanders VR, Edmondson AC, Yan AC … +1 more , De Leon DD
BMC Med Genomics · 2025 Oct · PMID 41121266 · Full text
BACKGROUND: CARS1 loss of function compound heterozygous or homozygous variants have been reported in five individuals to cause a neurodevelopmental phenotype that includes microcephaly and brittle hair and nails. Additi...
BACKGROUND: CARS1 loss of function compound heterozygous or homozygous variants have been reported in five individuals to cause a neurodevelopmental phenotype that includes microcephaly and brittle hair and nails. Additional multisystem involvement in these five people have included neurologic, cardiac, ophthalmologic and endocrine problems. CASE PRESENTATION: We report a sixth person with novel compound heterozygous variants in CARS1. In addition to the previously reported features such as intellectual disability, neurologic features, microcephaly and hair abnormalities, this patient had persistent hypoglycemia due to congenital hyperinsulinism. CONCLUSIONS: This report identifies two novel variants in CARS1 and expands the phenotype of this multisystem disorder to include congenital hyperinsulinism.
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