BMC Medical Genomics最新文献

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.