Joint effects of CD8A and ICOS in Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS)

Abstract

Background: Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS) are complex disorders with unclear origins, underscoring the need for in-depth molecular investigations into their mechanisms. The main aim of this study is to identify the shared key genes between LQTS and BWS, shedding light on potential common molecular pathways underlying these syndromes.

Methods: The LQTS and BWS datasets are available for download from the GEO database. Differential expression genes (DEGs) were identified. Weighted gene co-expression network analysis (WGCNA) was used to detect significant modules and central genes. Gene enrichment analysis was performed. CIBERSORT was used for immune cell infiltration analysis. The predictive protein interaction (PPI) network of core genes was constructed using STRING, and miRNAs regulating central genes were screened using TargetScan.

Results: Five hundred DEGs associated with Long QT Syndrome and Beckwith-Wiedemann Syndrome were identified. GSEA analysis revealed enrichment in pathways such as T cell receptor signaling, MAPK signaling, and adrenergic signaling in cardiac myocytes. Immune cell infiltration indicated higher levels of memory B cells and naive CD4 T cells. Four core genes (CD8A, ICOS, CTLA4, LCK) were identified, with CD8A and ICOS showing low expression in the syndromes and high expression in normal samples, suggesting potential inverse regulatory roles.

Conclusion: The expression of CD8A and ICOS is low in long QT syndrome and Beckwith-Wiedemann syndrome, indicating their potential as key genes in the pathogenesis of these syndromes. The identification of shared key genes between LQTS and BWS provides insights into common molecular mechanisms underlying these disorders, potentially facilitating the development of targeted therapeutic strategies.

Keywords: Beckwith-Wiedemann syndrome; Biomarkers; CD8A; ICOS; Long QT Syndrome.

Fig. 1

Volcano plots illustrating the Differentially Expressed Genes (DEGs) in Long QT Syndrome and Beckwith-Wiedemann Syndrome

Fig. 2

Enrichment analysis of DEGs. A Gene Ontology Biological Process (GO BP) analysis. B Gene Ontology Cellular Component (GO CC) analysis. C Gene Ontology Molecular Function (GO MF) analysis. D Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. E Gene Set Enrichment Analysis (GSEA) Biological Process (BP) analysis. F GSEA Cellular Component (CC) analysis. G GSEA Molecular Function (MF) analysis. H GSEA KEGG analysis

Fig. 3

Enrichment analysis using Metascape. A Enriched terms in Gene Ontology related to Tyrosine Kinase Receptor Signaling, Positive Regulation of GTPase Activity, Innate Immune Response, and Cardiac Conduction. B Enrichment network with colored nodes representing enriched terms and p-value color-coding indicating confidence

Fig. 4

Immune infiltration analysis. A Proportion of immune cells in the whole gene expression matrix. B Co-expression patterns of immune cell components shown in an intercorrelation heatmap

Fig. 5

Weighted Gene Co-expression Network Analysis identifies hub genes in Long QT Syndrome and Beckwith-Wiedemann Syndrome. A Soft-thresholding (power) with β = 8. B Hierarchical clustering dendrogram of all genes. C Module eigengene dendrogram. D Heatmap showing correlations between different modules. E Scatter plot depicting the correlation between Gene Significance (GS) and Module Membership (MM) for hub genes. F Venn diagram showing the intersection of differentially expressed genes

Fig. 6

Protein–Protein Interaction (PPI) network and identification of hub genes. A PPI network. B Hub genes identified using four algorithms, with the union of these sets as the core genes. C, D, E, F Four core intersecting genes (CD8A, ICOS, CTLA4, LCK)

Fig. 7

Expression profiles of hub genes in samples. A Heatmap visualizing gene expression in the merged matrix of GSE121578 and GSE95486. B Comparative Toxicogenomics Database (CTD) analysis linking core genes (CD8A, ICOS) to heart diseases, Long QT Syndrome, heart failure, hepatomegaly, hypoglycemia, and inflammation