[Combined analysis of epigenetic and transcriptomic data from children with Wiedemann-Steiner syndrome due to variants of KMT2A gene].

OBJECTIVE

To investigate epigenetic and transcriptional alterations in children with Wiedemann-Steiner syndrome (WDSTS) due to variants of KMT2A gene using genome-wide DNA methylation array and RNA sequencing (RNA-seq), and identify the key pathways and candidate genes.

METHODS

A retrospective study was carried out for 16 children with WDSTS and 10 healthy controls who visited Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine between November 2016 and December 2024. Peripheral blood samples were collected. Genomic DNA and total RNA were extracted using commercially made kits. Genome-wide DNA methylation profiling was conducted to identify differentially methylated positions (DMPs) and annotated genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. RNA-seq was performed to identify differentially expressed genes (DEGs) and conduct GO/KEGG functional annotation. Methylation and expression data were integrated to identify overlapping genes showing significant changes at both levels, followed by GO, KEGG and gene-pathway network analyses. This study was approved by the Ethics Committee of the hospital (Ethics No.: GKLW-A-2024-006-01).

RESULTS

A total of 2 652 DMPs corresponding to 1 262 genes were identified, which included 833 hypermethylated genes (66%) and 429 hypomethylated genes (34%). Hypermethylated genes were mainly enriched for functions related to cell junctions, while hypomethylated genes were significantly involved in nervous system development and morphogenesis. RNA-seq identified 2 627 DEGs, including 765 up-regulated genes (29%) and 1 862 down-regulated genes (71%). Up-regulated genes were mainly associated with immune-related processes, and down-regulated genes were mainly related to substance transport. Integrative analysis identified 93 overlapping genes with significant changes in both methylation and expression. And these genes were enriched in extracellular matrix-related processes, calcium ion binding, neurodevelopment, and cell adhesion. Key candidate genes, including LAMB1, LAMB2 and NID1, were further prioritized.

CONCLUSION

Integrated analysis of DNA methylation and transcriptome data reveals WDSTS-related epigenetic-transcriptional alterations and provides clues for exploring disease mechanisms and optimizing diagnostic strategies.