Human Endogenous Retroviruses and Epigenetic Regulators Are Dysregulated in Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder caused by genetic and epigenetic alterations at chromosome 11p15.5. Increasing evidence suggests that imprinting defects may be accompanied by broader epigenomic perturbations affecting repetitive elements such as human endogenous retroviruses (HERVs). We quantified the transcriptional levels of the HERV-H, HERV-K, and HERV-W-pol genes, the HERV-derived env genes, Syncytin-1 (SYN1) and Syncytin-2 (SYN2), and the epigenetic regulators, TRIM28 and SETDB1, in whole blood from children and adolescents with BWS, stratified by molecular subtype (ICR2 loss of methylation, n = 14; UPD(11)pat, n = 10), and compared with age-matched healthy controls using quantitative real-time PCR. The BWS samples showed significantly increased transcription of HERV-H and HERV-K relative to controls, whereas HERV-W was unchanged. The SYN1 transcripts were significantly higher in UPD(11)pat compared with controls, while SYN2 did not differ between groups. TRIM28 and SETDB1 were significantly overexpressed in BWS, irrespective of molecular subtype, and no significant differences were observed between ICR2 and UPD(11)pat for HERV-H, HERV-K, HERV-W, TRIM28, or SETDB1. These findings indicate selective dysregulation of endogenous retroelements and key repressors in BWS, consistent with epigenetic alterations extending beyond canonical imprinted loci.