Hypomethylation of the MEG8:Int2-DMR in patients with pathogenic PLAG1 variants suggests new role of the chr14q32 imprinting cluster in Silver-Russell syndrome

Our results indicate that pathogenic PLAG1 variants leading to stable aberrant PLAG1 proteins and possibly acting in a dominant-negative manner influence methylation of the MEG8 locus. This study suggests a new pathogenetic mechanism of the PLAG1 gene in SRS, involving imprinted genes in the chr14q32 cluster through deregulation of the MEG8:Int2-DMR and provides an epigenetic signature that may be used to assess the damaging potential of the PLAG1 variants.