Ehmt2 Loss-of-function Alterations Cause a Kleefstra-like Syndrome

Abstract

Abstract The dysregulation of the epigenetic machinery has been linked to neurodevelopmental defects in humans. One such syndrome is Kleefstra syndrome (KS), which results from heterozygous alterations in the EHMT1 gene, leading to loss of function. EHMT1 and EHMT2 are highly similar histone methyltransferases that play crucial roles in development. Despite their similarity, alterations in EHMT2 have not been previously reported. In this study, we present a pediatric patient exhibiting a phenotype overlapping with KS, harboring a de novo single base substitution in EHMT2. This substitution results in the amino acid change p.Ala1077Ser in the catalytic SET domain, causing a decrease in the affinity of this domain for histone H3 tail and a three- to five-fold reduction in enzyme activity. As part of an advanced diagnostic strategy, we leveraged epigenomics and proteomics data to comprehensively characterize the EHMT2 p.Ala1077Ser variant. Analysis of DNA methylation, histone methylation, and gene expression profiles reveals a substantial overlap between the EHMT2 p.Ala1077Ser variant and KS. Based on these findings, we propose that EHMT2 haploinsufficiency leads to a Kleefstra-like syndrome. While we cannot entirely rule out dominant negative effects caused by the EHMT2 p.Ala1077Ser variant, our data, in conjunction with previously published studies, suggest that the loss of EHMT2 function is more detrimental to cells than the loss of EHMT1. This may explain the rarity of individuals with alterations in EHMT2.