Ehmt2 loss-of-function alterations cause a kleefstra-like syndrome

Dysregulation of the epigenetic machinery is associated with neurodevelopmental defects in humans. Kleefstra syndrome (KS) is a neurodevelopmental syndrome caused by heterozygous alterations in the gene EHMT1 that cause loss-of-function. EHTM1 and EHMT2 are highly similar histone methyltransferases that play relevant roles in development. Despite their similarity, individuals with alterations in EHMT2 have never been described. Here, we describe a pediatric patient with a KS overlapping phenotype and a single base de novo substitution in EHMT2 that causes the amino acid change p.Ala1077Ser in the catalytic SET domain. This change causes a reduction in the affinity of the catalytic domain for the H3 tail and in the activity of the enzyme by three- to five-fold. DNA methylation, histone methylation and gene expression profiles suggest a significant overlap between the EHMT2 p.Ala1077Ser variant and KS. Based on this evidence we suggest that EHMT2 haploinsufficiency causes a Kleefstra-like syndrome. Although we cannot rule out dominant negative effects caused by the EHMT2 p.Ala1077Ser variant, our data and previously published data suggest that loss of EHMT2 function is probably more detrimental to cells than loss of EHMT1 explaining why individuals with alterations in EHMT2 are very rare. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded with project PID2021-128087OB-I00 by MCIN /AEI /10.13039/501100011033 / FEDER, UE to M.J.B, and AESI PT20CIII/00009 (ISCIII Platform of Biobanks and Biomodels PT-20). Funding was also partially provided by the Genome Canada and the Ontario Genomics Institute Genomics Applications Partnership Program Grant (OGI-188). This study used tools provided through the RD-Connect GPAP, which received funding originally from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 305444. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The research ethics committee of Instituto de Salud Carlos III gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors