De novo EHMT2 variants cause an autosomal dominant EHMT2-related Kleefstra syndrome via loss of G9a methyltransferase activity

EHMT1 and EHMT2 genes encode human euchromatin histone lysine methyltransferase 1 and 2 (EHMT1 alias GLP; EHMT2 alias G9a) that form heteromeric GLP/G9a complexes with essential roles in epigenetic regulation of gene expression. While EHMT1 haploinsufficiency has been established as the cause of Kleefstra syndrome 1, the pathogenesis of G9a dysfunction in human disease remains largely unknown. We identified seven de novo EHMT2 variants in patients with clinical presentation, episignatures, histone modifications and transcriptomic profiles similar to those of Kleefstra syndrome 1. In vitro studies reveal that these variants encode for structurally stable G9a proteins that are catalytically incompetent due to aberrant interactions either with histone H3 tail or with S-adenosylmethionine. Heterozygous mice carrying a patient-derived variant exhibit growth retardation, facial/skull dysmorphia and aberrant behavior. Here we report pathogenic EHMT2 variants that likely exert dominant-negative effect on GLP/G9a complexes and thus genocopy the EHMT1 haploinsufficiency via a distinct molecular mechanism, defining an autosomal dominant EHMT2-related Kleefstra syndrome.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2026-07-01
DOI
https://doi.org/10.1038/s41467-026-74987-w
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

De novo EHMT2 variants cause an autosomal dominant EHMT2-related Kleefstra syndrome via loss of G9a methyltransferase activity

Tania Attié‐Bitach, Hana Hartmannová, Viktor Stránecký, Petr Nickl et al.
Nature Communications
Genomics and Rare Diseases
article

De novo EHMT2 variants cause an autosomal dominant EHMT2-related Kleefstra syndrome via loss of G9a methyltransferase activity

Tania Attié‐Bitach, Hana Hartmannová, Viktor Stránecký, Petr Nickl, Eva Bermejo, Lenka Nosková, Frédéric Tran Mau‐Them, Purificación Marín Reina, Sheila Ramos-Del Saz, Dmitrijs Rots, Beatriz Baladrón, Lidia Mirela Mielu, David Pajuelo Reguera, Jeanne Amiel, Vítězslav Brinsa, Jan Procházka, Beatriz Martı́nez-Delgado, Ivana Buková, Alan Kádek, Helena Trešlová, Gema Gómez‐Mariano, Cynthia J. Tifft, František Špoutil, Kateřina Hodaňová, Petra Melenovská, Petr Dušek, Jennifer Kerkhof, Radislav Sedláček, Daniel Jirák, Diana Sánchez-Ponce, María J. Barrero, Jakub Sikora, Andrea Gřegořová, Antonio Vitobello, David Moore, Esther Hernández‐SanMiguel, Manuel Posada de la Paz, Lyse Ruaud, Javier Alonso, Kateryna Pysanenko, Bekim Sadiković, Mark Hamilton, Petr Man, Didier Lacombe, Stanislav Kmoch, Rosario Cazorla-Calleja, Matthew L. Tedder, Aleš Hnı́zda, О. В. Федосєєва, Tjitske Kleefstra, Jessica Rzasa, Ariadna Bada-Navarro, Marina Herrero-Matesanz, Sarah Hilton, Marta Fernández-Prieto, Estrella López‐Martín, Haley McConkey, Sourav Ghosh, Michael A. Levy, Sylvie Cervenkova, Christopher Campbell, Ellen F. Macnamara, Shanshan Chow, Louise Thompson, Karolína Musilová, Lenka Steiner Mrázová, Siddharth Banka, Kristýna Neffeová, Lea Pavlovičová, Martina Pavlíková
article en

Abstract

EHMT1 and EHMT2 genes encode human euchromatin histone lysine methyltransferase 1 and 2 (EHMT1 alias GLP; EHMT2 alias G9a) that form heteromeric GLP/G9a complexes with essential roles in epigenetic regulation of gene expression. While EHMT1 haploinsufficiency has been established as the cause of Kleefstra syndrome 1, the pathogenesis of G9a dysfunction in human disease remains largely unknown. We identified seven de novo EHMT2 variants in patients with clinical presentation, episignatures, histone modifications and transcriptomic profiles similar to those of Kleefstra syndrome 1. In vitro studies reveal that these variants encode for structurally stable G9a proteins that are catalytically incompetent due to aberrant interactions either with histone H3 tail or with S-adenosylmethionine. Heterozygous mice carrying a patient-derived variant exhibit growth retardation, facial/skull dysmorphia and aberrant behavior. Here we report pathogenic EHMT2 variants that likely exert dominant-negative effect on GLP/G9a complexes and thus genocopy the EHMT1 haploinsufficiency via a distinct molecular mechanism, defining an autosomal dominant EHMT2-related Kleefstra syndrome.

Nature Communications
Western University (CA), Hôpital Necker-Enfants Malades (FR), National Institutes of Health (US), Radboud University Nijmegen (NL), Technical University of Liberec (CZ), Université de Bordeaux (FR), Inserm (FR), Université de Bourgogne (FR), Czech Academy of Sciences (CZ), Charles University (CZ), Western General Hospital (GB), London Health Sciences Centre (CA), Instituto de Salud Carlos III (ES), Erasmus MC (NL), Radboud University Medical Center (NL), University of Manchester (GB), Centre Hospitalier Universitaire de Bordeaux (FR), Hospital Universitari i Politècnic La Fe (ES), University Hospital Ostrava (CZ), National Human Genome Research Institute (US), Manchester University NHS Foundation Trust (GB), Assistance Publique – Hôpitaux de Paris (FR), Hospital Universitario Puerta de Hierro Majadahonda (ES), Bordeaux Population Health (FR), St Mary's Hospital (GB), Centro de Investigación Biomédica en Red (ES), Czech Academy of Sciences, Institute of Microbiology (CZ), Institute of Clinical and Experimental Medicine (CZ), Hôpital Mère-Enfant (FR), Czech Academy of Sciences, Institute of Molecular Genetics (CZ), Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (AT), MSD (Spain) (ES), Greenwood Genetic Center (US), Genomics (United Kingdom) (GB), Queen Elizabeth University Hospital (GB), General University Hospital in Prague (CZ), Erasmus University Rotterdam (NL)
Univerzita Karlova v Praze, Genome Canada, Ontario Genomics, Ontario Genomics Institute, European Commission, Grantová Agentura České Republiky, Ministerstvo Zdravotnictví Ceské Republiky, Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, Agencia Estatal de Investigación
Good health and well-being
Openalex Percentile: Top 8%
Genomics and Rare Diseases
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.