Peer-reviewedCC BY 4.0Nature Communications
De novo EHMT2 variants cause an autosomal dominant EHMT2-related Kleefstra syndrome via loss of G9a methyltransferase activity
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.
Related
- Base Editing as a Therapeutic Strategy for Autosomal Dominant Tubulointerstitial Kidney Disease caused by Pathogenic UMOD Variants
- The population frequency of predicted pathogenic variants in the genes associated with Autosomal Dominant Polycystic Liver Disease (ADPLD) and kidney cysts
- Autosomal Dominant TWNK Mutations More Likely Manifest with Multisystem Disease than Isolated External Ophthalmoplegia
- Evaluation of γδ T cells in autosomal dominant polycystic kidney disease
- Response to: Autosomal Dominant TWNK Mutations more likely Manifest with Multisystem Disease than Isolated External Ophthalmoplegia
BibTeX
@article{hnizda2026novo,
title = {{De novo EHMT2 variants cause an autosomal dominant EHMT2-related Kleefstra syndrome via loss of G9a methyltransferase activity}},
author = {Aleš Hnízda and Beatriz Martinez-Delgado and Diana Sanchez-Ponce and Javier Alonso and Jeanne Amiel and Tania Attie-Bitach and Ariadna Bada-Navarro and Beatriz Baladron and Eva Bermejo-Sanchez and Vítězslav Brinsa and Ivana Buková and Rosario Cazorla-Calleja and Sylvie Červenková and Shanshan Chow and Petr Dušek and Olha Fedosieieva and Marta Fernandez-Prieto and Sourav Ghosh and Gema Gomez-Mariano and Andrea Gřegořová and Mark James Hamilton and Hana Hartmannová and Esther Hernandez-Sanmiguel and Marina Herrero-Matesanz and Kateřina Hodaňová and Alan Kádek and Jennifer Kerkhof and Tjitske Kleefstra and Didier Lacombe and Michael A Levy and Estrella Lopez-Martin and Ruaud Lyse and Petr Man and Purificacion Marin-Reina and Ellen F Macnamara and Haley Mcconkey and Petra Melenovská and Lidia M Mielu and David Moore and Lenka Steiner Mrázová and Karolína Musilová and Kristýna Neffeová and Petr Nickl and David Pajuelo Reguera and Martina Pavlíková and Lea Pavlovičová and Manuel Posada and Jan Procházka and Kateryna Pysanenko and Sheila Ramos del Saz and Dmitrijs Rots and Jessica Rzasa and Radislav Sedláček and Viktor Stránecký and František Špoutil and Matthew L Tedder and Louise Thompson and Cynthia J Tifft and Frederic Tran Mau-Them and Helena Trešlová},
journal = {Nature Communications},
year = {2026},
month = jul,
doi = {10.1038/s41467-026-74987-w},
url = {https://u-bordeaux.hal.science/hal-05767340v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - De novo EHMT2 variants cause an autosomal dominant EHMT2-related Kleefstra syndrome via loss of G9a methyltransferase activity
AU - Aleš Hnízda
AU - Beatriz Martinez-Delgado
AU - Diana Sanchez-Ponce
AU - Javier Alonso
AU - Jeanne Amiel
AU - Tania Attie-Bitach
AU - Ariadna Bada-Navarro
AU - Beatriz Baladron
AU - Eva Bermejo-Sanchez
AU - Vítězslav Brinsa
AU - Ivana Buková
AU - Rosario Cazorla-Calleja
AU - Sylvie Červenková
AU - Shanshan Chow
AU - Petr Dušek
AU - Olha Fedosieieva
AU - Marta Fernandez-Prieto
AU - Sourav Ghosh
AU - Gema Gomez-Mariano
AU - Andrea Gřegořová
AU - Mark James Hamilton
AU - Hana Hartmannová
AU - Esther Hernandez-Sanmiguel
AU - Marina Herrero-Matesanz
AU - Kateřina Hodaňová
AU - Alan Kádek
AU - Jennifer Kerkhof
AU - Tjitske Kleefstra
AU - Didier Lacombe
AU - Michael A Levy
AU - Estrella Lopez-Martin
AU - Ruaud Lyse
AU - Petr Man
AU - Purificacion Marin-Reina
AU - Ellen F Macnamara
AU - Haley Mcconkey
AU - Petra Melenovská
AU - Lidia M Mielu
AU - David Moore
AU - Lenka Steiner Mrázová
AU - Karolína Musilová
AU - Kristýna Neffeová
AU - Petr Nickl
AU - David Pajuelo Reguera
AU - Martina Pavlíková
AU - Lea Pavlovičová
AU - Manuel Posada
AU - Jan Procházka
AU - Kateryna Pysanenko
AU - Sheila Ramos del Saz
AU - Dmitrijs Rots
AU - Jessica Rzasa
AU - Radislav Sedláček
AU - Viktor Stránecký
AU - František Špoutil
AU - Matthew L Tedder
AU - Louise Thompson
AU - Cynthia J Tifft
AU - Frederic Tran Mau-Them
AU - Helena Trešlová
PY - 2026
DA - 2026/07/01
JO - Nature Communications
DO - 10.1038/s41467-026-74987-w
UR - https://u-bordeaux.hal.science/hal-05767340v1
AB - 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.
SN - 2041-1723
SN - 2041-1723
ER -