Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome

Dmitrijs Rots; Arianne Bouman; Ayumi Yamada; Michael Levy; Alexander Dingemans; Bert de Vries; Martina Ruiterkamp-Versteeg; Nicole de Leeuw; Charlotte Ockeloen; Rolph Pfundt; Elke de Boer; Joost Kummeling; Bregje van Bon; Hans van Bokhoven; Nael Nadif Kasri; Hanka Venselaar; Marielle Alders; Jennifer Kerkhof; Haley Mcconkey; Alma Kuechler; Bart Elffers; Rixje van Beeck Calkoen; Susanna Hofman; Audrey Smith; Maria Irene Valenzuela; Siddharth Srivastava; Zoe Frazier; Isabelle Maystadt; Carmelo Piscopo; Giuseppe Merla; Meena Balasubramanian; Gijs Santen; Kay Metcalfe; Soo-Mi Park; Laurent Pasquier; Siddharth Banka; Dian Donnai; Daniel Weisberg; Gertrud Strobl-Wildemann; Annemieke Wagemans; Maaike Vreeburg; Diana Baralle; Nicola Foulds; Ingrid Scurr; Nicola Brunetti-Pierri; Johanna van Hagen; Emilia Bijlsma; Anna Hakonen; Carolina Courage; David Geneviève; Lucile Pinson; Francesca Forzano; Charu Deshpande; Maria Kluskens; Lindsey Welling; Astrid Plomp; Els Vanhoutte; Louisa Kalsner; Janna Hol; Audrey Putoux; Johanna Lazier; Pradeep Vasudevan; Elizabeth Ames; Jessica O'Shea; Damien Lederer; Julie Fleischer; Mary O'Connor; Melissa Pauly; Georgia Vasileiou; André Reis; Catherine Kiraly-Borri; Arjan Bouman; Chris Barnett; Marjan Nezarati; Lauren Borch; Gea Beunders; Kübra Özcan; Stéphanie Miot; Catharina Volker-Touw; Koen van Gassen; Gerarda Cappuccio; Katrien Janssens; Nofar Mor; Inna Shomer; Dan Dominissini; Matthew Tedder; Alison Muir; Bekim Sadikovic; Han Brunner; Lisenka Vissers; Yoichi Shinkai; Tjitske Kleefstra

doi:10.1016/j.ajhg.2024.06.008

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Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome

Journal article

Peer reviewed

Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome

Dmitrijs Rots, Arianne Bouman, Ayumi Yamada, Michael Levy, Alexander Dingemans, Bert de Vries, Martina Ruiterkamp-Versteeg, Nicole de Leeuw, Charlotte Ockeloen, Rolph Pfundt, …

American Journal of Human Genetics, Vol.111(8), pp.1605-1625

08/2024

DOI: https://doi.org/10.1016/j.ajhg.2024.06.008

PMCID: PMC11339614

PMID: 39013458

Abstract

NDD

neurodevelopmental disorders

DNA methylation

EHMT1

H3K9

Kleefstra syndrome

Humans

Histone-Lysine N-Methyltransferase

Phenotype

Child

Child, Preschool

Histocompatibility Antigens

Adolescent

Heart Defects, Congenital

Haploinsufficiency

Mutation

Chromosome Deletion

Craniofacial Abnormalities

Intellectual Disability

Genetic Association Studies

Chromosomes, Human, Pair 9

DNA Methylation

Female

Male

The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the "reader" function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only "writer" methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management.

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Title: Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome
Creators - without role: Dmitrijs Rots - Radboud University Nijmegen
Arianne Bouman - Radboud University Nijmegen
Ayumi Yamada - RIKEN
Michael Levy - London Health Sciences Centre
Alexander Dingemans - Radboud University Medical Center
Bert de Vries - Radboud University Medical Center
Martina Ruiterkamp-Versteeg - Radboud University Medical Center
Nicole de Leeuw - Radboud University Nijmegen
Charlotte Ockeloen - Radboud University Nijmegen
Rolph Pfundt - Radboud University Nijmegen
Elke de Boer - Radboud University Nijmegen
Joost Kummeling - Radboud University Nijmegen
Bregje van Bon - Radboud University Medical Center
Hans van Bokhoven - Radboud University Nijmegen
Nael Nadif Kasri - Radboud University Medical Center
Hanka Venselaar - Radboud University Nijmegen
Marielle Alders - Amsterdam University Medical Centers
Jennifer Kerkhof - London Health Sciences Centre
Haley Mcconkey - London Health Sciences Centre
Alma Kuechler - Essen University Hospital
Bart Elffers
Rixje van Beeck Calkoen
Susanna Hofman - Evean
Audrey Smith - St Mary's Hospital
Maria Irene Valenzuela - Hebron University
Siddharth Srivastava - Boston Children's Hospital
Zoe Frazier - Boston Children's Hospital
Isabelle Maystadt - Institute of Pathology and Genetics
Carmelo Piscopo - Ospedale Antonio Cardarelli
Giuseppe Merla - Casa Sollievo della Sofferenza
Meena Balasubramanian - Sheffield Children's NHS Foundation Trust
Gijs Santen - Leiden University Medical Center
Kay Metcalfe - St Mary's Hospital
Soo-Mi Park - University of Cambridge
Laurent Pasquier - Centre Hospitalier Universitaire de Rennes
Siddharth Banka - St Mary's Hospital
Dian Donnai - St Mary's Hospital
Daniel Weisberg - St Mary's Hospital
Gertrud Strobl-Wildemann - Praxis für Humangenetik
Annemieke Wagemans - Maastricht University
Maaike Vreeburg - Maastricht University
Diana Baralle - University Hospital Southampton NHS Foundation Trust
Nicola Foulds - University Hospital Southampton NHS Foundation Trust
Ingrid Scurr - University Hospitals Bristol NHS Foundation Trust
Nicola Brunetti-Pierri - University of Naples Federico II
Johanna van Hagen - Amsterdam University Medical Centers
Emilia Bijlsma - Leiden University Medical Center
Anna Hakonen - Helsinki University Hospital
Carolina Courage - Helsinki University Hospital
David Geneviève - Université de Montpellier
Lucile Pinson - ERN ITHACA
Francesca Forzano - Guy's and St Thomas' NHS Foundation Trust
Charu Deshpande - Manchester University NHS Foundation Trust
Maria Kluskens
Lindsey Welling
Astrid Plomp - University of Amsterdam
Els Vanhoutte - Maastricht University
Louisa Kalsner - Connecticut Children's Medical Center
Janna Hol - Erasmus University Rotterdam
Audrey Putoux - Hospices Civils de Lyon
Johanna Lazier - Children's Hospital of Eastern Ontario
Pradeep Vasudevan - University Hospitals of Leicester NHS Trust
Elizabeth Ames - C. S. Mott Children's Hospital
Jessica O'Shea - C. S. Mott Children's Hospital
Damien Lederer - Institute of Pathology and Genetics
Julie Fleischer - Southern Illinois University School of Medicine
Mary O'Connor - University of Illinois Urbana-Champaign
Melissa Pauly - Universitätsklinikum Erlangen
Georgia Vasileiou - Comprehensive Cancer Center Erlangen
André Reis - Friedrich-Alexander-Universität Erlangen-Nürnberg
Catherine Kiraly-Borri
Arjan Bouman - Erasmus MC
Chris Barnett - Women's and Children's Hospital
Marjan Nezarati - North York General Hospital
Lauren Borch - North York General Hospital
Gea Beunders - University Medical Center Groningen
Kübra Özcan - Psychiatric Association of Turkey
Stéphanie Miot - Université de Montpellier
Stéphanie Miot - Université de Montpellier, Institut des Neurosciences de Montpellier - INM
Catharina Volker-Touw - University Medical Center [Utrecht]
Koen van Gassen - University Medical Center [Utrecht]
Gerarda Cappuccio - Federico II University Hospital
Katrien Janssens - Antwerp University Hospital
Nofar Mor - Sheba Medical Center
Inna Shomer - Sheba Medical Center
Dan Dominissini - Tel Aviv University
Matthew Tedder - Greenwood Genetic Center
Alison Muir - GeneDx [Gaithersburg, MD, USA]
Bekim Sadikovic - London Health Sciences Centre
Han Brunner - Radboud University Nijmegen
Lisenka Vissers - Radboud University Medical Center
Yoichi Shinkai - Pioneer
Tjitske Kleefstra - Radboud University Nijmegen
Publication Details: American Journal of Human Genetics, Vol.111(8), pp.1605-1625
Identifiers: 9941200909311
Academic Unit: Cell souches plasticité cellul régénérat tissulaire immuno des maladies inflamm - IRMB; Institut des Neurosciences de Montpellier - INM
Language: English
Resource Type: Journal article
Local Fields: hal-04954538