Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes

Dmitrijs Rots; Sanaa Choufani; Victor Faundes; Alexander J.M. Dingemans; Shelagh Joss; Nicola Foulds; Elizabeth A. Jones; Sarah Stewart; Pradeep Vasudevan; Tabib Dabir; Soo-Mi Park; Rosalyn Jewell; Natasha Brown; Lynn Pais; Sébastien Jacquemont; Khadijé Jizi; Conny M.A. van Ravenswaaij-Arts; Hester Y. Kroes; Constance T.R. M. Stumpel; Charlotte W. Ockeloen; Illja J. Diets; Mathilde Nizon; Marie Vincent; Benjamin Cogné; Thomas Besnard; Marios Kambouris; Emily Anderson; Elaine H. Zackai; Carey McDougall; Sarah Donoghue; Anne O'Donnell-Luria; Zaheer Valivullah; Melanie O'Leary; Siddharth Srivastava; Heather Byers; Nancy Leslie; Sarah Mazzola; George E. Tiller; Moin Vera; Joseph J. Shen; Richard Boles; Vani Jain; Elise Brischoux-Boucher; Esther Kinning; Brittany N. Simpson; Jacques C. Giltay; Jacqueline Harris; Boris Keren; Anne Guimier; Pierre Marijon; Bert B.A. de Vries; Constance S. Motter; Bryce A. Mendelsohn; Samantha Coffino; Erica H. Gerkes; Alexandra Afenjar; Paola Visconti; Elena Bacchelli; Elena Maestrini; Andree Delahaye-Duriez; Catherine Gooch; Yvonne Hendriks; Hieab Adams; Christel Thauvin-Robinet; Sarah Josephi-Taylor; Marta Bertoli; Michael J. Parker; Julie W. Rutten; Oana Caluseriu; Hilary J. Vernon; Jonah Kaziyev; Jia Zhu; Jessica Kremen; Zoe Frazier; Hailey Osika; David Breault; Sreelata Nair; Suzanne M.E. Lewis; Fabiola Ceroni; Marta Viggiano; Annio Posar; Helen Brittain; Traficante Giovanna; Gori Giulia; Lina Quteineh; Russia Ha-Vinh Leuchter; Evelien Zonneveld-Huijssoon; Cecilia Mellado; Isabelle Marey; Alicia Coudert; Mariana Inés Aracena Alvarez; Milou G.P. Kennis; Arianne Bouman; Maian Roifman; María Inmaculada Amorós Rodríguez; Juan Dario Ortigoza-Escobar; Vivian Vernimmen; Margje Sinnema; Rolph Pfundt; Han G. Brunner; Lisenka E.L.M. Vissers; Tjitske Kleefstra; Rosanna Weksberg; Siddharth Banka

doi:10.1016/j.ajhg.2024.06.009

Retour

Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes

Article de revue

Avec comité de lecture

Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes

Dmitrijs Rots, Sanaa Choufani, Victor Faundes, Alexander J.M. Dingemans, Shelagh Joss, Nicola Foulds, Elizabeth A. Jones, Sarah Stewart, Pradeep Vasudevan, Tabib Dabir, …

American journal of human genetics, Vol.111(8), pp.1626-1642

08/08/2024

DOI: https://doi.org/10.1016/j.ajhg.2024.06.009

PMID: 39013459

Résumé

DNA methylation

EHMT1

Kabuki syndrome

Kleefstra syndrome

KMT2C

KMT2D

neurodevelopmental disorder

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition. Pathogenic KMT2C variants cause a disorder, which was named Kleefstra syndrome 2, suggesting its clinical features are highly similar to Kleefstra syndrome. In this study, we delineate the clinical and molecular features of this disorder and show that it is, in fact, different from both Kleefstra and Kabuki syndromes.

Indicateurs

1 Consultations de la notice

See more details

Détails

Titre: Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes
Créateurs - sans rôle: Dmitrijs Rots - Radboud University Medical Center
Sanaa Choufani - Genetics and Genome Biology Program, Research Institute, the Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Victor Faundes - Laboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de Los Alimentos (INTA), Universidad de Chile, Santiago, Chile
Alexander J.M. Dingemans - Radboud University Medical Center
Shelagh Joss - West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, UK
Nicola Foulds - Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton SO16 5YA, UK
Elizabeth A. Jones - Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
Sarah Stewart - Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
Pradeep Vasudevan - Leicester Royal Infirmary
Tabib Dabir - Belfast City Hospital
Soo-Mi Park - Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Rosalyn Jewell - Leeds Teaching Hospitals NHS Trust
Natasha Brown - Victorian Clinical Genetics Service, Murdoch Children’s Research Institute, Melbourne, VIC, Australia
Lynn Pais - Broad Institute
Sébastien Jacquemont - Department of Pediatrics, University of Montreal, Montreal, QC, Canada
Khadijé Jizi - Service de Génétique Médicale, CHU Ste-Justine, Montréal, QC, Canada
Conny M.A. van Ravenswaaij-Arts - University of Groningen, University Medical Centre Groningen, Department Genetics, Groningen, the Netherlands
Hester Y. Kroes - Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
Constance T.R. M. Stumpel - Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
Charlotte W. Ockeloen - Radboud University Medical Center
Illja J. Diets - Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
Mathilde Nizon - Centre Hospitalier Universitaire de Nantes
Marie Vincent - Centre Hospitalier Universitaire de Nantes
Benjamin Cogné - Centre Hospitalier Universitaire de Nantes
Thomas Besnard - Centre Hospitalier Universitaire de Nantes
Marios Kambouris - Division of Genetics, Department of Pathology and Laboratory Medicine Department, Sidra Medicine, Doha, Qatar
Emily Anderson - Liverpool Centre for Genomic Medicine, Liverpool Women’s NHS Foundation Trust, Liverpool, UK
Elaine H. Zackai - Children's Hospital of Philadelphia
Carey McDougall - Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Sarah Donoghue - Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Anne O'Donnell-Luria - Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Zaheer Valivullah - Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Melanie O'Leary - Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Siddharth Srivastava - Department of Neurology, Boston Children’s Hospital, Boston, MA, USA
Heather Byers - Department of Pediatrics, Stanford University, Stanford, CA, USA
Nancy Leslie - Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Sarah Mazzola - Center for Personalized Genetic Healthcare, Cleveland Clinic, Cleveland, OH, USA
George E. Tiller - Department of Genetics, Kaiser Permanente, Los Angeles, CA, USA
Moin Vera - Department of Genetics, Kaiser Permanente, Los Angeles, CA, USA
Joseph J. Shen - Division of Genetics, Department of Pediatrics, UCSF Fresno, Fresno, CA, USA
Richard Boles - NeuraBilities Healthcare, Philadelphia, PA, USA
Vani Jain - All Wales Medical Genomics Service, Wales Genomic Health Centre, Cardiff Edge Business Park, Longwood Drive, Whitchurch, Cardiff CF14 7YU, UK
Elise Brischoux-Boucher - Université de franche-comté
Esther Kinning - Clinical Genetics, Birmingham Women’s and Children’s, Birmingham, UK
Brittany N. Simpson - University of Cincinnati
Jacques C. Giltay - University Medical Center Utrecht
Jacqueline Harris - Kennedy Krieger Institute
Boris Keren - Department of Genetics, APHP Sorbonne University, Paris, France
Anne Guimier - Hôpital Necker-Enfants Malades
Pierre Marijon - Laboratoire de Biologie Médicale Multisites Seqoia FMG2025, 75014 Paris, France
Bert B.A. de Vries - Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
Constance S. Motter - Genetic Center, Akron Children’s Hospital, Akron, OH, USA
Bryce A. Mendelsohn - Kaiser Permanente
Samantha Coffino - Department of Pediatric Neurology, Kaiser Permanente, Oakland, CA, USA
Erica H. Gerkes - University Medical Center Groningen
Alexandra Afenjar - Sorbonne Université
Paola Visconti - IRCCS Istituto Delle Scienze Neurologiche di Bologna, UOSI Disturbi Dello Spettro Autistico, Bologna, Italy
Elena Bacchelli - University of Bologna
Elena Maestrini - University of Bologna
Andree Delahaye-Duriez - Hôpital Jean-Verdier
Catherine Gooch - Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA
Yvonne Hendriks - Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
Hieab Adams - Radboud University Medical Center
Christel Thauvin-Robinet - Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Dijon, France
Sarah Josephi-Taylor - Department of Clinical Genetics, The Children’s Hospital at Westmead, Sydney, NSW, Australia
Marta Bertoli - Northern Genetics Service, Newcastle Upon Tyne NHS Foundation Trust, Newcastle Upon Tyne, UK
Michael J. Parker - Sheffield Children's Hospital
Julie W. Rutten - Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
Oana Caluseriu - University of Alberta
Hilary J. Vernon - Johns Hopkins University School of Medicine
Jonah Kaziyev - Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Jia Zhu - Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Jessica Kremen - Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Zoe Frazier - Boston Children's Hospital
Hailey Osika - Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
David Breault - Boston Children's Hospital
Sreelata Nair - Department of Fetal Medicine, Lifeline Super Specialty Hospital, Kerala, India
Suzanne M.E. Lewis - Department of Medical Genetics, BC Children’s Hospital Research Institute, The University of British Columbia, Vancouver, BC, Canada
Fabiola Ceroni - Pharmacy and Biotechnology Department, University of Bologna, Bologna, Italy
Marta Viggiano - Pharmacy and Biotechnology Department, University of Bologna, Bologna, Italy
Annio Posar - IRCCS Istituto Delle Scienze Neurologiche di Bologna, UOSI Disturbi Dello Spettro Autistico, Bologna, Italy
Helen Brittain - Department of Clinical Genetics, Birmingham Women’s & Children’s NHS Trust, Birmingham, UK
Traficante Giovanna - Medical Genetics Unit, Meyer Children’s Hospital IRCCS Florence, Florence, Italy
Gori Giulia - Medical Genetics Unit,Meyer Children’s Hospital IRCCS, Florence, Italy
Lina Quteineh - Division of Genetic Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland
Russia Ha-Vinh Leuchter - Division of Development and Growth, Department of Pediatrics, University of Geneva, Geneva, Switzerland
Evelien Zonneveld-Huijssoon - University Medical Center Groningen
Cecilia Mellado - Sección de Genética y Errores Congénitos Del Metabolismo, División de Pediatría, Pontificia Universidad Católica de Chile, Santiago, Chile
Isabelle Marey - CHU Grenoble Alpes, Grenoble, France
Alicia Coudert - CHU Grenoble Alpes, Grenoble, France
Mariana Inés Aracena Alvarez - Unit of Genetics and Metabolic Diseases, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Milou G.P. Kennis - Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
Arianne Bouman - Radboud University Medical Center
Maian Roifman - The Prenatal Diagnosis and Medical Genetics Program, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada
María Inmaculada Amorós Rodríguez - Deparment of Pediatrics, Hospital Punta Europa Algeciras, Cadiz, Spain
Juan Dario Ortigoza-Escobar - Institut de Recerca Sant Joan de Déu
Vivian Vernimmen - Maastricht University
Margje Sinnema - Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
Rolph Pfundt - Radboud University Medical Center
Han G. Brunner - Radboud University Medical Center
Lisenka E.L.M. Vissers - Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
Tjitske Kleefstra - Radboud University Medical Center
Rosanna Weksberg - Genetics and Genome Biology Program, Research Institute, the Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Siddharth Banka - Manchester University NHS Foundation Trust
Détails de publication: American journal of human genetics, Vol.111(8), pp.1626-1642
Éditeur: Elsevier Inc
Nombre de pages: 17
Identifiants: 99158867209311
Unité académique: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Langue: English
Type de ressource: Journal article