HGG Advances (Jan 2023)
A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder
- Lot Snijders Blok,
- Jolijn Verseput,
- Dmitrijs Rots,
- Hanka Venselaar,
- A. Micheil Innes,
- Connie Stumpel,
- Katrin Õunap,
- Karit Reinson,
- Eleanor G. Seaby,
- Shane McKee,
- Barbara Burton,
- Katherine Kim,
- Johanna M. van Hagen,
- Quinten Waisfisz,
- Pascal Joset,
- Katharina Steindl,
- Anita Rauch,
- Dong Li,
- Elaine H. Zackai,
- Sarah E. Sheppard,
- Beth Keena,
- Hakon Hakonarson,
- Andreas Roos,
- Nicolai Kohlschmidt,
- Anna Cereda,
- Maria Iascone,
- Erika Rebessi,
- Kristin D. Kernohan,
- Philippe M. Campeau,
- Francisca Millan,
- Jesse A. Taylor,
- Hanns Lochmüller,
- Martin R. Higgs,
- Amalia Goula,
- Birgitta Bernhard,
- Danita J. Velasco,
- Andrew A. Schmanski,
- Zornitza Stark,
- Lyndon Gallacher,
- Lynn Pais,
- Paul C. Marcogliese,
- Shinya Yamamoto,
- Nicholas Raun,
- Taryn E. Jakub,
- Jamie M. Kramer,
- Joery den Hoed,
- Simon E. Fisher,
- Han G. Brunner,
- Tjitske Kleefstra
Affiliations
- Lot Snijders Blok
- Human Genetics Department, Radboud University Medical Center, Nijmegen, the Netherlands; Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Correspondence:
- Jolijn Verseput
- Human Genetics Department, Radboud University Medical Center, Nijmegen, the Netherlands
- Dmitrijs Rots
- Human Genetics Department, Radboud University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
- Hanka Venselaar
- Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands
- A. Micheil Innes
- The Department of Medical Genetics and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Connie Stumpel
- Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW-School for Oncology and Reproduction), Maastricht UMC+, Maastricht, the Netherlands
- Katrin Õunap
- Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
- Karit Reinson
- Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
- Eleanor G. Seaby
- Translational Genomics Group, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Genomic Informatics Group, University Hospital Southampton, Southampton, UK
- Shane McKee
- Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast HSC Trust, Belfast BT9 7AB, UK
- Barbara Burton
- Ann and Robert H. Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Katherine Kim
- Ann and Robert H. Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Johanna M. van Hagen
- Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Quinten Waisfisz
- Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Pascal Joset
- Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
- Katharina Steindl
- Institute of Medical Genetics, University of Zuirch, Schlieren-Zurich, Switzerland
- Anita Rauch
- Institute of Medical Genetics, University of Zuirch, Schlieren-Zurich, Switzerland; University Children’s Hospital Zurich, Zurich, Switzerland
- Dong Li
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Elaine H. Zackai
- Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Sarah E. Sheppard
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Beth Keena
- Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Hakon Hakonarson
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Andreas Roos
- Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, Centre for Neuromuscular Disorders in Children, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada; Department of Neurology, University Hospital Bergmannsheil, Heimer Institute for Muscle Research, 44789 Bochum, Germany
- Nicolai Kohlschmidt
- Institute of Clinical Genetics and Tumor Genetics, Bonn, Germany
- Anna Cereda
- Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy
- Maria Iascone
- Laboratory of Medical Genetics, ASST Papa Giovanni XXIII, Bergamo, Italy
- Erika Rebessi
- Pediatric Neurological Unit and Epilespy Center, Fatebenefratelli Hospital, Milan, Italy
- Kristin D. Kernohan
- Newborn Screening Ontario, Children’s Hospital of Eastern Ontario and Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
- Philippe M. Campeau
- CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Sainte-Justine Hospital, University of Montreal, Montreal, QC H3T 1C5, Canada
- Francisca Millan
- GeneDx, Gaithersburg, MD 20877, USA
- Jesse A. Taylor
- Division of Plastic Surgery, Department of Surgery, The Children’s Hospital of Philadelpia, Philadelphia, PA, USA
- Hanns Lochmüller
- Children’s Hospital of Eastern Ontario Research Institute, Division of Neurology, Department of Medicine, the Ottawa Hospital, Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada
- Martin R. Higgs
- Lysine Methylation and DNA Damage Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Amalia Goula
- Lysine Methylation and DNA Damage Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Birgitta Bernhard
- North-West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Munroe-Meyer, Harrow, UK
- Danita J. Velasco
- Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, USA
- Andrew A. Schmanski
- Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, USA
- Zornitza Stark
- Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
- Lyndon Gallacher
- Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
- Lynn Pais
- Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Paul C. Marcogliese
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
- Shinya Yamamoto
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
- Nicholas Raun
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
- Taryn E. Jakub
- International Max Planck Research School for Language Sciences, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands
- Jamie M. Kramer
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
- Joery den Hoed
- Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands
- Simon E. Fisher
- Language & Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition & Behaviour, Radboud University, Nijmegen, the Netherlands
- Han G. Brunner
- Human Genetics Department, Radboud University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW-School for Oncology and Reproduction), Maastricht UMC+, Maastricht, the Netherlands
- Tjitske Kleefstra
- Human Genetics Department, Radboud University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Corresponding author
- Journal volume & issue
-
Vol. 4,
no. 1
p. 100157
Abstract
Summary: WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.
