A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder.

Abstract

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.

• Authors: 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
• Journal: HGG advances (HGG Adv) Vol. 4 Issue 1 Pg. 100157 (01 12 2023) ISSN: 2666-2477 [Electronic] United States
• PMID: 36408368 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors.

Chemical References

• Chromatin
• WDR5 protein, human
• Intracellular Signaling Peptides and Proteins
• Set1 protein, Drosophila
• Histone-Lysine N-Methyltransferase
• Drosophila Proteins

Topics

• Animals
• Humans
• Autism Spectrum Disorder (genetics)
• Drosophila melanogaster (genetics)
• Neurodevelopmental Disorders (genetics)
• Language Development Disorders
• Cluster Analysis
• Chromatin
• Intracellular Signaling Peptides and Proteins (genetics)
• Histone-Lysine N-Methyltransferase (genetics)
• Drosophila Proteins (genetics)