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

Abstract WDR5 is a broadly studied, highly conserved 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. Here, we present data from ten unrelated individuals with six different rare de novo missense variants in WDR5 ; one identical variant was found in four individuals, and another variant in two individuals. All ten individuals had neurodevelopmental disorders including speech/language delays (N=10), intellectual disability (N=8), epilepsy (N=6) and autism spectrum disorder (N=4). Additional phenotypic features included abnormal growth parameters (N=6), heart anomalies (N=2) and hearing loss (N=2). All six missense variants occurred in regions of the WDR5 locus that are known to be extremely intolerant for variation. Three-dimensional 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 family complexes. Thus, we define a new neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of associated features including intellectual disability, speech/language impairments, epilepsy and autism spectrum disorders. This finding highlights the important role of COMPASS family proteins in neurodevelopmental disorders.