Interpretation of next-generation sequencing data of individuals with an apparent sporadic neurodevelopmental disorder (NDD) often focusses on pathogenic variants in genes associated with NDD, assuming full clinical penetrance with limited variable expressivity. Consequently, inherited variants in genes associated with dominant disorders may be overlooked when the transmitting parent is clinically unaffected. While de novo variants explain a substantial proportion of cases with NDDs, a significant number remains undiagnosed possibly explained by coding variants associated with reduced penetrance and variable expressivity. We characterized twenty families with inherited heterozygous missense or protein-truncating variants (PTVs) in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome, characterized by intellectual disability, speech delay and recognizable facial features (SNIBCPS). Notably, the majority of the inherited CHD3 variants were maternally transmitted. Computational facial and human phenotype ontology-based comparisons demonstrated that the phenotypic features of probands with inherited CHD3 variants overlap with the phenotype previously associated with de novo variants in the gene, while carrier parents are mildly or not affected, suggesting variable expressivity. Additionally, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of related healthy carriers with a CHD3 PTV, suggested that compensation of expression from the wildtype allele is unlikely to be an underlying mechanism. Our results point to a significant role of inherited variation in SNIBCPS, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation towards understanding the broader contributions of such variation to the landscape of human disease.

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.