Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein's function mechanism. Furthermore, there is some correlation between the magnitude of the change and the severity of the resultant phenotype. A comparison of the distribution of the pathogenic mutations along the length of DYRK1A with that of natural variants, as found in the ExAC database, confirms that mutations in the N-terminal end of the kinase domain are more disruptive of protein function. In particular, pathogenic mutations occur in significantly closer proximity to the ATP and the substrate peptide than the natural variants. Overall, we suggest that de novo dominant mutations in DYRK1A account for nearly 0.5% of severe developmental disorders due to substantially reduced kinase function.

Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2-1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case-control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e - 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e - 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic-phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders.