Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes Stefan H. Lelieveld, Laurens Wiel,

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Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes Stefan H. Lelieveld, Laurens Wiel, Hanka Venselaar, Rolph Pfundt, Gerrit Vriend, Joris A. Veltman, Han G. Brunner, Lisenka E.L.M. Vissers, Christian Gilissen The American Journal of Human Genetics Volume 101, Issue 3, Pages 478-484 (September 2017) DOI: 10.1016/j.ajhg.2017.08.004 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Examples of Identified Genes with Clustering Mutations Protein domains are annotated based on Pfam HMM search.26 cDNA locations of de novo missense mutations are depicted by blue pins. Genes shown here are as follows: SMAD4 (A), CDK13 (B), PACS2 (C). Figures visualizing the clustering of de novo missense mutations in the other 12 genes are provided in Figures S1–S15. The American Journal of Human Genetics 2017 101, 478-484DOI: (10.1016/j.ajhg.2017.08.004) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Intolerance to Missense Variation Violin plots show the distribution of the gene-based dN/dS (y axis) per gene set (x axis). The median dN/dS is indicated by a red horizontal line. The NHI genes are more intolerant to missense variation than HI genes (HI genes median: 0.460; NHI genes median: 0.428; p = 2.24e-03). In addition, the identified genes with clustering mutations are more intolerant to missense variation than HI genes (genes with clustering mutations median: 0.352; p = 8.45e-03). The American Journal of Human Genetics 2017 101, 478-484DOI: (10.1016/j.ajhg.2017.08.004) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 Examples of Modeling of Missense Mutations on 3D Protein Structures Wild-type residues are marked in blue; de novo mutations are indicated as red globes or lines (Tables S17). (A) 3D structure of GNA1, acting through HI, showing that the modeled missense mutations are buried and likely to disrupt protein folding. (B) Structure of PPP2R5D, acting through NHI, where the modeled missense mutations affect mostly surface residues and are expected to have no or only local structural effects. (C) Zoom-in of known missense variants p.Arg496Cys and p.Ile500Val in SMAD4 known to act through a gain-of-function mechanism. These variants are located on the surface of the monomer and in contact with another SMAD4 monomer.38 (D) Zoom-in of the missense variant p.Gly343Arg in ACTL6B which is located at the surface. The side-chain points toward the solvent, therefore the larger Arginine will fit. (E) Zoom-in of the missense variant p.Pro65Leu in PCGF2 close to the interaction site with other molecules. The American Journal of Human Genetics 2017 101, 478-484DOI: (10.1016/j.ajhg.2017.08.004) Copyright © 2017 American Society of Human Genetics Terms and Conditions