Distribution of PTPN11 genetic variants associated with rare diseases. Schematic overview of the exonic structure of PTPN11, consisting of 15 exons (above) and the encoded protein SHP2 (below) with two SH2 domains and the catalytic PTP domain. Frequently occurring mutations are indicated color-coded corresponding to the boxes with the 2–4 most frequently occurring mutations highlighted. Created using BioRender (BioRender.com).

SHP2 has a central role in signaling. Schematic representation of SHP2 signaling in (left) growth factor signaling, (middle) JAK/STAT signaling and (right) PZR signaling. SHP2 binds to phosphotyrosine residues (yellow dots) in transmembrane growth factor receptors, cytokine receptors or PZR via its SH2 domains. Subsequently, RAS/MAPK signaling, PI3K/AKT signaling, STAT3/5 signaling or signaling via SRC to ERK1/2/MAPK is activated as indicated. Created using BioRender (BioRender.com).

Models used to study SHP2 variants in NS, NSML and leukemia. Advantages and disadvantages of the models are listed in the first column, how the models were derived in the second column. The third column displays the different variants that were used, color-coded as in Figure 1. The observed phenotypes and original references are listed in columns 4 and 5, respectively. Created using BioRender (BioRender.com).