SPRY1 and Sagittal craniosynostosis: We identified one de novo LOF in both SPRY1 and SPRY4, developmental regulators of the MAP kinase/ERK pathway; these variants comprised two of only 11 de novo LOFs other than those in SMAD6. The SPRY4 mutation (p.E160*) arose de novo in a proband with sagittal craniosynostosis and no family history (Figure 6a).