RAC1 and Macrocephaly: Variants in the TRIO GEF1 domain that decrease Rac1 activity are associated with milder ID and microcephaly, whereas variants in the adjacent spectrin repeat 8 domain that increase Rac1 activity are associated with more severe ID and macrocephaly (Barbosa et al., 2020; Bonnet et al., 2023; Kloth et al., 2021; Bircher et al., 2022).