ARHGEF1 and Global developmental delay: Clusters of variants in the SR8 and GEF1 domains impacted cellular Rac1 activity in different ways and were associated with distinct endophenotypes in heterozygous carriers: SR8 domain variants were linked to developmental delay, macrocephaly, and hyperactive Rac1 activity in cells, whereas GEF1 domain variants were linked to mild intellectual disability, microcephaly, and reduced Rac1 activity in cells (15).