Mutations in RAPGEF4 were associated with autism,18 while RAPGEF3 single-nucleotide polymorphisms were associated with anxiety and depression.17 Individual knockout of either Rapgef3 or 4 had no behavioral effect while the double knockout led to reduced spatial memory which we did not observe, suggesting there is potential for compensation within this gene family.62 Here, RAPGEF3 is linked to major depressive disorder.