Distinct inter-SH2 domain PIK3R1 mutations, mostly causing skipping of exon 11 and deletion of residues 434–475, hyperactivate PI3Kδ in immune cells, causing highly penetrant monogenic immunodeficiency (Deau et al., 2014; Lucas et al., 2014b). The gene discussed is PIK3R1; the disease is immunodeficiency disease.