In all of these patients, classical CSR defects were excluded, i.e., phenotypic or genetic defects in CD40L, CD40, AICDA, UNG, or the recently identified PI3K defects, established in Activated PI3K-p110delta syndrome, types 1 and 2 (APDS-1 and APDS-2, caused by a number of gain-of-function mutations in PIK3CD and PIK3R1, respectively) [23–25]. The gene discussed is PIK3R1; the disease is Down syndrome.