In-depth immunophenotyping and functional characterization (Fig. 5, Fig. 6, and Fig. 7), together with compelling clinical overlap with the non-immunological features seen in STIM1/ORAI1 channelopathies, such as ED and peripheral neuropathy, establish monoallelic missense variants in ITPR3 as a cause of syndromic CID. Here, ITPR3 is linked to combined immunodeficiency.