BENTA disease is genetically linked to germline-encoded, gain-of-function mutations in caspase recruitment domain 11 (CARD11), a scaffolding protein largely expressed in lymphocytes and required for antigen receptor (AgR)-induced NF-κB activation.3,4 Like somatic mutations found in approximately 10% of diffuse large B-cell lymphomas, CARD11 mutations in patients with BENTA fall within or immediately adjacent to the coiled-coil (CC) domain.5 CC mutations likely abrogate the requirement for AgR-triggered phosphorylation of the inhibitory linker domain, which supports the "open" conformational change necessary for BCL10-MALT1 recruitment and downstream signal transduction via the IκB kinase complex.6 We recently encountered 3 new patients with disease symptoms suggesting BENTA, including moderate, polyclonal B-cell lymphocytosis with a markedly diminished memory B-cell compartment (Table I). The CARD domain is critical for BCL10 interaction and downstream TCR signaling, as well as regulatory T-cell development.7 This mutation was previously reported in 1 case of diffuse large B-cell lymphoma,8 and identified in an unbiased screen for gain-of-function CARD11 mutants capable of activating NF-κB and promoting human diffuse large B-cell lymphoma tumor growth in vitro.6 Indeed, we confirmed that transfection of the C49Y CARD11 mutant into the CARD11-deficient Jurkat T-cell line JPM50.6 resulted in spontaneous protein aggregation, colocalization with MALT1 and active IκB kinase,9 and constitutive NF-κB activation in the absence of AgR stimulation, comparable to other BENTA mutants described (Fig 1, C and D).