Submission Details

CARD11 (i.e., CARMA1) was first reported in relation to immunodeficiency 11A (i.e., severe combined immunodeficiency due to CARD11 deficiency) in 2013 (Stepensky P et al., PMID: 23374270). This disease is characterized by infant-onset increased susceptibility to infection with diminished specific T- and B-cell populations (despite normal-sized total T- and B-cell populations) and activity, as well as hypogammaglobulinemia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance patterns, and phenotypic variability for the diseases associated with CARD11. Therefore, the following disease entities have been split into multiple disease entities: autosomal recessive immunodeficiency 11A (i.e., severe combined immunodeficiency due to CARD11 deficiency; OMIM: 615206), autosomal dominant immunodeficiency 11B with atopic dermatitis (OMIM: 617638), and autosomal dominant B-cell expansion with NFkB and T-cell anergy (BENTA; OMIM: 616452). The split curations for immunodeficiency 11B with atopic dermatitis and BENTA have been curated separately. Four variants (three nonsense and one large intragenic deletion) that have been reported as homozygous in four probands in four publications (PMIDs: 23374270, 23561803, 26289640, 32815076) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by animal models, expression studies, and in vitro functional assays in cell lines and patient cells (PMIDs: 12356734, 12818158, 20233721, 23374270, 23561803, 26289640). Expression studies indicate CARD11 is highly and specifically expressed in the spleen, blood, and immune cells (PMID: 12818158) and functional studies in a cell line indicate a role for CARD11 in positive regulation of NFkB (PMID: 12356734). Furthermore, mouse models deficient in CARD11 recapitulated aspects of patient disease, particularly defects in lymphocyte activation, proliferation, and function and hypogammaglobulinemia (PMID: 12818158, 20233721). Immune cells isolated from patients carrying CARD11 variants displayed defects in activation, proliferation, cytokine production, and NFkB activity (PMID: 23374270, 23561803, 26289640). In summary, CARD11 is definitively associated with autosomal recessive immunodeficiency 11A. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.