Submission Details

CARD11 was first reported in relation to autosomal dominant B-cell expansion with NFKB and T-cell anergy (BENTA) disease in 2012 (Snow AL et al., PMID: 23129749). This is a heterogeneous disease characterized by polyclonal B-cell lymphocytosis, splenomegaly, lymphadenopathy, and recurrent upper respiratory tract infections. 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 11A and immunodeficiency 11B with atopic dermatitis have been curated separately. Six variants (missense and small in-frame deletion variants) that have been reported in 12 probands in 8 publications (PMIDs: 23129749, 25352053, 25930198, 26861442, 28336733, 29963038, 31897776, 34557185) are included in this curation. Of these patients, at last 6 carried de novo variants. The mechanism of pathogenicity is known to be gain of function, which is typically determined based on increased constitutive NFkB activation in vitro. This gene-disease association is also supported by experimental evidence, including expression, protein interaction, and biochemical function studies on CARD11 and assessment of functional alterations by CARD11 variants in vitro in cell lines and patient cells (PMIDs: 12154356, 12356734, 12818158, 25352053). CARD11 has been demonstrated to be specifically expressed in lymphocytes (PMID: 12818158), interact with IKKa/IKKB (PMID: 12154356), and have roles in positive regulation of NFkB activation downstream of receptor activation and lymphocyte proliferation (PMID: 12356734, 12818158). The presence of variants in CARD11 identified in patients with BENTA were found to cause increased constitutive activation of NFkB in vitro in cell lines and patient cells (PMID: 23129749, 25352053, 25930198, 31897776, 34557185). These variants were also associated with increased proliferation in patient T and B cells (PMID: 25352053). In summary, CARD11 is definitively associated with autosomal dominant BENTA. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.