Submission Details

AICDA was first reported in relation to Autosomal Recessive Hyper-IgM syndrome (HIGM) in 2000 (Revy P, et al., 2000, PMID: 11007475). Activation-induced cytidine deaminase (AID) is involved in somatic hypermutation (SHM), gene conversion, and class-switch recombination (CSR) in B-lymphocytes by deaminating C to U during transcription of Ig-variable and Ig-switch region DNA. AID-deficient patients are prone to infections and lymphoid hyperplasia related to giant germinal centers (PMID: 14962793). Additionally, patients with HIGM2 are prone to develop autoimmune diseases; B cells from AID-deficient patients express an abnormal Ig repertoire and high frequencies of autoreactive antibodies, demonstrating that AID is required for the establishment of both central and peripheral B-cell tolerance (PMID: 21700883). The mechanism for disease is biallelic loss of function (Muramatsu et al, PMID: 10373455). Of note, AICDA is also related to autosomal dominant HIGM. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in molecular mechanisms (biallelic loss of function vs. monoallelic dominant negative), inheritance pattern (recessive vs. dominant) and phenotypic variability (autoimmune disease has only been reported in the recessive form). Therefore, the disease entities have been split and autosomal dominant HIGM has been curated separately.

At least 41 unique variants (i.e. missense, in-frame indel, nonsense, frameshift, large deletion, etc.) have been reported in 110 cases of autosomal recessive HIGM (Reviewed in PMID: 22992148). Evidence supporting this gene-disease relationship includes case level and experimental data. Variants in this gene reported in 13 probands in three publications (PMIDs: 11007475, 14962793 and 11112359) have been included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by animal models (PMIDs: 10373455, 25252954) that recapitulate disease, expression studies (PMIDs: 10373455, 10950930) showing expression specifically in B cells of lymphoid tissues, biochemical function studies (PMID: 12692563), and functional alteration experiments showing defective CSR (PMID: 16964591). In summary, AICDA is definitively associated with autosomal recessive Hyper-IgM syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been held up over time.