TCF3 was first reported in relation to autosomal agammaglobulinemia in 2013 ( PMID: 24216514). TCF3 encodes the 2 broadly expressed founding members of the basic helix-loop-helix (bHLH) family of transcription factors, E12 and E47. They are identical except for their bHLH domains, which are provided by alternatively spliced exons. E12 and E47 are essential in the differentiation process of common lymphoid progenitors into B-lineage cells and are key regulators of B-cell development. Both autosomal dominant and autosomal recessive inheritance have been reported. Due to lack of distinctive features in the small number of patients reported and the experimental evidence that supports autosomal recessive and autosomal dominant disease, the antibody deficiency GCEP came to the decision of lumping both modes of inheritance at this stage.
A de-novo mutation that results in a dominant negative effect, has been reported in 5 unrelated individuals in 2 publications (PMIDs: 24216514 and 33905048). A heterozygous frameshift has been detected in a proband with reduced switched memory cells and recurrent infections (PMID: 29114388). Biallelic TCF3 mutations (a large deletion and a nonsense) have been reported in 3 patients (PMIDs: 30063982 and Barbouche, et al., 2016)
Experimental evidence includes expression in relevant tissues and animal model. B cells of E2A (-I-) mice are arrested at an early stage of B cell differentiation. Heterozygote animals also showed decreased numbers of both pro-B and mature B cells (PMID: 8001124). In summary TCF3 is definitively associated with autosomal agammaglobulinemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Gene Clinical Validity Standard Operating Procedures (SOP) -SOP8
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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