The epistasis phenomena may be exemplified by digenic variants in genes in which products are playing roles in the same physiological pathways, e.g., variants in TACI, stimulating a T-cell independent class switch recombination, and TCF3 (Transcription Factor 3) aka E2A, a central point of T-cell independent and T-cell dependent immunoglobulin class switching and secretion with a clinical phenotype of immunodeficiency and autoimmunity showing a digenic nature of CVID [44]. This evidence concerns the gene TCF3 and immunodeficiency disease.