Noticeably, the epistasis phenomena may be exerted 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 (CSR), and transcription factor 3 (TCF3 aka E2A), playing a role in T-cell-independent and T-cell-dependent immunoglobulin class switching and secretion with a clinical phenotype of immunodeficiency and autoimmunity [21]. Here, TCF3 is linked to immunodeficiency disease.