ICF syndrome, along with other primary immunodeficiencies, in the context of DNA methylation changes occurring throughout the B cell differentiation (and activation) process. Schematic representation of the previously described dynamic demethylation during B cell differentiation. Notably, although less prominent, methylation gains are also observed during this process (98, 113). In immunodeficiencies, defective DNA methylation changes have been reported in germinal center and memory B cells in CVID and HIGM2, with the latter also showing major changes at the naive B cell state (114, 115, 116). Despite the current lack of detailed understanding of DNA methylation modifications during B cell development, it is reasonable to speculate that, given the structural role of all four ICF-related genes in both the establishment and maintenance of DNA methylation patterns, ICF mutations could affect methylation dynamics at any stage of this process. Furthermore, transcription factors described to regulate the different steps of B cell differentiation, from early lineage commitment to peripheral activation and germinal center response, could be influencing or be influenced by altered DNA methylation landscapes and thus could guide in the understanding of epigenetic dysregulation in immunodeficiencies and represent targets for directed therapies (118). Some of these factors have, in fact, been shown to carry causative mutations in monogenic immunodeficiencies (indicated in bold red) (118). HSC, hematopoietic stem cells; MPP, multipotent progenitor; LMPP, lymphoid-prime multipotent progenitor; ELP, early lymphoid progenitor; CLP, common lymphoid progenitor; GC, germinal center.