Described causes for immunodeficiency in ICF. Different mechanisms may be behind the development of humoral B cell immunodeficiency in ICF, some of them coincident and other distinct between subclasses of patients, and even between individual patients. Many of these, one must refer, are still to be properly described. Trans effects caused by chromosome instability caused by a genome-wide defective DNA methylation can translate in modifications to normal immune cell development, such as immune cell senescence caused by telomere shortening described in ICF patients (53). Such instability may lead to increased apoptosis in rapidly dividing immune cells, impairing clonal expansion of B (or T cells) in response to antigens, limiting the immune repertoire and weakening immune responses. Altered DNA methylation patterns of specific immune-related genes have also been described in ICF. The most prominent examples are CD27, whose promoter hypermethylation is associated with downregulation of the gene itself and upregulation of the antisense gene, and hypomethylation of intragenic regions of PTPRC (CD45) associated with modifications to exon splicing (86). Plus, inefficient CSR, particularly in ICF2–4 patients, appears to be an undisputed contributor (103, 104).