ICF syndrome: An epigenetic paradigm for primary immunodeficiencies

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder and a paradigmatic epigenetic inborn error of immunity. It is caused by mutations in genes essential for DNA methylation and chromatin regulation - DNMT3B (ICF1), ZBTB24 (ICF2), CDCA7 (ICF3), and HELLS (ICF4). All subtypes share hypogammaglobulinemia, centromeric instability of chromosomes 1, 9, and 16, and characteristic facial anomalies. ICF highlights the role of DNA methylation in genome stability and immune development: DNMT3B deficiency impairs de novo methylation, while the ZBTB24-CDCA7-HELLS axis affects heterochromatin remodeling and methylation maintenance. These defects drive chromosomal abnormalities and immune dysfunction, including impaired B cell maturation and class-switch recombination. Although each subtype shows distinct genotype-phenotype correlations, all converge on altered methylation of repetitive DNA and deregulated immune-related genes. ICF serves as a key model to understand how epigenetic disruption causes immunodeficiency. Limited treatments include supportive care and hematopoietic stem cell transplantation. Insights from ICF also inform other primary immunodeficiencies with epigenetic alterations, such as common variable immunodeficiency.