ICF syndrome is a rare autosomal recessive disorder associated with immunodeficiency, centromeric instability, and facial abnormalities. About 35 patients are listed and most of the families are from Europe and North Africa. Patients exhibit a severe combined immunodeficiency resulting from a defect in humoral immunity by absence or reduction of serum immunoglobulins. Patients present with recurrent infections and generally die before adulthood. The facial dymorphism includes mainly a hypertelorism, flat nasal bridge, mild micrognatie, and low-set ears. Mental retardation is not a common feature of the ICF phenotype, but some cases of moderate retardation have been reported. Centromeric instability involves heterochromatin decondensation and stretching, associations between centromeres or juxtacentromeric regions forming multi-branched configurations, and chromosome aberrations such as deletions and duplications. The presence of these aberrations allows the diagnosis of ICF syndrome in patients showing variable combined immunodeficiency. Most of the chromosome aberrations concern chromosomes 1, 9, 16, and Y that share large blocks of classical satellites, one of the major components of human constitutive heterochromatin. A marked undermethylation of classical satellite 2 is found in all tissues examined, while chromosome abnormalities are observed only in peripheral blood cells. The inactive X chromosome, which represents facultative heterochromatin, is globally undermethylated in female ICF patients, but at the molecular level CpG islands of X-linked genes are variably demethylated. Demethylation does not induce full reactivation of X - linked genes. Other repeated sequences, such as young Alu sequences, D4Z4 and NBL2 repeats, and alpha satellites may be undermethylated in ICF patients. Imprinted loci were also found inconsistently demethylated. Exonic mutations in the catalytic domain of the gene encoding the de novo DNA methyltransferase DNMT3B, located on the ICF chromosome region 20q11-q13, were first described in five unrelated ICF patients and further confirmed in other ones. More recently, two classes of ICF patients were individualized based on their specific methylation defects and correlated with the presence or absence of DNMT3B mutations. This finding illustrates the specificity of the methylation process and indicates that causal mutations for the second class of ICF can be located either outside the exonic regions of DNMT3B or in another gene.