DNMT3B Mutations and DNA Methylation Defect Define Two Types of ICF Syndrome

Centre hospitalier re´gional et universitaire de Marseille, Hoˆpital de laTimone, Marseille, FranceCommunicated by Haig H. KazazianICF syndrome is a rare autosomal recessive disease characterized by variable immunodeficiency, centromericinstability, and facial abnormalities. Mutations in the catalytic domain of DNMT3B, a gene encoding a de novoDNA methyltransferase, have been recognized in a subset of patients. ICF syndrome is a genetic disease directlyrelated to a genomic methylation defect that mainly affects classical satellites 2 and 3, both components ofconstitutive heterochromatin. The variable incidence of DNMT3B mutations and the differential methylationdefect of alpha satellites allow the identification of two types of patients, both showing an undermethylation ofclassical satellite DNA. This classification illustrates the specificity of the methylation process and raisesquestions about the genetic heterogeneity of the ICF syndrome. Hum Mutat 25:56–63, 2005.