Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype-phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B-and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling.

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Keywords DNMT3B, genotype-phenotype, ICF syndrome, ZBTB24
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Journal European Journal of Human Genetics
Weemaes, C.M.R, van Tol, M.J.D, Wang, J, van Ostaijen-Ten Dam, M.M, van Eggermond, M.C, Thijssen, P.E, … van der Maarel, S.M. (2013). Heterogeneous clinical presentation in icf syndrome: Correlation with underlying gene defects. European Journal of Human Genetics, 21(11), 1219–1225. doi:10.1038/ejhg.2013.40