Genetic variation in ICF syndrome: Evidence for genetic heterogeneity

ICF syndrome is a rare autosomal recessive immunoglobulin deficiency, somet imes combined with defective cellular immunity. Other features that are fre quently observed in ICF syndrome patients include facial dysmorphism, devel opmental delay, and recurrent infections. The most diagnostic feature of IC F syndrome is the branching of chromosomes 1, 9, and 16 due to pericentrome ric instability. Positional candidate cloning recently discovered the de no vo DNA methyltransferase: 3B (DNMT3B) as the responsible gene by identifyin g seven different mutations in nine ICF patients. DNMT3B specifically methy lates repeat sequences adjacent to the centromeres of chromosome 1, 9, and 16. Our panel of 14 ICF patients was subjected to mutation analysis in the DNMT3B gene. Mutations in DNMT3B were discovered in only nine of our 14 ICF patients. Moreover, two ICF patients from consanguineous families who did not show autozygosity (i.e. homozygosity by descent) for the DNMT3B locus d id not reveal DNMT3B mutations, suggesting genetic heterogeneity for this d isease. Mutation analysis revealed 11 different mutations, including seven novel ones: eight different missense mutations, two different nonsense muta tions, and a splice-site mutation leading to the insertion of three aa's. T he missense mutations occurred in or near the catalytic domain of DNMT3B pr otein, indicating a possible interference with the normal functioning of th e enzyme. However, none of the ICF patients was homozygous for a nonsense a llele, suggesting that absence of this enzyme is not compatible with life. Compound heterozygosity for a missense and a nonsense mutation did not seem to correlate with a more severe phenotype. Hum Mutat 16:509-517, 2000. (C) 2000 Wiley Liss, Inc.