Mutations in ZBTB24 Are Associated with Immunodeficiency, Centromeric Instability, and Facial Anomalies Syndrome Type 2

Abstract

Autosomal-recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is mainly characterized by recurrent, often fatal, respiratory and gastrointestinal infections. About 50% of patients carry mutations in the DNA methyltransferase 3B gene (DNMT3B) (ICF1). The remaining patients carry unknown genetic defects (ICF2) but share with ICF1 patients the same immunological and epigenetic features, including hypomethylation of juxtacentromeric repeat sequences. We performed homozygosity mapping in five unrelated ICF2 patients with consanguineous parents and then performed whole-exome sequencing in one of these patients and Sanger sequencing in all to identify mutations in the zinc-finger- and BTB (bric-a-bric, tramtrack, broad complex)-domain-containing 24 (ZBTB24) gene in four consanguineously descended ICF2 patients. Additionally, we found ZBTB24 mutations in an affected sibling pair and in one patient for whom it was not known whether his parents were consanguineous. ZBTB24 belongs to a large family of transcriptional repressors that include members, such as BCL6 and PATZ1, with prominent regulatory roles in hematopoietic development and malignancy. These data thus indicate that ZBTB24 is involved in DNA methylation of juxtacentromeric DNA and in B cell development and/or B and T cell interactions. Because ZBTB24 is a putative DNA-binding protein highly expressed in the lymphoid lineage, we predict that by studying the molecular function of ZBTB24, we will improve our understanding of the molecular pathophysiology of ICF syndrome and of lymphocyte biology in general.

DNA replication is altered in Immunodeficiency Centromeric instability Facial anomalies (ICF) cells carrying DNMT3B mutations

“…5 The remaining 40% of patients, either carry mutations in the ZBTB24 transcription factor (ICF type 2) or do not have known mutations. 6,7 ICF cells are characterized by several molecular defects. Non-coding repetitive sequences (ie, satellites 2 and 3, subtelomeric sequences, and Alu sequences) [8][9][10] and genes located in constitutive and facultative heterochromatin (hereafter named C-heterochromatin and F-heterochromatin, respectively) are hypomethylated.…”

Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects

“…7 All described variants are based on the reference DNMT3B (NM_006892.3) and ZBTB24 (NM_014797.2) accessions.…”

“…In ICF patients, large, often centromeric, DNA repeats show reduced CpG methylation, and ICF2 and ICFX patients differ from ICF1 patients by the presence of additional a-satellite repeat hypomethylation. 7,9 The aim of the present study is to identify possible differences in the clinical presentation and immunological characteristics of patients with ICF1, ICF2 and ICFX syndrome.…”

“…1 Recently, mutations in the zinc-finger and BTB domain-containing 24 gene (ZBTB24) on chromosome 6q21 were described in most DNMT3B mutationnegative patients, and these cases were designated as ICF2 patients. 7,8 Mutations in DNMT3B or ZBTB24 do not explain all ICF patients and there remains a small group with unknown etiology, 7 here provisionally designated as ICFX. In ICF patients, large, often centromeric, DNA repeats show reduced CpG methylation, and ICF2 and ICFX patients differ from ICF1 patients by the presence of additional a-satellite repeat hypomethylation.…”

Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract

“…Mutations in this gene lead to the rare syndrome immunodeficiencycentromeric instability facial anomalies, a diagnosis that was not established previously in this patient. 17 This syndrome features pleiotropic clinical presentations, which include immunodeficiency of variable extent, developmental delay, intellectual disability, and mild facial dimorphism. Immunodeficiencycentromeric instability facial anomalies has also been reported to include congenital malformations, including CAKUT.…”