A novel deletion in ZBTB24 in a Lebanese family with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2

Abstract

The immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive disease characterized by targeted chromosome breakage, directly related to a genomic methylation defect. It manifests with phenotypic and clinical variability, with the most consistent features being developmental delay, facial anomalies, cytogenetic defects and immunodeficiency with a reduction in serum immunoglobulin levels. From the molecular point of view, ICF syndrome was always divided into ICF type I (ICF1) and ICF type 2 (ICF2). Mutations in DNMT3B gene are responsible for ICF1, while mutations in ZBTB24 have been reported to be responsible for ICF2. In this study, we describe a Lebanese family with three ICF2 affected brothers. Sanger sequencing of the coding sequence of ZBTB24 gene was conducted and revealed a novel deletion: c.396_397delTA (p.His132Glnfs*19), resulting in a loss-of-function of the corresponding protein. ZBTB24 belongs to a large family of transcriptional factors and may be involved in DNA methylation of juxtacentromeric DNA. Detailed molecular and functional studies of the ZBTB24 and DNMT3B genes are needed to understand the pathophysiology of ICF syndrome.

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

“…An ICF1 case with a mild phenotype was recently also reported to have a homozygous c.2308A4G (pK770E) mutation in DNMT3B. 8 In ICF2, immunoglobulin class deficiencies are less extreme: one patient has normal serum immunoglobulins and six of them have normal levels of IgA and/or IgM. Blanco-Betancourt et al 2 studied two ICF1 patients and two DNMT3B mutationnegative ICF patients; three of these patients had agammaglobulinemia.…”

“…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.…”

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.…”

Epigenetics in the Human Brain

“…The MECP2 gene product, methyl-CpG-binding protein 2, is highly expressed in the nervous system and occupies widespread territories of neuronal chromatin, dependent on the local density of methyl-CpG-dinucleotides (Skene et al, 2010). Loss-of-function mutations and other MECP2 structural variants have been linked to Rett syndrome, a disorder of early childhood associated with developmental ............................................................................................................................................................ and cognitive regression and a broad range of neurological symptoms (Amir et al, 1999;Chouery et al, 2011). The molecular and cellular mechanisms linking MECP2 mutations to neuronal dysfunction and brain disease remain incompletely understood.…”