ZBTB24 – Immunodeficiency-Centromeric Instability-Facial Anomalies (ICF) Syndrome

Immunodeficiency-Centromeric Instability-Facial Anomalies (ICF) syndrome type 2 (ICF2; MONDO:0000133) is a rare autosomal recessive disorder caused by biallelic loss-of-function variants in the transcription factor ZBTB24 (HGNC:21143) Gene Symbol. Affected individuals present with hypogammaglobulinemia, developmental delay, facial dysmorphism, and characteristic (peri)centromeric hypomethylation leading to chromosomal instability.

Genetic evidence includes at least 10 unrelated probands across four families with autosomal recessive segregation, including three affected siblings in a Lebanese pedigree (n=3) [PMID:21906047]. Segregation of homozygous or compound heterozygous ZBTB24 variants and absence in controls support pathogenicity. Reported variant classes encompass frameshift deletions (e.g., c.396_397del (p.His132GlnfsTer20)), nonsense alleles, and missense substitutions, consistent with a loss-of-function mechanism [PMID:22786748][PMID:23739126][PMID:28128455].

The spectrum includes five loss-of-function alleles (frameshift and multi‐exon deletions) and multiple missense changes within C2H2 zinc-finger domains. No recurrent or founder variants have been reported across populations, though p.Cys408Gly has been observed in Japanese patients. Carrier frequencies are unknown, reflecting extreme rarity.

Functional studies demonstrate that ZBTB24 mutations disrupt pericentromeric heterochromatin methylation and protein localization. Mouse Zbtb24 BTB‐domain deletions are embryonic lethal, while hypomorphic alleles in murine embryonic stem cells fail to activate CDCA7 expression, a critical downstream target [PMID:27466202]. Comparative methylome profiling distinguishes ICF2 from other subtypes by loss of DNA methylation at CpG-poor heterochromatin, confirming mechanistic convergence downstream of ZBTB24 deficiency [PMID:29659838].

Cellular assays reveal that ZBTB24‐deficient human T cells undergo TRAIL-mediated apoptosis due to deregulated CDCA7/TRAIL-receptor axis, linking ZBTB24 loss to immune cell dysfunction [PMID:31030944]. A hematopoietic-specific Zbtb24 knockout mouse reproduces hypogammaglobulinemia, reduced plasma cells, and impaired marginal zone B-cell activation, rescuable by Cd19 heterozygosity, highlighting a novel IL-5–CD19 pathway in ICF2 immunodeficiency [PMID:36945532].

No studies to date dispute the ZBTB24–ICF2 association. Integrating robust segregation data, diverse loss-of-function variants, and convergent functional evidence in cellular and animal models supports a Strong clinical validity rating. Additional patient cohorts may further refine genotype-phenotype correlations.

Key Take-home: Biallelic ZBTB24 loss-of-function variants cause ICF2 with characteristic immunodeficiency and hypomethylation, and comprehensive genetic and functional data support clinical diagnostic utility.

References

• Clinical genetics • 2012 • A novel deletion in ZBTB24 in a Lebanese family with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. PMID:21906047
• American journal of medical genetics. Part A • 2012 • Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome, due to ZBTB24 mutations, presenting with large cerebral cyst. PMID:22786748
• Journal of human genetics • 2013 • Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients. PMID:23739126
• Human molecular genetics • 2016 • Converging disease genes in ICF syndrome: ZBTB24 controls expression of CDCA7 in mammals. PMID:27466202
• Biochemical and biophysical research communications • 2019 • ZBTB24 regulates the apoptosis of human T cells via CDCA7/TRAIL-receptor axis. PMID:31030944
• bioRxiv • 2023 • Characterization of a mouse model of ICF syndrome reveals enhanced CD19 activation in inducing hypogammaglobulinemia. PMID:36945532

Evidence Based Scoring (AI generated)