ZBTB24 – ICF Syndrome Type 2

Immunodeficiency-centromeric instability-facial anomalies syndrome type 2 (ICF2) is a rare autosomal recessive combined immunodeficiency characterized by hypogammaglobulinemia, pericentromeric DNA hypomethylation, and distinctive facial features. Biallelic loss-of-function variants in the transcription factor ZBTB24 (HGNC:21143) underlie the disease, leading to impaired B-cell differentiation and antibody deficiency.

Inheritance is autosomal recessive with multiple consanguineous and non-consanguineous pedigrees described. To date, 39 probands with ZBTB24 mutations have been reported (PMID:32061411), including sibships of three affected brothers demonstrating segregation of biallelic variants (PMID:21906047). This supports robust AR transmission.

The variant spectrum encompasses predominantly truncating alleles and missense changes within zinc-finger domains. For example, the recurrent frameshift c.433_434del (p.Ala145ProfsTer7) (PMID:32061411) abolishes protein function. Missense mutations disrupting C2H2 motifs have also been documented and correlate with variable immunoglobulin isotype deficiencies.

Functional investigations reveal that ZBTB24 loss disrupts transcriptional activation of CDCA7, leading to genome-wide hypomethylation in patient cells and murine models (PMID:27466202; PMID:36945532). Patient-derived iPSCs homozygous for the p.Cys408Gly mutation recapitulate centromeric hypomethylation and impaired hematopoietic differentiation (PMID:39040103).

Mechanistically, ZBTB24 functions as a BTB-zinc-finger transcription factor that directly regulates CDCA7 expression to maintain DNA methylation. In B cells, ZBTB24 deficiency derepresses Il5ra, enhances IL-5 signaling, and elevates CD19 phosphorylation, impairing plasma cell differentiation in CRISPR mouse models (PMID:39277732; PMID:37990035).

Together, the integration of genetic, segregation, and experimental data yields a Strong ClinGen classification for the ZBTB24–ICF2 association. ZBTB24 mutation testing is recommended in early-onset hypogammaglobulinemia with facial anomalies to inform diagnosis, genetic counseling, and targeted management.

References

• Immunobiology • 2020 • A young girl with hypogammaglobulinemia and granulomatous hepatitis caused by a novel mutation in ZBTB24 gene: A case based analysis. PMID:32061411
• Clinical Genetics • 2012 • A novel deletion in ZBTB24 in a Lebanese family with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. PMID:21906047
• Human Molecular Genetics • 2016 • Converging disease genes in ICF syndrome: ZBTB24 controls expression of CDCA7 in mammals. PMID:27466202
• bioRxiv • 2023 • Characterization of a mouse model of ICF syndrome reveals enhanced CD19 activation in inducing hypogammaglobulinemia. PMID:36945532
• Frontiers in Immunology • 2024 • A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency. PMID:39040103
• Cellular & Molecular Biology Letters • 2024 • The ICF2 gene Zbtb24 specifically regulates the differentiation of B1 cells via promoting heme synthesis. PMID:39277732
• Cellular & Molecular Immunology • 2023 • Enhanced CD19 activity in B cells contributes to immunodeficiency in mice deficient in the ICF syndrome gene Zbtb24. PMID:37990035

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