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For genetically heterogeneous diseases a better understanding of how the underlying gene defects are functionally interconnected will be important for dissecting disease etiology. The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is a chromatin disorder characterized by mutations in  DNMT3B ,  ZBTB24 ,  CDCA7  or  HELLS . Here, we generated a Zbtb24 BTB domain deletion mouse and found that loss of functional Zbtb24 leads to early embryonic lethality. Transcriptome analysis identified  Cdca7  as the top down-regulated gene in  Zbtb24  homozygous mutant mESCs, which can be restored by ectopic ZBTB24 expression. We further demonstrate enrichment of ZBTB24 at the  CDCA7  promoter suggesting that ZBTB24 can function as a transcription factor directly controlling  Cdca7  expression. Finally, we show that this regulation is conserved between species and that  CDCA7  levels are reduced in patients carrying  ZBTB24  nonsense mutations. Together, our findings demonstrate convergence of the two ICF genes  ZBTB24  and  CDCA7  at the level of transcription.

Converging disease genes in ICF syndrome: ZBTB24 controls expression of CDCA7 in mammals