In-depth immune profiling of a patient with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2 caused by a novel mutation in <i>ZBTB24</i>

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare genetic disorder characterized by recurrent, severe infections. Mutations in DNA methylation genes such as DNMT3B (ICF1), ZBTB24 (ICF2), CDCA7 (ICF3), and HELLS (ICF4) cause ICF. ICF2 syndrome has been previously described, yet the extent of its clinical presentation and immunological consequences needs to be further elucidated. We describe a patient with a novel homozygous mutation in ZBTB24 (Q375Hfs*3). While infections with extracellular pathogens are frequent in other reported ICF2 patients, our patient also displays infections by intracellular pathogens. At the molecular level, we showed that the novel mutation results in a truncated ZBTB24 protein that disrupts its function in DNA methylation. We thoroughly characterized the immunological consequences of ZBTB24 deficiency using mass cytometry coupled with state-of-the-art computational methods. Our analysis revealed reduced frequencies of natural killer cells and class-switched memory B cell populations in our patient, along with low levels of the immunoglobulin isotypes IgG4 and IgM. Despite observing normal cell frequencies within the T and myeloid compartments, the clinical presentation of this patient suggests a functional defect in immune cells known to be critical to combat intracellular pathogens. Overall, this study expands the clinical and immunological features of ZBTB24 deficiency and highlights the importance of ZBTB24 to the human immune response.