Loss of the immunomodulatory transcription factor BATF2 in humans is associated with a neurological phenotype

Epilepsy and mental retardation are known to be associated with pathogenic mutations of a broad range of genes that are expressed in the brain and play a role in neurodevelopment. Here, we report a family with three affected individuals whose clinical symptoms closely resemble a neurodevelopmental disorder. Whole-exome sequencing identified a homozygous stop-gain mutation p.Q19* in the BATF2 gene in the patients. The BATF2 transcription factor is predominantly expressed in macrophages and monocytes, and has been reported to modulate AP-1 transcription factor-mediated pro-inflammatory responses. Transcriptome analysis showed an altered base-level expression of interferon-stimulated genes in the patients' blood, typical for type I interferonopathies. Peripheral blood mononuclear cells from all three patients demonstrated elevated responses to innate immune stimuli, which could be reproduced in CRISPR–Cas9-generated BATF2-/- human monocytic cell lines. BATF2 is, therefore, a novel disease-associated gene for severe epilepsy and mental retardation, related to dysregulation of immune responses, which underscores the relevance of neuroinflammation for epilepsy. Overall design: THP-1 human leukemia monocytic cells treated with 9.2s RNA or R848 ligands of TLR7/8 were compared to untreated cells using two independent CRISPR-Cas9-generated BATF2-/- cell lines or wild-type cells. Three replicates were used in experiments 1 and 3. Two replicates were used in experiment 2.