BHLHE22 is a Class II basic helix-loop-helix transcription factor expressed exclusively in the retina and central nervous system 1. It functions as a transcriptional repressor that inhibits DNA binding of TCF3/E47 homodimers and heterodimers, regulating genes involved in neural development and neuronal differentiation. BHLHE22 acts as an area-specific transcription factor regulating neocortical arealization and plays a crucial role in retinogenesis, particularly in specifying amacrine and bipolar subtypes 1. It forms transcriptional repressor complexes, notably with PRMT5 and LIP, to control gene expression [PMID:36941015; 25]. Disease relevance includes neurodevelopmental disorders: BHLHE22 variants cause autosomal dominant and recessive neurodevelopmental disease with absent corpus callosum, severe motor and cognitive delays, and abnormal tone 1. It is implicated in autism spectrum disorder as a key regulator of excitatory neuron specification 3. Additionally, BHLHE22 associations extend to cancer and psychiatric phenotypes: upregulation drives immunosuppressive bone tumor microenvironment in prostate cancer bone metastases 4, while lower expression in endometrial cancer associates with unfavorable prognosis 5. Rare variants link to severe major depressive disorder 6. BHLHE22 hypermethylation serves as a biomarker for endometrial cancer detection in cervical scrapings 7.