SETD1B is a histone lysine methyltransferase that catalyzes methyl group transfer to histone H3 lysine 4 (H3K4), generating H3K4me1, H3K4me2, and H3K4me3 marks at active chr12 sites 12. As part of the Set1C/COMPASS complex, SETD1B regulates transcriptional programming and is essential for hematopoietic stem cell maintenance and lymphoid lineage specification 3. Pathogenic SETD1B variants cause a syndromic neurodevelopmental disorder characterized by global developmental delay, language delay/regression, intellectual disability, autism, and variable seizure phenotypes, with developmental impairment often preceding seizure onset 45. Males are significantly overrepresented and more severely affected 4. Seizures are frequently treatment-refractory but show responsiveness to lamotrigine in some cases 6. Beyond neurological disease, SETD1B functions as a tumor suppressor in lymphoid malignancies 7. SETD1B loss and deletion occur in 7% of follicular lymphomas and 16% of diffuse large B cell lymphomas, conferring resistance to BCL2 inhibitors by suppressing proapoptotic BCL2 family protein expression 7. SETD1B is also occasionally altered in oesophageal squamous cell carcinoma 8. These findings establish SETD1B as a critical epigenetic regulator controlling both normal neurodevelopment and hematopoiesis while suppressing lymphomagenesis.