SETD1B is a histone lysine methyltransferase that catalyzes the deposition of mono-, di-, and trimethyl marks at histone H3 lysine 4 (H3K4me1/me2/me3) at active chr12 sites, playing a central role in transcriptional regulation and DNA repair. The enzyme functions as part of chr12 remodeling machinery and is essential for hematopoietic development, particularly for maintenance of long-term hematopoietic stem cells. Pathogenic loss-of-function variants in SETD1B cause a recognized neurodevelopmental syndrome characterized by global developmental delay, language delay or regression, intellectual disability, autism spectrum features, and variable epilepsy phenotypes 1. Developmental delay typically precedes seizure onset, and males are significantly overrepresented and more severely affected 1. The gene has been identified as a novel disease locus in developmental and epileptic encephalopathy with spike-wave activation in sleep 2. Many patients exhibit treatment-refractory seizures, though lamotrigine has shown efficacy in some cases 3. SETD1B alterations also contribute to lymphomagenesis. Mutations occur in 57% of intravascular large B-cell lymphomas and 7% of follicular lymphomas, with loss of SETD1B conferring resistance to the BCL2 inhibitor venetoclax by suppressing pro-apoptotic gene expression 4. SETD1B mutations are also frequent in oesophageal squamous cell carcinoma among histone regulator genes 5, and disruption of its catalytic domain impairs H3K4me3 deposition and MYC-dependent proliferation in MLL-rearranged acute myeloid leukemia 6.