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One such microdeletion on chromosome 17q11.2, involving the NF1 gene and flanking regions ( NF1 total gene deletion NF1 -TGD), occurs in a subset of Neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability. Using patient-derived human induced pluripotent stem cell (hiPSC)-cerebral organoids (hCOs), we identified both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1 -TGD hCOs. While increased NSC proliferation resulted from decreased NF1 /RAS regulation, the neuronal defects (delayed neuronal differentiation, increased immature neuron apoptosis, and impaired dendrite maturation) were caused by reduced cytokine receptor-like factor 3 ( CRLF3 ) expression. Furthermore, we demonstrated a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T>C, p.Leu389Pro). Collectively, these findings identify a new causative gene within the NF1 -TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1. Overall design: Examination of different transcript expression in human iPSC-neural progenitor cells harboring different types of microdeletion events or after CRLF3 gene knockdownxref:PubMed:34233200ENAfalsePatient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesisPatient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis2025-09-242021-06-09PRJNA699232GSE166080960634233200