Characterization of SETBP1-deficient hESCs in vitro differentiated towards cortical neuroprogenitors and neurons

Disruptions of SETBP1 (SET binding protein 1) on 18q12.3 by heterozygous gene deletion or loss-of-function variants cause SETBP1 disorder. Clinical features are frequently associated with moderate to severe intellectual disability, autistic traits and speech and motor delays. Despite SETBP1 association with neurodevelopmental disorders, little is known about its possible role during brain development. Using CRISPR/CAS9 genome editing technology, we generated SETBP1-deficient hESC lines and found that the derived cortical neural progenitors (NPCs) exhibit protracted proliferation and distorted layer-specific neuronal differentiation with overall decrease in neurogenesis. We analysed by genome wide transcriptome profiling the DEG and dysregulated pathways related to SETBP1-deficiency. 3 biological replicate samples each collected at 3 time points of cortical differentiation (days 15, 21, and 34, n=9 each for SETBP1-/- and the isogenic control cells, respectively). 75bp paired-end sequencing was performed on a HiSeq 4000 sequencer (Illumina, USA) yielding 30 – 45 million reads per sample.