Isogenic modeling of 1q21.1 reciprocal CNVs in human ES cells reveals divergent neurodevelopmental trajectories

Copy number variations (CNVs) in the distal 1q21.1 region, both deletion (1q del) and duplication (1q dup) are associated with various neurodevelopmental and neuropsychiatric disorders such as autism spectrum disorder, intellectual disability, epilepsy, and schizophrenia. Besides common phenotypes, 1q del and 1q dup manifest opposite clinical phenotypes, e.g. microcephaly in 1q del and macrocephaly in 1q dup. However, molecular and cellular mechanisms underlying these phenotypes are still elusive. Here, to identify molecular mechanisms associated with neurodevelopmental phenotypes from the viewpoint of neurogenesis and neurodevelopment, we generate isogenic human ES cell (hESC) lines with reciprocal 1q21.1 CNVs using CRISPR/Cas9 system and differentiate them into 2-dimensional (2-D) neurons and neural progenitor cell (NPC) spheroids. Our study recapitulates reciprocal brain size in the NPC spheroids and shows dosage-dependent differentiation changes i.e. more GABAergic components in 1q del and more proliferative state in 1q dup. These results demonstrate that 1q21.1 CNVs dramatically affect cell fate in the early neurodevelopmental periods. This is the first isogenic cell model of human 1q21.1 CNVs, and our findings provide new insights into the underlying mechanisms of neurodevelopmental disorders.