The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [scMultiome]

Background/objectives: Deletions and duplications of the distal 1q21.1 region are associated with syndromic forms of autism (MIM612474, 612475). Variable phenotypes have been reported, including congenital heart defects, autism, schizophrenia, head circumference and height defects. Methods: To elucidate which gene(s) are responsible for the 1q21.1 duplication/deletion- associated phenotypes, we performed gene manipulation in zebrafish and mice. We deciphered the function of candidate driver(s) by multi-omics approaches on human iPSC- derived neural progenitor cells (NPC) and cerebral organoids (CO). Results: We modeled duplication of the 1q21.1 region by overexpressing the 8 genes in the region in zebrafish. We found that only overexpression of CHD1L led to macrocephaly and increased larval body length. Conversely, deletion of the CHD1L zebrafish ortholog resulted in microcephaly and decreased larval body length. These mirror phenotypes are also observed when Chd1l expression is modulated in a mammalian model, notably with a variation in the number of mature Tbr1-positive neurons in the mouse embryo. NPCs derived from control and CHD1L Knock-out isogenic hiPSCs were subjected to transcriptomic and chromatin accessibility analyses. These approaches revealed that CHD1L regulates the expression levels and accessibility of genes involved in neuronal differentiation and synaptogenesis, including autism susceptibility genes such as UNC5D and DPP6. Strikingly, absence of CHD1L shifts the cellular identity from forebrain to retinal fate in CO. Finally, pathogenic missense and truncating variants of CHD1L were found in individuals with autism and/or height defects. Conclusion: CHD1L is a major contributor of the 1q21.1 duplication/deletion-associated microcephaly and growth defects. CHD1L dosage is required during human brain regionalization.