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Human brain organoids reveal accelerated development of cortical neuron classes as a shared feature of autism risk genes

By Bruna Paulsen, Silvia Velasco, Amanda J. Kedaigle, Martina Pigoni, Giorgia Quadrato, Anthony Deo, Xian Adiconis, Ana Uzquiano, Kwanho Kim, Sean K. Simmons, Kalliopi Tsafou, Alex Albanese, Rafaela Sartore, Catherine Abbate, Ashley Tucewicz, Samantha Smith, Kwanghun Chung, Kaspar Lage, Aviv Regev, Joshua Z. Levin, Paola Arlotta

Posted 12 Nov 2020
bioRxiv DOI: 10.1101/2020.11.10.376509

Genetic risk for autism spectrum disorder (ASD) has been associated with hundreds of genes spanning a wide range of biological functions. The phenotypic alterations in the human brain resulting from mutations in ASD risk genes remain unclear, and the level at which these alterations converge on shared disease pathology is poorly understood. Here, we leveraged reproducible organoid models of the human cerebral cortex to identify cell type-specific developmental abnormalities associated with haploinsufficiency in three ASD risk genes, SUV420H1 (KMT5B), PTEN, and CHD8. We performed comprehensive single-cell RNA-sequencing (scRNA-seq) of over 400,000 cells, and proteomic analysis on individual organoids sampled at different developmental stages to investigate phenotypic convergence among these genes. We find that within a defined period of early cortical development, each of the three mutations demonstrates accelerated development of cortical neurons. Notably, they do so by affecting different neuronal populations: excitatory deep layer (SUV420H1) and callosal (PTEN) neurons, and inhibitory interneurons (CHD8). This work shows that haploinsufficiency in ASD risk genes converge on early developmental defects in the generation of neurons of the cortical microcircuit. ### Competing Interest Statement P.A. is a SAB member at System 1 Biosciences and Foresite Labs, and is a co-founder of Serqet. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and until August 31, 2020 was a SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov and Thermo Fisher Scientific. From August 1, 2020, A.R. is an employee of Genentech.

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