PT - JOURNAL ARTICLE AU - Milos Kostic AU - Joseph J. Raymond AU - Beata Henry AU - Tayfun Tumkaya AU - Jivan Khlghatyan AU - Jill Dvornik AU - Jack S. Hsiao AU - Seon Hye Cheon AU - Jonathan Chung AU - Yishan Sun AU - Ricardo E. Dolmetsch AU - Kathleen A. Worringer AU - Robert J. Ihry TI - Patient brain organoids identify a link between the 16p11.2 copy number variant and the <em>RBFOX1</em> gene AID - 10.1101/2021.11.21.469432 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.11.21.469432 4099 - http://biorxiv.org/content/early/2021/11/23/2021.11.21.469432.short 4100 - http://biorxiv.org/content/early/2021/11/23/2021.11.21.469432.full AB - Copy number variants (CNVs) that delete or duplicate 30 genes within the 16p11.2 genomic region give rise to a range of neurodevelopmental phenotypes with high penetrance in humans. Despite the identification of this small region, the mechanisms by which 16p11.2 CNVs lead to disease are unclear. Relevant models, like human cortical organoids (hCOs), are needed to understand the human-specific mechanisms of neurodevelopmental disease. We generated hCOs from 18 patients and controls, profiling 167,958 cells with single cell (sc)RNA-seq. Analysis revealed neuronal-specific differential expression of genes outside of the 16p11.2 region that were related to cell-cell adhesion, neuronal projection growth, and neurodevelopmental disorders. Furthermore, 16p11.2 deletion syndrome organoids exhibited reduced mRNA and protein levels of RBFOX1, a gene which can also harbor CNVs linked to neurodevelopmental phenotypes. We found that many genes previously shown to be regulated by RBFOX1 are also perturbed in organoids from patients with 16p11.2 deletion syndrome, and thus identified a novel link between independent CNVs associated with neuronal development and autism. Overall, this work suggests convergent signaling, which indicates the possibility of a common therapeutic mechanism across multiple rare neuronal diseases.Competing Interest StatementAll authors were employees of the Novartis Institutes for Biomedical Research while this research was performed