Convergence of cell-type specific transcriptomic changes in ASD subtypes

Yonatan Perez ¹ Dmitry Velmeshev ¹ Li Wang ¹ Matthew White ¹ Clara Siebert ¹ Stormy Chamberlain ² Arnold Kriegstein ¹

¹Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, USA
²Departments of Genetics and Genome Sciences and Pediatrics, Connecticut Children's Medical Center, University of Connecticut Health Center, USA

In addition to idiopathic cases, autism spectrum disorder (ASD) is also caused by several genetic syndromes. One of the most common genetic causes of ASD is duplication 15q (dup15q) syndrome. Due to its genetic and phenotypic homogeneity, dup15q provides a well-defined setting to investigate ASD mechanisms. Previous bulk gene expression studies identified shared transcriptomic changes between idiopathic ASD and dup15q syndrome. However, how specific cell types are affected in different types of ASD is unknown. Previous studies have shown that upper-layer projection neurons are preferentially affected in idiopathic ASD brains. In the current study, we used single cell genomics to study dup15q iPSC derived cortical organoids and post-mortem brains. We discovered convergence of cell-type specific transcriptomic changes between dup15q and idiopathic ASD, especially in L2-3 neurons, indicating that cell-specific molecular changes are conserved between different subtypes of ASD. Moreover, we show that dysregulation of certain early developmental programs of dup15q are maintained in the mature brain. Our study identifies convergent cell type-specific gene expression changes in ASD and highlights molecular and cellular mechanisms that are shared between heterogenous types of ASD.