Autism is a clinically heterogeneous neurodevelopmental disorder characterized by impaired social interactions, restricted interests, and repetitive behaviors. Despite significant advances in the genetics of autism, understanding how genetic changes perturb brain development and affect clinical symptoms remains elusive. Here, we present a multiplex human pluripotent stem cell (hPSC) platform, in which 30 isogenic disease lines are pooled in a single dish and differentiated into prefrontal cortex (PFC) lineages to efficiently test early-developmental hypotheses of autism. We define subgroups of autism mutations that perturb PFC neurogenesis and are correlated to abnormal WNT/βcatenin responses. Class 1 mutations (8 of 27) inhibit while class 2 mutations (5 of 27) enhance PFC neurogenesis. Remarkably, autism patient data reveal that individuals carrying subclass-specific mutations differ clinically in their corresponding language acquisition profiles. Our study provides a framework to disentangle genetic heterogeneity associated with autism and points toward converging molecular and developmental pathways of diverse autism-associated mutations.Copyright © 2020 Elsevier Inc. All rights reserved.
About The Expert
Gustav Y Cederquist
Jason Tchieu
Scott J Callahan
Kiran Ramnarine
Sean Ryan
Chao Zhang
Chelsea Rittenhouse
Nadja Zeltner
Sun Young Chung
Ting Zhou
Shuibing Chen
Doron Betel
Richard M White
Mark Tomishima
Lorenz Studer
References
PubMed