Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada
Muhammad Faheem
Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada
Sean H White
Department of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Canada
Deivid C Rodrigues
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
Song Sun
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada; The Donnelly Centre, University of Toronto, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada
Wei Wei
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
Alina Piekna
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
Tadeo Thompson
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
Jennifer L Howe
Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada
Leon Chalil
Department of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Canada
Vickie Kwan
Department of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Canada
Susan Walker
Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada
Peter Pasceri
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
Frederick P Roth
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada; The Donnelly Centre, University of Toronto, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada; Department of Computer Science, University of Toronto, Toronto, Canada; Canadian Institute for Advanced Research (CIFAR), Toronto, Canada
Ryan KC Yuen
Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada
Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada; McLaughlin Centre, University of Toronto, Toronto, Canada
Induced pluripotent stem cell (iPSC)-derived neurons are increasingly used to model Autism Spectrum Disorder (ASD), which is clinically and genetically heterogeneous. To study the complex relationship of penetrant and weaker polygenic risk variants to ASD, ‘isogenic’ iPSC-derived neurons are critical. We developed a set of procedures to control for heterogeneity in reprogramming and differentiation, and generated 53 different iPSC-derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with ASD. Heterozygous de novo and rare-inherited presumed-damaging variants were characterized in ASD risk genes/loci. Combinations of putative etiologic variants (GLI3/KIF21A or EHMT2/UBE2I) in separate families were modeled. We used a multi-electrode array, with patch-clamp recordings, to determine a reproducible synaptic phenotype in 25% of the individuals with ASD (other relevant data on the remaining lines was collected). Our most compelling new results revealed a consistent spontaneous network hyperactivity in neurons deficient for CNTN5 or EHMT2. The biobank of iPSC-derived neurons and accompanying genomic data are available to accelerate ASD research.Editorial note: This article has been through an editorial process in which authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).