RT Journal Article
SR Electronic
T1 <em>CNTN5</em><sup>−/+</sup> or <em>EHMT2</em><sup>−/+</sup> iPSC-Derived Neurons from Individuals with Autism Develop Hyperactive Neuronal Networks
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 368928
DO 10.1101/368928
A1 Eric Deneault
A1 Muhammad Faheem
A1 Sean H. White
A1 Deivid C. Rodrigues
A1 Song Sun
A1 Wei Wei
A1 Alina Piekna
A1 Tadeo Thompson
A1 Jennifer L. Howe
A1 Leon Chalil
A1 Vickie Kwan
A1 Susan Walker
A1 Peter Pasceri
A1 Frederick P. Roth
A1 Ryan K.C. Yuen
A1 Karun K. Singh
A1 James Ellis
A1 Stephen W. Scherer
YR 2018
UL http://biorxiv.org/content/early/2018/07/14/368928.abstract
AB Induced pluripotent stem cell (iPSC)-derived cortical neurons are increasingly used as a model to study developmental aspects of Autism Spectrum Disorder (ASD), which is clinically and genetically heterogeneous. To study the complex relationship of rare (penetrant) variant(s) and common (weaker) polygenic risk variant(s) to ASD, “isogenic” iPSC-derived neurons from probands and family-based controls, for modeling, is critical. We developed a standardized set of procedures, designed 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 (14 ASD-affected individuals, 3 unaffected siblings, 8 unaffected parents). Heterozygous de novo (7 families; 16p11.2, NRXN1, DLGAP2, CAPRIN1, VIP, ANOS1, THRA) and rare-inherited (2 families; CNTN5, AGBL4) presumed-damaging variants were characterized in ASD risk genes/loci. In three additional families, functional candidates for ASD (SET), and combinations of putative etiologic variants (GLI3/KIF21A and EHMT2/UBE2I combinations in separate families), were modeled. We used a large-scale multi-electrode array (MEA) as our primary high-throughput phenotyping assay, followed by patch clamp recordings. Our most compelling new results revealed a consistent spontaneous network hyperactivity in neurons deficient for CNTN5 or EHMT2. Our biobank of iPSC-derived neurons and accompanying genomic data are available to accelerate ASD research.