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Series GSE129806 Query DataSets for GSE129806
Status Public on Jan 06, 2020
Title Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk.

Methods: Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of unknown significance in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted.

Results: cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells (NPCs) from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including misregulation of suites of genes associated with neural development, neuronal function, and behavior, and altered expression of ASD risk-associated genes.

Conclusions: We have provided evidence of morphological, physiologic, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes.
Overall design RNA-sequencing of human induced pluripotent stem cell-derived cortical inhibitory and excitatory neural progenitors for four cell lines from four different individuals with varying autism affectation; four biological replicates per cell line.
Contributor(s) Lewis EM, Meganathan K, Zhang B, Gontarz P, Kroll KL
Citation(s) 31893020
Submission date Apr 15, 2019
Last update date Apr 06, 2020
Contact name Kristen L Kroll
Organization name Washington University School of Medicine
Department Developmental Biology
Lab Kristen Kroll
Street address 320 McDonnell Sciences/660 S. Euclid Ave.
City Saint Louis
State/province MO
ZIP/Postal code 63110
Country USA
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (32)
GSM3722326 UC_cExN_R1
GSM3722327 UC_cExN_R2
GSM3722328 UC_cExN_R3
BioProject PRJNA532877
SRA SRP192565

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE129806_merged_gene_name_RPKM.csv.gz 5.7 Mb (ftp)(http) CSV
GSE129806_merged_gene_name_counts.txt.gz 1.7 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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