Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype
- PMID: 31914384
- DOI: 10.1016/j.celrep.2019.12.002
Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype
Abstract
Pathogenic mutations in either one of the epigenetic modifiers EHMT1, MBD5, MLL3, or SMARCB1 have been identified to be causative for Kleefstra syndrome spectrum (KSS), a neurodevelopmental disorder with clinical features of both intellectual disability (ID) and autism spectrum disorder (ASD). To understand how these variants lead to the phenotypic convergence in KSS, we employ a loss-of-function approach to assess neuronal network development at the molecular, single-cell, and network activity level. KSS-gene-deficient neuronal networks all develop into hyperactive networks with altered network organization and excitatory-inhibitory balance. Interestingly, even though transcriptional data reveal distinct regulatory mechanisms, KSS target genes share similar functions in regulating neuronal excitability and synaptic function, several of which are associated with ID and ASD. Our results show that KSS genes mainly converge at the level of neuronal network communication, providing insights into the pathophysiology of KSS and phenotypically congruent disorders.
Keywords: EHMT1; Kleefstra syndrome spectrum; autism; intellectual disability; micro-electrode arrays; neurodevelopmental disorder; neuronal networks.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
Similar articles
-
Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder.PLoS Genet. 2017 Oct 25;13(10):e1006864. doi: 10.1371/journal.pgen.1006864. eCollection 2017 Oct. PLoS Genet. 2017. PMID: 29069077 Free PMC article.
-
Euchromatin histone methyltransferase 1 regulates cortical neuronal network development.Sci Rep. 2016 Oct 21;6:35756. doi: 10.1038/srep35756. Sci Rep. 2016. PMID: 27767173 Free PMC article.
-
Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and normal intellectual performance.Gene. 2016 Dec 31;595(2):131-141. doi: 10.1016/j.gene.2016.09.027. Epub 2016 Sep 17. Gene. 2016. PMID: 27651234
-
A Novel Frameshift Variant and a Partial EHMT1 Microdeletion in Kleefstra Syndrome 1 Patients Resulting in Variable Phenotypic Severity and Literature Review.Genes (Basel). 2025 Apr 29;16(5):521. doi: 10.3390/genes16050521. Genes (Basel). 2025. PMID: 40428343 Free PMC article. Review.
-
New Insights into Kleefstra Syndrome: Report of Two Novel Cases with Previously Unreported Features and Literature Review.Cytogenet Genome Res. 2018;156(3):127-133. doi: 10.1159/000494532. Epub 2018 Nov 17. Cytogenet Genome Res. 2018. PMID: 30448833 Review.
Cited by
-
Epigenetic Regulation and Neurodevelopmental Disorders: From MeCP2 to the TCF20/PHF14 Complex.Genes (Basel). 2024 Dec 23;15(12):1653. doi: 10.3390/genes15121653. Genes (Basel). 2024. PMID: 39766920 Free PMC article. Review.
-
Exome Study of Single Nucleotide Variations in Patients with Syndromic and Non-Syndromic Autism Reveals Potential Candidate Genes for Diagnostics and Novel Single Nucleotide Variants.Cells. 2025 Jun 17;14(12):915. doi: 10.3390/cells14120915. Cells. 2025. PMID: 40558542 Free PMC article.
-
Following Excitation/Inhibition Ratio Homeostasis from Synapse to EEG in Monogenetic Neurodevelopmental Disorders.Genes (Basel). 2022 Feb 21;13(2):390. doi: 10.3390/genes13020390. Genes (Basel). 2022. PMID: 35205434 Free PMC article.
-
SETD1A Mediated H3K4 Methylation and Its Role in Neurodevelopmental and Neuropsychiatric Disorders.Front Mol Neurosci. 2021 Nov 3;14:772000. doi: 10.3389/fnmol.2021.772000. eCollection 2021. Front Mol Neurosci. 2021. PMID: 34803610 Free PMC article.
-
Human neuronal networks on micro-electrode arrays are a highly robust tool to study disease-specific genotype-phenotype correlations in vitro.Stem Cell Reports. 2021 Sep 14;16(9):2182-2196. doi: 10.1016/j.stemcr.2021.07.001. Epub 2021 Jul 29. Stem Cell Reports. 2021. PMID: 34329594 Free PMC article.
Publication types
MeSH terms
Substances
Supplementary concepts
LinkOut - more resources
Full Text Sources
Molecular Biology Databases