CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories.

Abstract

Mutations in the chromodomain helicase DNA-binding 8 (CHD8) gene are a frequent cause of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses macrocephaly, implicating cortical abnormalities, how CHD8 haploinsufficiency affects neurodevelopmental is unclear. Here, employing human cerebral organoids, we find that CHD8 haploinsufficiency disrupted neurodevelopmental trajectories with an accelerated and delayed generation of, respectively, inhibitory and excitatory neurons that yields, at days 60 and 120, symmetrically opposite expansions in their proportions. This imbalance is consistent with an enlargement of cerebral organoids as an in vitro correlate of patients' macrocephaly. Through an isogenic design of patient-specific mutations and mosaic organoids, we define genotype-phenotype relationships and uncover their cell-autonomous nature. Our results define cell-type-specific CHD8-dependent molecular defects related to an abnormal program of proliferation and alternative splicing. By identifying cell-type-specific effects of CHD8 mutations, our study uncovers reproducible developmental alterations that may be employed for neurodevelopmental disease modeling.

• Authors: Carlo Emanuele Villa, Cristina Cheroni, Christoph P Dotter, Alejandro López-Tóbon, Bárbara Oliveira, Roberto Sacco, Aysan Çerağ Yahya, Jasmin Morandell, Michele Gabriele, Mojtaba R Tavakoli, Julia Lyudchik, Christoph Sommer, Mariano Gabitto, Johann G Danzl, Giuseppe Testa, Gaia Novarino
• Journal: Cell reports (Cell Rep) Vol. 39 Issue 1 Pg. 110615 (04 05 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 35385734 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• CHD8 protein, human
• DNA-Binding Proteins
• Transcription Factors
• DNA Helicases

Topics

• Autism Spectrum Disorder (genetics)
• Autistic Disorder (genetics)
• DNA Helicases (genetics)
• DNA-Binding Proteins (genetics)
• Haploinsufficiency (genetics)
• Humans
• Megalencephaly (genetics)
• Transcription Factors (genetics)