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Updated: Sep 18, 2025
In vivo Evaluation of Mucociliary Clearance in Mice
Published on: December 18, 2020
Ciliary biology intersects autism and congenital heart disease
Nia Teerikorpi1,2, Kate E McCluskey1,2, Ethel Bader1,2
1Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Insights
Autism spectrum disorder and congenital heart disease co-occur, with shared genes impacting neural progenitor cells and cilia biology. Identifying these genes aids early intervention for autism risk in newborns with heart defects.
Area of Science:
- Genetics
- Developmental Biology
- Neuroscience
Background:
- Autism spectrum disorder (ASD) and congenital heart disease (CHD) frequently co-occur, but the molecular links are unclear.
- Early identification of CHD variants associated with ASD could enable timely interventions.
- Gene disruptions affecting neural progenitor cell (NPC) biology are common in ASD.
Purpose of the Study:
- To identify congenital heart disease (CHD) genes that disrupt neural progenitor cell (NPC) biology.
- To investigate the role of these genes in increasing the risk for autism spectrum disorder (ASD).
- To explore the shared molecular mechanisms, particularly ciliary biology, between ASD and CHD.
Main Methods:
- Conducted an in vitro pooled CRISPR interference screen to identify CHD genes affecting NPC biology.
- Analyzed gene enrichment for ciliary biology pathways.
- Performed in vivo studies using Xenopus tropicalis to validate gene function in development.
Main Results:
- Identified 45 CHD genes that disrupt NPC biology.
- Found enrichment of ASD and CHD genes in ciliary biology pathways.
- Demonstrated that perturbing seven specific genes (CEP290, CHD4, KMT2E, NSD1, OFD1, RFX3, TAOK1) impairs primary cilia formation in vitro.
- Validated TAOK1's role in motile cilia and heart development in vivo.
Conclusions:
- Highlighted a set of CHD genes that may confer risk for ASD.
- Underscored the significant role of cilia in the shared biology of ASD and CHD.
- Provided potential targets for early intervention in infants with CHD and at risk for ASD.
Abstract:
Autism spectrum disorder (ASD) and congenital heart disease (CHD) frequently co-occur, yet the underlying molecular mechanisms of this comorbidity remain unknown. Given that children with CHD are identified as newborns, understanding which CHD variants are associated with autism could help select individuals for early intervention. Autism gene perturbations commonly dysregulate neural progenitor cell (NPC) biology, so we hypothesized that CHD genes disrupting neurogenesis are more likely to increase ASD risk. Therefore, we performed an in vitro pooled CRISPR interference screen to identify CHD genes disrupting NPC biology and identified 45 CHD genes. A cluster of ASD and CHD genes are enriched for ciliary biology, and perturbing any one of seven such genes (CEP290, CHD4, KMT2E, NSD1, OFD1, RFX3 and TAOK1) impairs primary cilia formation in vitro. In vivo investigation of TAOK1 in Xenopus tropicalis reveals a role in motile cilia formation and heart development, supporting its prediction as a CHD gene. Together, our findings highlight a set of CHD genes that may carry risk for ASD and underscore the role of cilia in shared ASD and CHD biology.
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