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Updated: Jun 17, 2025
Observation of the Ciliary Movement of Choroid Plexus Epithelial Cells Ex Vivo
Published on: July 13, 2015
Ciliary biology intersects autism and congenital heart disease
Nia Teerikorpi1,2, Micaela C Lasser1, Sheng Wang1
1Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Insights
Researchers identified 45 congenital heart disease (CHD) genes impacting neural progenitor cell development, suggesting they may increase autism spectrum disorder (ASD) risk. Cilia biology emerged as a key factor in this shared comorbidity.
Area of Science:
- Developmental Biology
- Genetics
- Neuroscience
- Cardiology
Background:
- Autism spectrum disorder (ASD) frequently co-occurs with congenital heart disease (CHD), but underlying molecular mechanisms are unclear.
- Identifying CHD variants associated with ASD risk could enable early diagnosis and intervention for affected children.
- Limited overlap exists between known ASD and CHD genes, necessitating novel strategies for prioritizing CHD genes for ASD risk.
Purpose of the Study:
- To identify congenital heart disease (CHD) genes that disrupt neural progenitor cell (NPC) biology, hypothesizing these genes are more likely to confer risk for autism spectrum disorder (ASD).
- To explore the role of cilia in the shared biology of ASD and CHD.
- To validate specific CHD genes as potential risk factors for ASD.
Main Methods:
- Conducted an in vitro pooled CRISPR interference (CRISPRi) screen to assess the impact of CHD genes on neural progenitor cell (NPC) proliferation and survival.
- Analyzed physical interactions between ASD and CHD genes to identify clusters enriched for specific biological functions.
- Investigated the in vitro and in vivo effects of seven candidate genes (CEP290, CHD4, KMT2E, NSD1, OFD1, RFX3, TAOK1) on cilia formation and heart development.
Main Results:
- Identified 45 CHD genes that significantly affect NPC proliferation and/or survival.
- Discovered a cluster of interacting ASD and CHD genes enriched for ciliary biology.
- Observed that perturbation of seven candidate genes impacts primary cilia formation in vitro; in vivo studies confirmed TAOK1's role in motile cilia and heart development.
Conclusions:
- A subset of CHD genes impacting NPC biology may confer risk for ASD, highlighting neurogenesis as a potential link.
- Cilia play a significant role in the shared etiology of ASD and CHD.
- Findings identify specific CHD genes as potential contributors to ASD risk, warranting further investigation.
Abstract:
Autism spectrum disorder (ASD) commonly co-occurs with congenital heart disease (CHD), but the molecular mechanisms underlying this comorbidity remain unknown. Given that children with CHD come to clinical attention by the newborn period, understanding which CHD variants carry ASD risk could provide an opportunity to identify and treat individuals at high risk for developing ASD far before the typical age of diagnosis. Therefore, it is critical to delineate the subset of CHD genes most likely to increase the risk of ASD. However, to date there is relatively limited overlap between high confidence ASD and CHD genes, suggesting that alternative strategies for prioritizing CHD genes are necessary. Recent studies have shown that ASD gene perturbations commonly dysregulate neural progenitor cell (NPC) biology. Thus, we hypothesized that CHD genes that disrupt neurogenesis are more likely to carry risk for ASD. Hence, we performed an in vitro pooled CRISPR interference (CRISPRi) screen to identify CHD genes that disrupt NPC biology similarly to ASD genes. Overall, we identified 45 CHD genes that strongly impact proliferation and/or survival of NPCs. Moreover, we observed that a cluster of physically interacting ASD and CHD genes are enriched for ciliary biology. Studying seven of these genes with evidence of shared risk (CEP290, CHD4, KMT2E, NSD1, OFD1, RFX3, TAOK1), we observe that perturbation significantly impacts primary cilia formation in vitro. While in vivo investigation of TAOK1 reveals a previously unappreciated role for the gene in motile cilia formation and heart development, supporting its prediction as a CHD risk gene. Together, our findings highlight a set of CHD risk genes that may carry risk for ASD and underscore the role of cilia in shared ASD and CHD biology.
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