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The Role of Cilia and the Complex Genetics of Congenital Heart Disease
George C Gabriel1, Madhavi Ganapathiraju2,3, Cecilia W Lo1
1Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; email: gcg9@pitt.edu, cel36@pitt.edu.
Annual Review of Genomics and Human Genetics
|May 9, 2024
Summary
Congenital heart disease (CHD) genetics are complex. A study found that cilia-related genes and their protein interactions are crucial for CHD development, offering new insights into its genetic basis.
Area of Science:
- Developmental Biology
- Genetics
- Cell Biology
Background:
- Congenital heart disease (CHD) affects ~1% of live births, with a complex genetic etiology that remains incompletely understood.
- While genetic factors are known contributors to CHD, the specific genes and pathways involved are still being elucidated.
Purpose of the Study:
- To investigate the genetic underpinnings of congenital heart disease (CHD) using a large-scale mouse mutagenesis screen.
- To identify key cellular processes and gene networks involved in CHD pathogenesis.
- To explore the clinical relevance of identified genetic factors in human CHD patients.
Main Methods:
- A large-scale chemical mutagenesis screen in mice to identify mutations causing CHD.
- Analysis of identified genes involved in ciliogenesis, cilia-transduced cell signaling, and endocytic trafficking.
- Whole-exome sequencing in CHD patients to assess enrichment of pathogenic variants in ciliome genes.
- Construction of a protein-protein interaction network for identified CHD genes.
Main Results:
- A significant number of cilia-related genes were identified in the CHD screen, highlighting the critical role of cilia in heart development.
- Genes regulating ciliogenesis, cilia signaling, and endocytic trafficking were found to be important in CHD pathogenesis.
- Human CHD patient data showed enrichment for pathogenic variants in ciliome genes.
- CHD-associated genes formed a tightly connected protein-protein interaction network, suggesting functional importance.
Conclusions:
- Cilia-related genes and their protein interactions form a critical interactome that contributes to the complex genetic basis of CHD.
- Disruption of this ciliome-enriched interactome may underlie the pathogenesis of CHD, explaining its incomplete penetrance and variable expressivity.
- These findings provide a new genomic context for understanding CHD genetics and suggest potential therapeutic targets.
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