The Role of Cilia and the Complex Genetics of Congenital Heart Disease

• Published in: Annual review of genomics and human genetics Vol. 25; no. 1; pp. 309 - 327
• Main Authors: Gabriel, George C, Ganapathiraju, Madhavi, Lo, Cecilia W
• Format: Journal Article
• Language: English
• Published: United States Annual Reviews 01.08.2024
• Subjects: Animals; cilia; Cilia - genetics; Cilia - metabolism; Cilia - pathology; complex genetics; congenital heart disease; Heart Defects, Congenital - genetics; Heart Defects, Congenital - pathology; Humans; Mice; Mutation; Protein Interaction Maps; Signal Transduction; congenital heart disease; cilia; complex genetics
• ISSN: 1527-8204; 1545-293X; 1545-293X
• DOI: 10.1146/annurev-genom-121222-105345

Congenital heart disease (CHD) can affect up to 1% of live births, and despite abundant evidence of a genetic etiology, the genetic landscape of CHD is still not well understood. A large-scale mouse chemical mutagenesis screen for mutations causing CHD yielded a preponderance of cilia-related genes, pointing to a central role for cilia in CHD pathogenesis. The genes uncovered by the screen included genes that regulate ciliogenesis and cilia-transduced cell signaling as well as many that mediate endocytic trafficking, a cell process critical for both ciliogenesis and cell signaling. The clinical relevance of these findings is supported by whole-exome sequencing analysis of CHD patients that showed enrichment for pathogenic variants in ciliome genes. Surprisingly, among the ciliome CHD genes recovered were many that encoded direct protein–protein interactors. Assembly of the CHD genes into a protein–protein interaction network yielded a tight interactome that suggested this protein–protein interaction may have functional importance and that its disruption could contribute to the pathogenesis of CHD. In light of these and other findings, we propose that an interactome enriched for ciliome genes may provide the genomic context for the complex genetics of CHD and its often-observed incomplete penetrance and variable expressivity.