Gene ontology enrichment analysis of congenital diaphragmatic hernia-associated genes

Congenital diaphragmatic hernia (CDH) is a commonly occurring major congenital anomaly with a profound impact on neonatal mortality. The etiology of CDH is poorly understood and is complicated by multiple clinical presentations, reflecting the location and type of diaphragm defect. With the increased power of genetic screening, more genes are being associated with CDH, creating a knowledge gap between CDH-associated genes and their contribution to diaphragm embryogenesis. Our goal was to investigate CDH-associated genes and identify common pathways that may lead to abnormal diaphragm development. A comprehensive list of CDH-associated genes was identified from the literature and categorized according to multiple factors, including type of CDH. We undertook a large-scale gene function analysis using gene ontology to identify significantly enriched biological pathways and molecular functions associated with our gene set. We identified 218 CDH-associated genes. Our gene ontology analysis showed that genes representing distinct biological pathways are significantly enriched in relation to different clinical presentations of CDH. This includes retinoic acid signaling in Bochdalek CDH, myogenesis in diaphragm eventration, and angiogenesis in central tendon defects. We have identified unique genotype-phenotype relationships highlighting the major genetic drivers of the different types of CDH.