Molecular Genetics of Congenital Diaphragmatic Hernia

Abstract Congenital diaphragmatic hernia (CDH) is a common, phenotypically as well as genetically heterogeneous birth defect associated with high morbidity and mortality. Although CDH usually occurs sporadically, several familial clusters have been reported with different types of inheritance. Single gene disorders and microdeletions/microduplications are known causes of CDH, but the largest fraction of cases remain without explanation. Mouse knock‐outs and human studies demonstrate the importance of retinoic acid signalling in normal diaphragm development and CDH pathogenesis, though other pathways, such as hepatocyte growth factor (HGF)/c‐MET, sonic hedgehog (SHH) and slit homolog (SLIT)/roundabout homolog (ROBO) signalling, are also important. Advancement in genomic technology and insights from animal models have advanced significantly our understanding of CDH genetics, with the ultimate goal of generating more effective therapies for this severe condition. Key Concepts: CDH is a genetically heterogeneous condition, due to single gene disorders, microdeletions/microduplications and polygenic/multifactorial inheritance. Deletion syndromes frequently associated with CDH are 1q41‐q42, 8p23, 8q23 and 15q26. Syndromic conditions frequently associated with CDH are Cornelia de Lange; Craniofrontonasal, Denys–Drash, Donnai‐Barrow, Fryns and Simpson–Golabi–Behmel syndromes, as well as spondylocostal dysostosis (SCDO) and syndromic microphthalmia/anophthalmia. Familial clustering of CDH is uncommon, because of the high mortality and morbidity, but extremely informative to unravel the genetics of this condition. Nutritional, teratogenic, surgical and genetic animal models are used to study CDH. Over 40 genetic mouse models are currently known to have diaphragmatic defects. The diaphragm is formed by a mesenchymal substratum and by pre‐muscle hypaxial cells migrating from the cervical somites. Defects in the formation of the mesenchymal substratum, or in the migration, proliferation and differentiation of pre‐muscle cells results in diaphragmatic defects. Retinoic signalling is a crucial mechanism of CDH pathogenesis. Additional important pathways are SHH, HGF/c‐MET (pre‐muscle cell migration) and SLIT/ROBO (vascular development).