Genetic profile of isolated congenital diaphragmatic hernia revealed by targeted next‐generation sequencing

• Published in: Prenatal diagnosis 2018-08, Vol.38 (9), p.654-663
• Main Authors: Kammoun, Molka, Souche, Erika, Brady, Paul, Ding, Jia, Cosemans, Nele, Gratacos, Eduard, Devriendt, Koen, Eixarch, Elisenda, Deprest, Jan, Vermeesch, Joris Robert
• Format: Article
• Language: English
• Subjects: Diaphragm; Fetuses; Gene sequencing; Genes; Genetics; Genotypes; Hernia; Hernias; Lesions; Liver; Lungs; Phenotypes; Pulmonary circulation; Tbx1 protein
• ISSN: 0197-3851; 1097-0223
• DOI: 10.1002/pd.5327

Background Congenital diaphragmatic hernia (CDH) is characterized by a defective closure of the diaphragm occurring as an isolated defect in 60% of cases. Lung size, liver herniation, and pulmonary circulation are major prognostic indices. Isolated CDH genetics is heterogeneous and poorly understood. Whether genetic lesions are also outcome determinants has never been explored. Objectives To identify isolated CDH genetic causes, to fine map the mutational burden, and to search for a correlation between the genotype and the disease severity and outcome. Methods Targeted massively parallel sequencing of 143 human and mouse CDH causative and candidate genes in a cohort of 120 fetuses with isolated CDH and detailed outcome measures. Results Pathogenic and likely pathogenic variants were identified in 10% of the cohort. These variants affect both known CDH causative genes, namely, ZFPM2, GATA4, and NR2F2, and new genes, namely, TBX1, TBX5, GATA5, and PBX1. In addition, mutation burden analysis identified LBR, CTBP2, NSD1, MMP14, MYOD1, and EYA1 as candidate genes with enrichment in rare but predicted deleterious variants. No obvious correlation between the genotype and the phenotype or short‐term outcome has been found. Conclusion Targeted resequencing identifies a genetic cause in 10% of isolated CDH and identifies new candidate genes. What's already known about this topic? Congenital diaphragmatic hernia (CDH) is thought to have an important genetic component. Nevertheless, CDH genetics remains poorly understood, especially for isolated form. The correlation of isolated CDH severity and outcome with the genotype has not been investigated. What does this study add? Targeted massive parallel sequencing identifies isolated CDH likely causative variants in 10% of cases and identifies new candidate genes.