Genomic Contributors to Congenital Diaphragmatic Hernia: Results of Exome Sequencing in 560 Probands and Cross Reference of Findings in an Independent Cohort

There is a strong genetic contribution to the etiology of congenital diaphragmatic hernia (CDH). This study evaluated genetic testing results and diagnostic yield for fetuses and children with CDH. This was a retrospective cohort study of exome sequencing (ES) performed at GeneDx for fetuses and children ≤ 18 years of age with CDH compared with genome sequencing (GS) from an institutional cohort. ES was available for 560 individuals (62% [n = 349] complex/syndromic; 38% [n = 211] isolated/non-syndromic) with a reportable finding identified in 61% (n = 342) overall, including 64% in complex/syndromic cases and 56% in isolated/non-syndromic cases. In the institutional cohort, GS was available for 84 individuals (19% [n = 16] complex/syndromic; 81% [n = 68] isolated/non-syndromic). In this sub-cohort, 70 individuals had variants (539 total) in genes in which variants were reported in the GeneDx cohort (234 genes). The study cohort was compared to an unrelated cohort with neural tube defects and, when evaluating 73 genes with variants present in > 1 GeneDx proband, we noted a significantly higher variant burden in the CDH cohort. Overlap of genes with variants among unrelated cohorts suggests a potential etiologic association of many known and novel CDH genes; however, additional research is needed to understand the genes' causative roles as well as the impact of non-coding and gene-environment influences on the etiology of CDH.