Unraveling the Genetics of Congenital Diaphragmatic Hernia: An Ongoing Challenge

Abstract

Congenital diaphragmatic hernia (CDH) is a congenital structural anomaly in which the diaphragm has not developed properly. It may occur either as an isolated anomaly or with additional anomalies. It is thought to be a multifactorial disease in which genetic factors could either substantially contribute to or directly result in the developmental defect. Patients with aneuploidies, pathogenic variants or de novo Copy Number Variations (CNVs) impacting specific genes and loci develop CDH typically in the form of a monogenetic syndrome. These patients often have other associated anatomical malformations. In patients without a known monogenetic syndrome, an increased genetic burden of de novo coding variants contributes to disease development. In early years, genetic evaluation was based on karyotyping and SNP-array. Today, genomes are commonly analyzed with next generation sequencing (NGS) based approaches. While more potential pathogenic variants are being detected, analysis of the data presents a bottleneck—largely due to the lack of full appreciation of the functional consequence and/or relevance of the detected variant. The exact heritability of CDH is still unknown. Damaging de novo alterations are associated with the more severe and complex phenotypes and worse clinical outcome. Phenotypic, genetic—and likely mechanistic—variability hampers individualpatient diagnosis, short and long-term morbidity prediction and subsequent care strategies. Detailed phenotyping, clinical follow-up at regular intervals and detailed registries are needed to find associations between long-term morbidity, genetic alterations, and clinical parameters. Since CDH is a relatively rare disorder with only a few recurrent changes large cohorts of patients are needed to identify genetic associations. Retrospective whole genome sequencing of historical patient cohorts using will yield valuable data from which today's patients and parents will profit Trio whole genome sequencing has an excellent potential for future re-analysis and data-sharing increasing the chance to provide a genetic diagnosis and predict clinical prognosis. In this review, we explore the pitfalls and challenges in the analysis and interpretation of genetic information, present what is currently known and what still needs further study, and propose strategies to reap the benefits of genetic screening.

5p deletion with congenital diaphragmatic hernia: a case report

“…The pathological role of 5p deletion in CDH remains unknown, although few reports have suggested an association between 5p and CDH [ 12 , 13 ]. For instance, Cornelia de Lange syndrome often associates with CDH, and its most common cause is mutations in the NIPBL gene on 5p13.2 [ 13 ].…”

Neuropsychological outcome in survivors of congenital diaphragmatic hernia at 5 years of age, what does it tell?

“…In addition, the defect size could not be reliably retrieved for every participant, as structural recording of defect size only started in recent years. Second, we excluded patients with severe genetic syndromes, but we do not know whether the others might have had small genetic defects, as exome sequencing was not yet offered in this study period [30]. Therefore, we cannot say for certain whether the possible existence of small genetic defects might have influenced our findings.…”

The heart in congenital diaphragmatic hernia: Knowns, unknowns, and future priorities

“…Similarly, the potential shared mechanisms, including genetic and environmental factors, contributing to CDH and associated CHD remain unclear, but may involve disruption of common pathways in cardiac and diaphragmatic development ( 5 , 6 ). An increasing number of genetic mutations have been identified in CDH, however, the frequency of these is not affected by the presence or absence of associated anomalies including CHD ( 7 , 8 ). Of note, HLHS and aortic anomalies may represent one end of a spectrum of left heart hypoplasia in CDH that is distinct from other mechanisms of CHD, as discussed in more detail below.…”