The influence of genetics in congenital diaphragmatic hernia

https://doi.org/10.1053/j.semperi.2019.07.008Get rights and content

Abstract

Congenital diaphragmatic hernia (CDH) is a common birth defect that is associated with significant morbidity and mortality, especially when associated with additional congenital anomalies. Both environmental and genetic factors are thought to contribute to CDH. The genetic contributions to CDH are highly heterogeneous and incompletely defined. No one genetic cause accounts for more than 1–2% of CDH cases. In this review, we summarize the known genetic causes of CDH from chromosomal anomalies to individual genes. Both de novo and inherited variants contribute to CDH. Genes causing CDH are increasingly identified from animal models and from genomic strategies including exome and genome sequencing in humans. CDH genes are often transcription factors, genes involved in cell migration or the components of extracellular matrix. We provide clinical genetic testing strategies in the clinical evaluation that can identify a genetic cause in up to ∼30% of patients with non-isolated CDH and can be useful to refine prognosis, identify associated medical and neurodevelopmental issues to address, and inform family planning options.

Introduction

Congenital diaphragmatic hernia (CDH) is a common and severe birth defect that affects around 1 in 3000 live births.1 It is characterized by incomplete formation of the diaphragm, leading to the herniation of the abdominal viscera into the chest cavity. CDH can occur as an isolated defect but ∼40% of cases are non-isolated and associated with additional anomalies in other systems, most commonly including heart, brain, renal and genitourinary malformations.1, 2 Newborns with CDH often have severe respiratory distress resulting from pulmonary hypoplasia and pulmonary hypertension, which are the most significant causes of morbidity and mortality of CDH patients. Today, over 70% of cases can be prenatally diagnosed based on the imaging techniques including ultrasonography and fetal magnetic resonance imaging (MRI) at a mean gestational age of 24 weeks.3, 4 Prenatal diagnosis has altered the neonatal outcomes and significant progress has been made in the postnatal care of patients with CDH, with mortality rates reduced to ∼30%.5 However, the long-term morbidity and the medical cost for caring for CDH survivors remains a significant burden. Understanding the etiology of CDH is essential to discovery of new therapies to improve outcomes.

Both environmental and genetic factors contribute CDH. It has been known that nitrofen and manipulating retinoids cause CDH in animal models.6, 7 Most human cases are unexplained by known environmental factors. Evidence from genetic studies in patients with CDH and animal models provides important insight into the molecular mechanisms of diaphragm development. The genetic etiologies of CDH are highly heterogeneous. Chromosomal anomalies of aneuploidies, structural rearrangements, copy number variants (CNVs) and single-gene mutations all contribute to CDH. Identifying a genetic etiology for CDH in patients is increasingly clinically relevant to provide accurate prognostic information and guide medical management. Studies indicate that chromosomal anomalies detectable by karyotype are observed in 10% of CDH cases8, 9 and 3–10% of CDH are associated with a syndromic diagnosis.8, 10 Recent massively parallel sequencing techniques demonstrate that 10–22% of CDH patients have de novo damaging variants that are associated with a high relative risk of developmental disorders.11, 12, 13 In this review, we summarize the current knowledge of CDH genetics.

Section snippets

Chromosomal anomalies associated with CDH

Chromosomal anomalies have been reported in about 10% of all individuals with CDH1 and include complete or mosaic aneuploidies, cytogenetic rearrangements detectable by karyotype, and copy number variants (CNVs) identified by chromosome microarrays or other methods. Structural anomalies involve almost all chromosomes,10,14, 15, 16 and an updated list of CDH associated chromosomal anomalies (Supplementary Table 1) and recurrent CNVs are provided (Fig. 1).

Monogenic syndromes associated with CDH

CDH can be isolated but more commonly is an inconsistent feature of a syndrome with other developmental anomalies or neurodevelopmental disabilities. There are more than 70 well characterized syndromes associated with CDH18, 64, 65 and over 20 of these syndromes have established genetic causes.18, 65 It is estimated that 3–10% of CDH is associated with an underlying syndromic diagnosis8, 10 which has important implications for prognosis and management. The syndromes can be autosomal recessive,

CDH genes identified by animal model and humans

Recently, next-generation sequencing technology including whole exome sequencing (WES) and whole genome sequencing (WGS) facilitated the identification of novel single nucleotide variants and genes in sporadic and familial CDH patients.12,96, 97, 98 The genes identified so far are mainly in two broad groups: transcription factors, and molecules involved in cellular migration, or the components of extracellular matrix (ECM)99 (Table 1). Genetically manipulated mouse models of many of these genes

Other genes identified by sequencing

Due to the historically high mortality with CDH, few familial studies of CDH have been conducted because of decreased reproductive fitness. The low recurrence rates135 among siblings and the lack of family history in the majority of CDH patients with CDH support the model of de novo variants causing a substantial fraction of CDH, especially syndromic cases with low reproductive fitness. Exome/genome sequencing has supported the identification of new genes for CDH, often due to de novo mutations.

Genetic counseling

Prenatal ultrasound screening enables early CDH diagnosis. Assessment of the family history should include prenatal or neonatal deaths of uncertain cause, congenital anomalies and NDD in family members. Diaphragm defects in other family members can be subtle, and MRI imaging in parents can identify small hernias or eventrations that are clinically asymptomatic but that suggest a higher risk of recurrence due to incomplete penetrance.40, 96, 97 Perinatal genetic data from chromosome microarray

Conclusion

With the availability of new molecular genetic techniques to facilitate gene discoveries for CDH, our understanding of the role of genetics in the pathogenesis of CDH may make it possible to use preventative strategies and therapeutic interventions to partially alleviate the pulmonary disease in patients with CDH. Because CDH is so genetically heterogeneous, further studies need to include analysis of larger numbers of CDH patients using exome/genome sequencing, single cell sequencing or RNA

Declaration of Competing Interest

There is no conflict of interest for all authors.

Acknowledgments

We would like to thank the patients and their families for their generous contribution. This work was supported by NIH Gabriella Miller Kids First Pediatric Research Program (X01HL132366 and X01HL136998), NIH grants R01HD057036, R03HL138352, 1P01HD068250, and NSFC81501295. Additional funding support was provided by grants from CHERUBS, CDHUK, and the National Greek Orthodox Ladies Philoptochos Society, Inc. and generous donations from the Williams Family, Wheeler Foundation, Vanech Family

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