The influence of genetics in congenital diaphragmatic hernia
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
References (144)
- et al.
Analysis of an improved survival rate for congenital diaphragmatic hernia
J Pediatr Surg
(2003) - et al.
Teratogen-induced, dietary and genetic models of congenital diaphragmatic hernia share a common mechanism of pathogenesis
Am J Pathol
(2006) - et al.
Genetic factors in congenital diaphragmatic hernia
Am J Hum Genet
(2007) - et al.
Genetic causes of congenital diaphragmatic hernia
Semin Fetal Neonatal Med
(2014) - et al.
Congenital Diaphragmatic hernia and chromosome 15q26: determination of a candidate region by use of fluorescent in situ hybridization and array-based comparative genomic hybridization
Am J Hum Genet
(2005) - et al.
Friend of GATA 2 physically interacts with chicken ovalbumin upstream promoter-TF2 (COUP-TF2) and COUP-TF3 and represses COUP-TF2-dependent activation of the atrial natriuretic factor promoter
J Biol Chem
(2001) - et al.
Impaired mesenchymal cell function in Gata4 mutant mice leads to diaphragmatic hernias and primary lung defects
Dev Biol
(2007) - et al.
The discovery of microdeletion syndromes in the post-genomic era: review of the methodology and characterization of a new 1q41q42 microdeletion syndrome
Genet Med
(2007) - et al.
New cases and refinement of the critical region in the 1q41q42 microdeletion syndrome
Eur J Med Genet
(2011) - et al.
WT1 splice-site mutations are rarely associated with primary steroid-resistant focal and segmental glomerulosclerosis
Kidney Int
(2000)
Molecular pathogenesis of Marfan syndrome
Int J Cardiol
Variable expression pattern in Donnai-Barrow syndrome: report of two novel LRP2 mutations and review of the literature
Eur J Med Genet
Megalin-mediated reuptake of retinol in the kidneys of mice is essential for vitamin a homeostasis
J Nutr
Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation
Am J Hum Genet
Recessive and dominant mutations in retinoic acid receptor beta in cases with microphthalmia and diaphragmatic hernia
Am J Hum Genet
Wt1 and retinoic acid signaling are essential for stellate cell development and liver morphogenesis
Dev Biol
Overview of epidemiology, genetics, birth defects, and chromosome abnormalities associated with CDH
Am J Med Genet C Semin Med Genet
Differences in outcomes in prenatally diagnosed congenital diaphragmatic hernia compared to postnatal detection: a single-center experience
Fetal Diagn Ther
Proposal for standardized prenatal ultrasound assessment of the fetus with congenital diaphragmatic hernia by the European reference network on rare inherited and congenital anomalies (ERNICA)
Prenat Diagn
Etiology of congenital diaphragmatic hernia: the retinoid hypothesis
Pediatr Res
Congenital diaphragmatic hernia: evaluation of prenatal diagnosis in 20 European regions
Ultrasound Obstet Gynecol
De novo copy number variants are associated with congenital diaphragmatic hernia
J Med Genet
Congenital diaphragmatic defects and associated syndromes, malformations, and chromosome anomalies: a retrospective study of 60 patients and literature review
Am J Med Genet
Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia
Hum Genet
De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders
Plos Genet
Increased burden of de novo predicted deleterious variants in complex congenital diaphragmatic hernia
Hum Mol Genet
Systematic analysis of copy number variation associated with congenital diaphragmatic hernia
Proc Natl Acad Sci U S A
Where to look for the genes related to diaphragmatic hernia?
Genet Couns.
Congenital diaphragmatic hernia in 22q11.2 deletion syndrome
Am J Med Genet A
Prenatal profile of Pallister-Killian syndrome: retrospective analysis of 114 pregnancies, literature review and approach to prenatal diagnosis
Am J Med Genet A
Novel clinical manifestations in Pallister-Killian syndrome: comprehensive evaluation of 59 affected individuals and review of previously reported cases
Am J Med Genet A
Copy-number variation and association studies of human disease
Nat Genet
Refining the critical region for congenital diaphragmatic hernia on chromosome 15q26 from the study of four fetuses
Prenat Diagn
Prenatal detection and outcome of congenital diaphragmatic hernia (CDH) associated with deletion of chromosome 15q26: two patients and review of the literature
Am J Med Genet A
Congenital diaphragmatic hernia: is 15q26.1-26.2 a candidate locus
Am J Med Genet Part A
Identification of dosage-sensitive genes in fetuses referred with severe isolated congenital diaphragmatic hernia
Prenat Diagn
Mouse lacking COUP-TFII as an animal model of Bochdalek-type congenital diaphragmatic hernia
Proc Natl Acad Sci USA
Understanding abnormal retinoid signaling as a causative mechanism in congenital diaphragmatic hernia
Am J Respir Cell Mol Biol
De novo frameshift mutation in COUP-TFII (NR2F2) in human congenital diaphragmatic hernia
Am J Med Genet A
Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks
Am J Med Genet A
Chromosome 8p23.1 deletions as a cause of complex congenital heart defects and diaphragmatic hernia
Am J Med Genet Part A
Prenatal diagnosis of an 8p23.1 deletion in a fetus with a diaphragmatic hernia and review of the literature
Prenat Diagn
Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias
Nat Genet
Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23.1
Hum Mol Genet
Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia
J Med Genet
Five patients with novel overlapping interstitial deletions in 8q22.2q22.3
Am J Med Genet A
Fog2 is required for normal diaphragm and lung development in mice and humans
Plos Genet
Prevalence and penetrance of ZFPM2 mutations and deletions causing congenital diaphragmatic hernia
Clin Genet
Findings from aCGH in patients with congenital diaphragmatic hernia (CDH): a possible locus for Fryns syndrome
Am J Med Genet A
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