Genetic aspects of human congenital diaphragmatic hernia.

Center for Human Genetics, Massachusetts General Hospital, Boston, MA 02114, USA.
Clinical Genetics (Impact Factor: 3.65). 08/2008; 74(1):1-15. DOI: 10.1111/j.1399-0004.2008.01031.x
Source: PubMed

ABSTRACT Congenital diaphragmatic hernia (CDH) is a common major malformation affecting 1/3000-1/4000 births, which continues to be associated with significant perinatal mortality. Much current research is focused on elucidating the genetics and pathophysiology contributing to CDH to develop more effective therapies. The latest data suggest that many cases of CDH are genetically determined and also indicate that CDH is etiologically heterogeneous. The present review will provide a brief summary of diaphragm development and model organism work most relevant to human CDH and will primarily describe important human phenotypes associated with CDH and also provide recommendations for diagnostic evaluation of a fetus or infant with CDH.

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    ABSTRACT: Congenital diaphragmatic hernia (CDH) is a common birth defect affecting 1 in 3000 births. It is characterised by herniation of abdominal viscera through an incompletely formed diaphragm. Although chromosomal anomalies and mutations in several genes have been implicated, the cause for most patients is unknown. We used whole exome sequencing in two families with CDH and congenital heart disease, and identified mutations in GATA6 in both. In the first family, we identified a de novo missense mutation (c.1366C>T, p.R456C) in a sporadic CDH patient with tetralogy of Fallot. In the second, a nonsense mutation (c.712G>T, p.G238*) was identified in two siblings with CDH and a large ventricular septal defect. The G238* mutation was inherited from their mother, who was clinically affected with congenital absence of the pericardium, patent ductus arteriosus and intestinal malrotation. Deep sequencing of blood and saliva-derived DNA from the mother suggested somatic mosaicism as an explanation for her milder phenotype, with only approximately 15% mutant alleles. To determine the frequency of GATA6 mutations in CDH, we sequenced the gene in 378 patients with CDH. We identified one additional de novo mutation (c.1071delG, p.V358Cfs34*). Mutations in GATA6 have been previously associated with pancreatic agenesis and congenital heart disease. We conclude that, in addition to the heart and the pancreas, GATA6 is involved in development of two additional organs, the diaphragm and the pericardium. In addition, we have shown that de novo mutations can contribute to the development of CDH, a common birth defect.
    Journal of Medical Genetics 03/2014; 51(3):197-202. DOI:10.1136/jmedgenet-2013-101989 · 5.64 Impact Factor
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    ABSTRACT: Congenital diaphragmatic hernia (CDH) is a common and severe birth defect. Despite its clinical significance, the genetic and developmental pathways underlying this disorder are incompletely understood. In this study, we report a catalog of variants detected by a whole exome sequencing study on 275 individuals with CDH. Predicted pathogenic variants in genes previously identified in either humans or mice with diaphragm defects are enriched in our CDH cohort compared with 120 size-matched random gene sets. This enrichment was absent in control populations. Variants in these critical genes can be found in up to 30.9% of individuals with CDH. In addition, we filtered variants by using genes derived from regions of recurrent copy number variations in CDH, expression profiles of the developing diaphragm, protein interaction networks expanded from the known CDH-causing genes, and prioritized genes with ultrarare and highly disruptive variants, in 11.3% of CDH patients. These strategies have identified several high priority genes and developmental pathways that likely contribute to the CDH phenotype. These data are valuable for comparison of candidate genes generated from whole exome sequencing of other CDH cohorts or multiplex kindreds and provide ideal candidates for further functional studies. Furthermore, we propose that these genes and pathways will enhance our understanding of the heterogeneous molecular etiology of CDH.
    Proceedings of the National Academy of Sciences 08/2014; 111(34). DOI:10.1073/pnas.1412509111 · 9.81 Impact Factor
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    ABSTRACT: The article is a case report of a 20 years old pregnant woman that, at her first obstetrical exam, at 29 weeks of gestation was diagnosed with CDH with severe left side lung hypoplasia, mediastinal shift on the right side and a compressed right lung. At 39 weeks of gestation, by caesarian section, a 3300 grams female baby was born with an APGAR score of 8. The reconstructive surgery, thanks to a stable fetal status on mechanical ventilator, could be made 2 days later and it revealed a rare case of Bochdalek CDH in a pleuroperitoneal membrane and multiple accessory spleen. After 3 days of good postoperative status an episode of severe dyspnea revealed a rare complication, a postoperative hiatal hernia with the whole stomach into the thorax. A second successful reconstructive surgery was made in emergency and the baby was discharged 2 weeks later. CDH remains one of the most challenging topics of perinatology and neonatal surgery. Its mechanisms are still to be unveiled but the severe lesions, especially of the lungs require the full implication of a mixt team of highly skilled doctors, in order to increase the very low survival rate (around 40 percent in most studies). This, together with the very low incidence (1 CDH in every 2500 births) and a 10 percent incidence of Bochdalek CDH with sac in all CDH cases, make the background of a solid-base protocols of management extremely difficult. Therefore this should be a hot topic for researchers in the future. Key words:congenital diaphragmatic hernia, pulmonary hypertension, hypoplastic lung, surgery
    Archives of the Balkan Medical Union 12/2013; 48(4):431-434.


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