Genetics of congenital diaphragmatic hernia.
ABSTRACT Congenital diaphragmatic hernia (CDH) is a common structural birth defect that affects approximately 1 in 2500 live births. Although the exact etiology of most cases of CDH remains unknown, it is becoming increasingly clear that genetic factors play an important role in many cases of CDH. In this paper, we review critical findings in the areas of clinical and basic research that highlight the importance of genetics in the development of CDH. We also provide practical information that can aid physicians and surgeons as they evaluate and care for patients with isolated, nonisolated, and syndromic forms of CDH and their families.
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ABSTRACT: Congenital diaphragmatic hernia (CDH) is a common life-threatening congenital anomaly resulting in high rates of perinatal death and neonatal respiratory distress. Some of the non-isolated forms are related to single-gene mutations or genomic rearrangements, but the genetics of the isolated forms (60% of cases) still remains a challenging issue. Retinoid signaling (RA) is critical for both diaphragm and lung development, and it has been hypothesized that subtle disruptions of this pathway could contribute to isolated CDH etiology. Here we used time series of normal and CDH lungs in humans, in nitrofen-exposed rats and in surgically-induced hernia in rabbits to perform a systematic transcriptional analysis of the RA pathway key components. The results point to CRPBP2, CY26B1 and ALDH1A2 as deregulated RA signaling genes in human CDH. Furthermore, the expression profile comparisons suggest that ALDH1A2 overexpression is not a primary event, but rather a consequence of the CDH-induced lung injury. Taken together, these data show that RA signaling disruption is part of CDH pathogenesis, and also that dysregulation of this pathway should be considered organ-specifically. Copyright © 2014, American Journal of Physiology - Lung Cellular and Molecular Physiology.AJP Lung Cellular and Molecular Physiology 11/2014; 308(2):ajplung.00108.2014. DOI:10.1152/ajplung.00108.2014 · 4.04 Impact Factor
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ABSTRACT: This review outlines research that has advanced our understanding of the pathogenesis and etiology of congenital diaphragmatic hernia (CDH). The majority of CDH cases involve incomplete formation of the posterolateral portion of the diaphragm, clinically referred to as a Bochdalek hernia. The hole in the diaphragm allows the abdominal viscera to invade the thoracic cavity, thereby impeding normal lung development. As a result, newborns with CDH suffer from a combination of severe pulmonary hypoplasia and pulmonary hypertension. Despite advances in neonatal intensive care, mortality and serious morbidity remain high. Systematic studies using rat and transgenic mouse models in conjunction with analyses of human tissue are providing insights into the embryological origins of the diaphragmatic defect associated with CDH and abnormalities of developmentally-regulated signalling cascades.Respiratory Physiology & Neurobiology 05/2013; DOI:10.1016/j.resp.2013.04.015 · 1.97 Impact Factor
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ABSTRACT: Congenital diaphragmatic hernia (CDH) is a common life-threatening birth defect. Recessive mutations in the FRAS1-related extracellular matrix 1 (FREM1) gene have been shown to cause Bifid Nose with or without Anorectal and Renal anomalies (BNAR) syndrome and Manitoba OculoTrichoAnal (MOTA) syndrome, but have not been previously implicated in the development of CDH. We have identified a female child with an isolated left-sided posterolateral CDH covered by a membranous sac who had no features suggestive of BNAR or MOTA syndromes. This child carries a maternally-inherited ~86 kb FREM1 deletion that affects the expression of FREM1's full length transcripts and a paternally-inherited splice site mutation that causes activation of a cryptic splice site, leading to a shift in the reading frame and premature termination of all forms of the FREM1 protein. This suggests that recessive FREM1 mutations can cause isolated CDH in humans. Further evidence for the role of FREM1 in the development of CDH comes from an ENU-derived mouse strain, eyes2, which has a homozygous truncating mutation in Frem1. Frem1(eyes2) mice have eye defects, renal agenesis and develop retrosternal diaphragmatic hernias which are covered by a membranous sac. We confirmed that Frem1 is expressed in the anterior portion of the developing diaphragm and found that Frem1(eyes2) embryos had decreased levels of cell proliferation in their developing diaphragms when compared to wild type embryos. We conclude that FREM1 plays a critical role in the development of the diaphragm and that FREM1 deficiency can cause CDH in both humans and mice.Human Molecular Genetics 12/2012; DOI:10.1093/hmg/dds507 · 6.68 Impact Factor