Genetics of congenital diaphragmatic hernia.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Seminars in Pediatric Surgery (Impact Factor: 1.94). 06/2007; 16(2):88-93. DOI: 10.1053/j.sempedsurg.2007.01.003
Source: PubMed

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 relatively common, life-threatening birth defect. We present a family with recurrent CDH-paraesophageal and central-for whom exome sequencing (ES) revealed a frameshift mutation (c.4969_4970insA, p.Ile1657Asnfs*30) in the fibrillin 1 gene (FBN1) that causes Marfan syndrome. A diagnosis of Marfan syndrome had not been considered previously in this family. However, a review of the literature demonstrated that FBN1 mutations have an unusual pattern of CDH in which paraesophageal hernias are particularly common. Subsequent clinical evaluations revealed evidence for ectopia lentis in affected family members supporting a clinical diagnosis of Marfan syndrome. Since only two other cases of familial CDH have been described in association with FBN1 mutations, we investigated an oligogenic hypothesis by examining ES data for deleterious sequence changes in other CDH-related genes. This search revealed putatively deleterious sequence changes in four other genes that have been shown to cause diaphragm defects in humans and/or mice-FREM1, DES, PAX3 and MET. It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. However, their individual contribution is likely to be small compared to that of the frameshift mutation in FBN1. We conclude that ES can be used to identify both major and minor genetic factors that may contribute to CDH. These results also suggest that ES should be considered in the diagnostic evaluation of individuals and families with CDH, particularly when other diagnostic modalities have failed to reveal a molecular etiology. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
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    ABSTRACT: Congenital diaphragmatic hernia (CDH) is a frequent occurring cause of neonatal respiratory distress and occurs 1 in every 3,000 liveborns. Ventilatory support and pharmaceutical treatment of the co-occurring lung hypoplasia and pulmonary hypertension are insufficient in, respectively, 20% of isolated cases and 60% of complex ones leading to early perinatal death. The exact cause of CDH remains to be identified in the majority of human CDH patients and prognostic factors predicting treatment refraction are largely unknown. Their identification is hampered by the multifactorial and heterogenic nature of this congenital anomaly. However, application of high-resolution molecular cytogenetic techniques to patients' DNA now enables detection of chromosomal aberrations in 30% of the patients. Furthermore, recent insights in rodent embryogenesis pointed to a specific disruption of the early mesenchymal structures in the primordial diaphragm of CDH-induced offspring. Together, these data allowed for the introduction of new hypotheses on CDH pathogenesis, although many issues remain to be resolved. In this review, we have combined these new insights and remaining questions on diaphragm pathogenesis with a concise overview of the clinical, embryological, and genetic data available.
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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