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A genetics of justice julia alvarez12/13/2023 Furthermore, some CDH-associated genetic mutations affect not only development of the diaphragm but also directly affect the development of other organs, such as the heart and lungs. These insights have revealed the complexity of this disorder, as mutations in multiple genes and defects in different cellular mechanisms can result in CDH. Recently, advances have been made in our understanding of the genetic pathways that regulate normal diaphragm development and the genetic mutations that lead to CDH. Unfortunately, our ability to predict outcomes and to treat CDH is hindered by technical challenges and by differences in the degree of diaphragm, heart, and lung dysfunction among CDH patients. Prenatally, clinicians quantify lung volume to predict prognosis. CDH is diagnosed prenatally in ∼50% of cases ( Stege et al., 2003). CDH patients often have pulmonary hypoplasia and pulmonary hypertension (see Box 1, Glossary) and present with cardiopulmonary failure at birth. Individuals with congenital diaphragmatic hernias (CDHs, see Box 1, Glossary) have weakened or incompletely developed diaphragms that allow the contents of the abdomen to herniate into the thoracic cavity, thereby mechanically impeding lung and heart development. Defects in diaphragm development are common, occurring in about 1 in 3000 births worldwide ( Stege et al., 2003), and are associated with complicated and often devastating clinical outcomes. The diaphragm is a skeletal muscle that normally separates the thoracic and abdominal cavities and is essential for respiration. Studies of the association between particular genetic mutations and clinical outcomes should allow us to better understand the origin of this birth defect and to improve our ability to predict and identify patients most likely to benefit from specialized treatment strategies. New therapies, including fetal endoscopic tracheal occlusion and prenatal transplacental fetal treatments, aim to normalize lung development and pulmonary vascular tone to prevent and treat lung hypoplasia and pulmonary hypertension, respectively. Mutations in these genes affect diaphragm development and can have pleiotropic effects on pulmonary and cardiac development. The affected genes identified in CDH patients include transcription factors, such as GATA4, ZFPM2, NR2F2 and WT1, and signaling pathway components, including members of the retinoic acid pathway. In ∼30% of CDH patients, genomic analyses have identified a range of genetic defects, including chromosomal anomalies, copy number variants and sequence variants. Congenital diaphragmatic hernias (CDHs) and structural anomalies of the diaphragm are a common class of congenital birth defects that are associated with significant morbidity and mortality due to associated pulmonary hypoplasia, pulmonary hypertension and heart failure.
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