Mechanistic Insights into Lethal Lung Developmental Disorders. The Rare Informs the Common.
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ABSTRACT:
SUBMITTER: Abman SH
PROVIDER: S-EPMC6888662 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Lethal lung developmental disorders are a rare but important group of pediatric diffuse lung diseases presenting with neonatal respiratory failure. On the basis of histopathological appearance at lung biopsy or autopsy, they have been termed: alveolar capillary dysplasia with misalignment of the pulmonary veins, acinar dysplasia, congenital alveolar dysplasia, and other unspecified primary pulmonary hypoplasias. However, the histopathological continuum in these lethal developmental disorders has made accurate diagnosis challenging, which has implications for recurrence risk. Over the past decade, genetic studies in infants with alveolar capillary dysplasia with misalignment of the pulmonary veins have revealed the causative role of the dosage-sensitive FOXF1 gene and its noncoding regulatory variants in the distant lung-specific enhancer at chromosome 16q24.1. In contrast, the molecular bases of acinar dysplasia and congenital alveolar dysplasia have remained poorly understood. Most recently, disruption of the TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling pathway has been reported in patients with these lethal pulmonary dysplasias. Application of next-generation sequencing techniques, including exome sequencing and whole-genome sequencing, has demonstrated their complex compound inheritance. These data indicate that noncoding regulatory elements play a critical role in lung development in humans. We propose that for more precise lethal lung developmental disorder diagnosis, a diagnostic pathway including whole-genome sequencing should be implemented.
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Project description:Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.
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