Recurrent copy number variants associated with bronchopulmonary dysplasia

Abstract

Background: Variability in the incidence and severity of bronchopulmonary dysplasia (BPD) among premature infants suggests that genetic susceptibility plays a role in pathogenesis. An assessment of copy number variants (CNV) in BPD subjects may help to identify loci that harbor genetic susceptibility factors. Methods:We conducted a retrospective analysis of clinical DNA microarray data from our institution. We identified 19 BPD subjects, and 2 controls groups (full-term and preterm) with no lung-related disease. We reanalyzed raw data from each of these subjects to identify recurrent CNV loci in BPD subjects. results: We identified three loci (at 11q13.2, 16p13.3, and 22q11.23-q12.1) with recurrent CNV in BPD subjects. The frequency of these CNV was significantly higher in BPD subjects when compared with at least one control group. We interrogated 21 genes residing within the recurrent CNV regions for development-associated changes in expression. Fifteen genes demonstrated significant changes in expression between the pseudoglandular and canalicular stage in human lungs, a time commensurate with birth at highest risk for BPD. We also identified pathways represented by the genes present within the recurrent loci. conclusion: These data identify novel loci that may harbor genes contributing to the genetic susceptibility of BPD.

Intrauterine Hypoxia and Epigenetic Programming in Lung Development and Disease

“…Further analysis demonstrated that pathways associated with genes differentially methylated and expressed in BPD included ErbB signaling, neuregulin signaling, RhoA signaling, VEGF signaling, cardiomyocyte differentiation via BMP receptors, axonal guidance signaling, and glutathione-mediated detoxification [43]. Some of those pathways such as RhoA signaling, axonal guidance signaling and glutathione-mediated detoxification have been implicated in lung development and BPD pathogenesis [94][95][96]. Other than DNA methylation, histone marker modifications, especially on the outer promoter regions, are important for the epigenetic programming of gene expression [102][103][104] and play a crucial role in the developmental origin of lung diseases [105][106][107][108][109].…”

Recent advances in our understanding of the mechanisms of late lung development and bronchopulmonary dysplasia

“…Copy number variants have also been addressed as contributors to BPD susceptibility, where three loci, at 11q13.2, 16p13.3, and 22q11.23-q12.1, that exhibit copy number variants with increased frequency in BPD patients were identified (9). Genes residing within these regions included 15 genes that undergo temporal changes in expression during transition from the pseudoglandular to the canalicular stage, which is a most relevant period of lung development in BPD.…”

Copy Number Variation and Structural Genomic Findings in 116 Cases of Sudden Unexplained Death between 1 and 28 Months of Age

“…Four cases had CNVs at chr22q11.23–q12.1 (chr22:25672585–25903543) involving IGLL3P, LRP5L, CRYBB2P1 , and MIR6817 (three deletions and one duplication). This 22q11.23–q12.1 region is associated with bronchopulmonary dysplasia (BPD) in premature infants [ 86 ] and in our cases is not likely to be related to SUDP, as our cases were not born prematurely. Two cases had duplications at 15q26.2 (chr15:96869390–96950543 and chr15:96869390–96896882) encompassing NR2F2 .…”