De novo copy number variants are associated with congenital diaphragmatic hernia

Abstract

Background: Congenital diaphragmatic hernia (CDH) is a common birth defect with significant morbidity and mortality. Although the aetiology of CDH remains poorly understood, studies from animal models and patients with CDH suggest that genetic factors play an important role in the development of CDH. Chromosomal anomalies have been reported in CDH.

Methods: In this study, the authors investigated the frequency of chromosomal anomalies and copy number variants (CNVs) in 256 parent-child trios of CDH using clinical conventional cytogenetic and microarray analysis. The authors also selected a set of CDH related training genes to prioritise the genes in those segmental aneuploidies and identified the genes and gene sets that may contribute to the aetiology of CDH.

Results: The authors identified chromosomal anomalies in 16 patients (6.3%) of the series including three aneuploidies, two unbalanced translocation, and 11 patients with de novo CNVs ranging in size from 95 kb to 104.6 Mb. The authors prioritised the genes in the CNV segments and identified KCNA2, LMNA, CACNA1S, MYOG, HLX, LBR, AGT, GATA4, SOX7, HYLS1, FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, HOMER2, BNC1, BID, and TBX1 as genes that may be involved in diaphragm development. Gene enrichment analysis identified the most relevant gene ontology categories as those involved in tissue development (p=4.4×10(-11)) or regulation of multicellular organismal processes (p=2.8×10(-10)) and 'receptor binding' (p=8.7×10(-14)) and 'DNA binding transcription factor activity' (p=4.4×10(-10)).

Conclusions: The present findings support the role of chromosomal anomalies in CDH and provide a set of candidate genes including FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, SOX7, BNC1, BID, and TBX1 for further analysis in CDH.

Conflict of interest statement

Competing interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Gene enrichment sets were mapped as a network. Gene enrichment analysis results in 238 biological process and 46 molecular function gene ontology (GO) categories. Each node represents a GO. The GO categories are related by mutual overlap (edges). The major functional enrichment sets are highlighted by text. The two GO categories with bold fonts are the most significant ones.

Figure 2

The recurrent CDH regions. A. The deletions of 8p23.1 associated with CDH. The red bars with solid or gradient shape are the maximally deleted regions for each patient. There are two deletions identified in our patients and 01-0162 deletion narrowed to the minimum critical 8p23.1 CDH CNV region. Genes in the critical CNV are shown with blue bars. Priority genes are shown as red font and bar. B. The deletions of 15q25.2 associated with CDH. The minimum deleted regions for each patient are shown with solid bars. The light blue bar is the 1.5 Mb deletion in 01-0536. Thirteen genes in the narrowed critical 15q25.2 CDH region are indicated with blue bars. Priority genes are shown as red font and bar. C. The recurrent pathogenic 17q12 deletions among ISCAC database and CDH patients. Red squares indicate the data from ISCAC; green square represents a 1.4 Mb 17q12 deletion reported recently; light blue squares indicate the deletions of our CDH patients (02-0008 and 01-0454). Genes in the overlapped deletion regions are indicated with blue bar. LHX1 is the predicted priority gene in this region shown as red font and bar.