De novo copy number variants are associated with congenital diaphragmatic hernia.
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.
Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.
Lan
L
Yu
Julia
J
Wynn
Lijiang
L
Ma
Saurav
S
Guha
George B
GB
Mychaliska
Timothy M
TM
Crombleholme
Kenneth S
KS
Azarow
Foong Yen
FY
Lim
Dai H
DH
Chung
Douglas
D
Potoka
Brad W
BW
Warner
Brian
B
Bucher
Charles A
CA
LeDuc
Katherine
K
Costa
Charles
C
Stolar
Gudrun
G
Aspelund
Marc S
MS
Arkovitz
Wendy K
WK
Chung
D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D002898:Chromosomes, Human, Pair 8; D056915:DNA Copy Number Variations; D005260:Female; D023061:Gene Order; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006548:Hernia, Diaphragmatic / Q000175:diagnosis / Q000235:genetics; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D008297:Male; D012189:Retrospective Studies