De novo copy number variants are associated with congenital diaphragmatic hernia

Lan Yu, Julia Wynn, Lijiang Ma, Saurav Guha, George B. Mychaliska, Timothy M. Crombleholme, Kenneth Azarow, Foong Yen Lim, Dai H. Chung, Douglas Potoka, Brad W. Warner, Brian Bucher, Charles A. LeDuc, Katherine Costa, Charles Stolar, Gudrun Aspelund, Marc S. Arkovitz, Wendy K. Chung

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)650-659
Number of pages10
JournalJournal of Medical Genetics
Volume49
Issue number10
DOIs
StatePublished - Oct 2012
Externally publishedYes

Fingerprint

Genes
Aneuploidy
Congenital Diaphragmatic Hernias
Gene Ontology
Gene Dosage
Cytogenetic Analysis
Microarray Analysis
Diaphragm
Transcription Factors
Animal Models
Morbidity
Mortality
DNA
platelet-derived growth factor A

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Yu, L., Wynn, J., Ma, L., Guha, S., Mychaliska, G. B., Crombleholme, T. M., ... Chung, W. K. (2012). De novo copy number variants are associated with congenital diaphragmatic hernia. Journal of Medical Genetics, 49(10), 650-659. https://doi.org/10.1136/jmedgenet-2012-101135

De novo copy number variants are associated with congenital diaphragmatic hernia. / Yu, Lan; Wynn, Julia; Ma, Lijiang; Guha, Saurav; Mychaliska, George B.; Crombleholme, Timothy M.; Azarow, Kenneth; Lim, Foong Yen; Chung, Dai H.; Potoka, Douglas; Warner, Brad W.; Bucher, Brian; LeDuc, Charles A.; Costa, Katherine; Stolar, Charles; Aspelund, Gudrun; Arkovitz, Marc S.; Chung, Wendy K.

In: Journal of Medical Genetics, Vol. 49, No. 10, 10.2012, p. 650-659.

Research output: Contribution to journalArticle

Yu, L, Wynn, J, Ma, L, Guha, S, Mychaliska, GB, Crombleholme, TM, Azarow, K, Lim, FY, Chung, DH, Potoka, D, Warner, BW, Bucher, B, LeDuc, CA, Costa, K, Stolar, C, Aspelund, G, Arkovitz, MS & Chung, WK 2012, 'De novo copy number variants are associated with congenital diaphragmatic hernia', Journal of Medical Genetics, vol. 49, no. 10, pp. 650-659. https://doi.org/10.1136/jmedgenet-2012-101135
Yu, Lan ; Wynn, Julia ; Ma, Lijiang ; Guha, Saurav ; Mychaliska, George B. ; Crombleholme, Timothy M. ; Azarow, Kenneth ; Lim, Foong Yen ; Chung, Dai H. ; Potoka, Douglas ; Warner, Brad W. ; Bucher, Brian ; LeDuc, Charles A. ; Costa, Katherine ; Stolar, Charles ; Aspelund, Gudrun ; Arkovitz, Marc S. ; Chung, Wendy K. / De novo copy number variants are associated with congenital diaphragmatic hernia. In: Journal of Medical Genetics. 2012 ; Vol. 49, No. 10. pp. 650-659.
@article{7914da2af58e4b3b810b32561ec47df2,
title = "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.",
author = "Lan Yu and Julia Wynn and Lijiang Ma and Saurav Guha and Mychaliska, {George B.} and Crombleholme, {Timothy M.} and Kenneth Azarow and Lim, {Foong Yen} and Chung, {Dai H.} and Douglas Potoka and Warner, {Brad W.} and Brian Bucher and LeDuc, {Charles A.} and Katherine Costa and Charles Stolar and Gudrun Aspelund and Arkovitz, {Marc S.} and Chung, {Wendy K.}",
year = "2012",
month = "10",
doi = "10.1136/jmedgenet-2012-101135",
language = "English (US)",
volume = "49",
pages = "650--659",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",
number = "10",

}

TY - JOUR

T1 - De novo copy number variants are associated with congenital diaphragmatic hernia

AU - Yu, Lan

AU - Wynn, Julia

AU - Ma, Lijiang

AU - Guha, Saurav

AU - Mychaliska, George B.

AU - Crombleholme, Timothy M.

AU - Azarow, Kenneth

AU - Lim, Foong Yen

AU - Chung, Dai H.

AU - Potoka, Douglas

AU - Warner, Brad W.

AU - Bucher, Brian

AU - LeDuc, Charles A.

AU - Costa, Katherine

AU - Stolar, Charles

AU - Aspelund, Gudrun

AU - Arkovitz, Marc S.

AU - Chung, Wendy K.

PY - 2012/10

Y1 - 2012/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84870273018&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870273018&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2012-101135

DO - 10.1136/jmedgenet-2012-101135

M3 - Article

VL - 49

SP - 650

EP - 659

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 10

ER -