Detection of copy number variants reveals association of cilia genes with neural tube defects.
BACKGROUND
Neural tube defects (NTDs) are one of the most common birth defects caused by a combination of genetic and environmental factors. Currently, little is known about the genetic basis of NTDs although up to 70% of human NTDs were reported to be attributed to genetic factors. Here we performed genome-wide copy number variants (CNVs) detection in a cohort of Chinese NTD patients in order to exam the potential role of CNVs in the pathogenesis of NTDs.


METHODS
The genomic DNA from eighty-five NTD cases and seventy-five matched normal controls were subjected for whole genome CNVs analysis. Non-DGV (the Database of Genomic Variants) CNVs from each group were further analyzed for their associations with NTDs. Gene content in non-DGV CNVs as well as participating pathways were examined.


RESULTS
Fifty-five and twenty-six non-DGV CNVs were detected in cases and controls respectively. Among them, forty and nineteen CNVs involve genes (genic CNV). Significantly more non-DGV CNVs and non-DGV genic CNVs were detected in NTD patients than in control (41.2% vs. 25.3%, p<0.05 and 37.6% vs. 20%, p<0.05). Non-DGV genic CNVs are associated with a 2.65-fold increased risk for NTDs (95% CI: 1.24-5.87). Interestingly, there are 41 cilia genes involved in non-DGV CNVs from NTD patients which is significantly enriched in cases compared with that in controls (24.7% vs. 9.3%, p<0.05), corresponding with a 3.19-fold increased risk for NTDs (95% CI: 1.27-8.01). Pathway analyses further suggested that two ciliogenesis pathways, tight junction and protein kinase A signaling, are top canonical pathways implicated in NTD-specific CNVs, and these two novel pathways interact with known NTD pathways.


CONCLUSIONS
Evidence from the genome-wide CNV study suggests that genic CNVs, particularly ciliogenic CNVs are associated with NTDs and two ciliogenesis pathways, tight junction and protein kinase A signaling, are potential pathways involved in NTD pathogenesis.
Capital Institute of Pediatrics, Beijing, China.
Xiaoli
X
Chen
Yiping
Y
Shen
Yonghui
Y
Gao
Huizhi
H
Zhao
Xiaoming
X
Sheng
Jizhen
J
Zou
Va
V
Lip
Hua
H
Xie
Jin
J
Guo
Hong
H
Shao
Yihua
Y
Bao
Jianliang
J
Shen
Bo
B
Niu
James F
JF
Gusella
Bai-Lin
BL
Wu
Ting
T
Zhang
D044466:Asian People; D002923:Cilia / Q000235:genetics* / Q000502:physiology; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D009436:Neural Tube Defects / Q000235:genetics* / Q000473:pathology; D011247:Pregnancy