Detection of Copy Number Variants Reveals Association of Cilia Genes with Neural Tube Defects

Abstract

BackgroundNeural 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.MethodsThe 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.ResultsFifty-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.ConclusionsEvidence 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.

Rare DeleteriousPARD3Variants in the aPKC-Binding Region are Implicated in the Pathogenesis of Human Cranial Neural Tube Defects Via Disrupting Apical Tight Junction Formation

“…Fig. S1A), published previously [Chen, et al., ] was detected in a cranial NTD case. No PARD3 deletions were detected in 274 matched controls and our internal clinical array‐CGH database (Children's Hospital Boston).…”

Genetic architecture of reciprocal CNVs

“…Although some CNVs are found at high frequency in human populations and are thus thought to be a potential source of genetic diversity 2,3 , larger CNVs, especially de novo , are associated frequently with human disorders 4 ; in addition to the documented involvement of CNVs in birth defects (e.g. craniofacial, cardiac, respiratory, renal) 5-12 , CNVs are also understood to be enriched in the pathogenesis of neurodevelopmental and neurocognitive disorders, such as intellectual disability, schizophrenia, and autism spectrum disorders (ASD) 6,13-20 .…”

Genetic, Epigenetic, and Environmental Contributions to Neural Tube Closure

“…Functional studies in human cells and animal systems also showed the requirement for cilia in key developmental signaling pathways, most prominently the Sonic Hedgehog pathway during NT formation (2, 91, 103, 177). In the mouse, approximately 5% of the known NTD genes are related to cilia formation and function, providing a rich source of gene candidates for analysis in human NTD samples that is only beginning to be explored (34). …”

“…With the decreasing costs of exome and whole-genome sequencing, investigators are beginning to explore the genomes of NTD-affected individuals and families. It is not yet known how copy number variants (CNVs) may contribute to NTDs, beyond a few genetic syndromes associated with NTDs (trisomy for chromosome 3, 18, or the X chromosome) and the recent association between CNVs in cilia genes in NTD samples (34). Protein coding mutations and potential regulatory mutations will likely form the first wave of functional analyses.…”