Genetic analysis of Wnt/PCP genes in neural tube defects

• DOI: 10.1186/s12920-018-0355-9
• Publication Date: 2018-04-19T15:00:08Z
• Authors: Zhongzhong Chen; Yunping Lei; Xuanye Cao; Yufang Zheng; Fang Wang; Yihua Bao; Rui Peng; Richard H. Finnell; Ting Zhang; Hongyan Wang
• Keywords: Compound heterozygosity; Heterozygote advantage; Candidate gene; Loss function; Human genetics; Convergent extension

Abstract Background Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical closure (NTC). Knockout mice that are heterozygotes single PCP likely fail produce NTD phenotypes, yet damaging variants detected human NTDs almost always heterozygous, suggesting other deleterious interacting be present. Nonetheless, Wnt/PCP remains a genetic hotspot. Addressing these issues is essential for understanding etiology NTDs. Methods We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing 184 Chinese cases. subsequently replicated our findings CELSR1 gene an independent cohort 292 Caucasian samples from USA. Functional validations were confirmed using vitro assays. Results , CELSR2 and CELSR3 significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During validation stage, number loss function (LoF) was enriched compared LoF counts ExAC database ( p < 0.001). studies indicated compound heterozygote p.Thr2026Met DVL3 p.Asp403Asn result down regulation signals. Conclusions These data indicate CELSR genes, identified ~ 14% cases, expected pathway. Compound which observed 3.3% studied cohort, also amplify effects at level.