Association between rare variants in specific functional pathways and human neural tube defects multiple subphenotypes

Abstract

Background: Neural tube defects (NTDs) are failure of neural tube closure, which includes multiple central nervous system phenotypes. More than 300 mouse mutant strains exhibits NTDs phenotypes and give us some clues to establish association between biological functions and subphenotypes. However, the knowledge about association in human remains still very poor. Methods: High throughput targeted genome DNA sequencing were performed on 280 neural tube closure-related genes in 355 NTDs cases and 225 ethnicity matched controls, Results: We explored that potential damaging rare variants in genes functioning in chromatin modification, apoptosis, retinoid metabolism and lipid metabolism are associated with human NTDs. Importantly, our data indicate that except for planar cell polarity pathway, craniorachischisis is also genetically related with chromatin modification and retinoid metabolism. Furthermore, single phenotype in cranial or spinal regions displays significant association with specific biological function, such as anencephaly is associated with potentially damaging rare variants in genes functioning in chromatin modification, encephalocele is associated with apoptosis, retinoid metabolism and one carbon metabolism, spina bifida aperta and spina bifida cystica are associated with apoptosis; lumbar sacral spina bifida aperta and spina bifida occulta are associated with lipid metabolism. By contrast, complex phenotypes in both cranial and spinal regions display association with various biological functions given the different phenotypes. Conclusions: Our study links genetic variant to subphenotypes of human NTDs and provides a preliminary but direct clue to investigate pathogenic mechanism for human NTDs.

Systems Biology Analysis of Human Genomes Points to Key Pathways Conferring Spina Bifida Risk

“…Decades of clinical and animal model investigations have led to the consensus that genetic contributions to SB predisposition are most likely due to rare variants, and only a few examples are cited here[15, 41, 52, 87, 89]. However, since some relatively common alleles may contribute to SB genetic risk, we used a somewhat relaxed definition of rare, including for further analysis those variants with an allele frequency (AF) < 0.01 in any population from 1000 Genomes[1], NHLBI GO Exome Sequencing Project (ESP) [80], and the Genome Aggregation Database (gnomAD) [45].…”

Transfection of STAT3 Overexpression Plasmid Mediated by Recombinant Lentivirus Promotes Differentiation of Bone Marrow Mesenchymal Stem Cells Into Neural Cells in Fetal Rats With Spina Bifida Aperta

“…The worldwide incidence of NTDs ranges from 1.0 to 10.0 per 1000 births [16]. Almost equal frequencies between two major categories: anencephaly and spina bi da aperta [17]. The exact mechanism of NTDs is unknown up to now, a variety of genetic and environmental factors are implicated [18].…”

STAT3 Regulates the Pathogenesis and Bone Mesenchymal Stem Cells Transplantation of Spina Bifida Aperta Through Caspase-8

“…The worldwide incidence of NTDs ranges from 1.0 to 10.0 per 1000 births [16]. Almost equal frequencies between two major categories: anencephaly and spina bi da aperta [17]. The exact mechanism of NTDs is unknown up to now, a variety of genetic and environmental factors are implicated [18].…”