Association between rare variants in specific functional pathways and human neural tube defects multiple subphenotypes
Association between rare variants in specific functional pathways and human neural tube defects multiple subphenotypes
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特定功能通路中的罕见变异与人类神经管缺陷多个亚表型之间的关联
DOI：
10.1186/s13064-020-00145-7
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发表时间：
2020
影响因子：
3.6
通讯作者：
Li Huili
中科院分区：
文献类型：
--
作者：
Zou Jizhen;Wang Fang;Yang Xueyan;Wang Hongyan;Nisw;er Lee;Zhang Ting;Li Huili
神经管缺陷（Neural tube defects，NTDs）是指神经管闭合失败，包括多种中枢神经系统表型。超过300种小鼠突变株表现出NTDs表型，为我们建立生物学功能与亚表型之间的关联提供了一些线索。然而，在人类协会的知识仍然非常poor.MethodsHigh throughput targeted genome DNA测序进行了280神经管关闭相关基因在355例NTDs和225种族匹配的对照，ResultsWe探讨了潜在的破坏性罕见变异基因功能的染色质修饰，细胞凋亡，类维生素A代谢和脂质代谢与人类NTDs。更重要的是，我们的数据表明，除了平面细胞极性途径，颅脊柱裂也与染色质修饰和维甲酸代谢的遗传相关。此外，颅或脊髓区域的单一表型显示与特定生物学功能显著相关，如无脑畸形与染色质修饰基因的潜在损害性罕见变异相关，脑膨出与细胞凋亡、维甲酸代谢和一碳代谢相关，开放性脊柱裂和囊性脊柱裂与细胞凋亡相关;腰骶部开放性脊柱裂和隐性脊柱裂与脂质代谢有关。相比之下，复杂的表型在颅和脊髓区域显示与各种生物学功能给予不同的phenotypes.ConclusionsOur研究链接遗传变异的人类NTDs的亚表型，并提供了一个初步的，但直接的线索，调查人类NTDs的致病机制。
BackgroundNeural 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.MethodsHigh throughput targeted genome DNA sequencing were performed on 280 neural tube closure-related genes in 355 NTDs cases and 225 ethnicity matched controls,ResultsWe 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.ConclusionsOur study links genetic variant to subphenotypes of human NTDs and provides a preliminary but direct clue to investigate pathogenic mechanism for human NTDs.