Digenic variants of planar cell polarity genes in human neural tube defect patients.
Digenic variants of planar cell polarity genes in human neural tube defect patients.
复制标题
DOI：
10.1016/j.ymgme.2018.03.005
复制
发表时间：
2018-05
影响因子：
3.8
通讯作者：
Ren A
中科院分区：
文献类型：
--
作者：
Wang L;Xiao Y;Tian T;Jin L;Lei Y;Finnell RH;Ren A
神经管缺陷（NTD）被认为是一种复杂的遗传性疾病，尽管遗传因素的身份仍然很大程度上未知。小鼠模型研究表明 NTD 存在多因素寡基因遗传模式，但令人惊讶的是，已发表的人类研究的证据却缺乏。在本研究中，使用来自 510 例 NTD 病例的 DNA 样本进行靶向下一代测序，以筛选目标基因的整个编码区和内含子-外显子边界的 DNA 变异。这些候选基因是PCP基因，包括VANGL1、VANGL2、CELSR1、SCRIB、DVL2、DVL3和PTK7。使用桑格测序验证候选变体。总共鉴定出 397 个单核苷酸变异（SNV），平均深度约为 570×。在这些已识别的 SNV 中，有 74 个预计会影响蛋白质功能，且次要等位基因频率 < 0.01 或未知。在这 74 个错义 SNV 中，从 6 例 NTD 病例中鉴定出 10 个携带两个突变基因。在 6 例 NTD 病例中，3 例脊柱裂病例和 1 例无脑畸形病例携带 CELSR1 和 SCRIB 基因双基因变异； 1 例无脑畸形病例携带 CELSR1 和 DVL3 基因变异；一名脊柱裂病例携带 PTK7 和 SCRIB 基因变异。可获得亲本样本的3例被证实为复合杂合子。在 1000 个基因组数据库中没有发现任何双基因变异。研究结果表明，遗传变异可能以双基因方式相互作用，产生可见的 NTD 表型，并强调了这些遗传相互作用在人类 NTD 发展中的重要性。
Neural tube defects (NTDs) are considered to be a complex genetic disorder, although the identity of the genetic factors remains largely unknown. Mouse model studies suggest a multifactorial oligogenic pattern of inheritance for NTDs, yet evidence from published human studies is surprisingly absent. In the present study, targeted next-generation sequencing was performed to screen for DNA variants in the entire coding regions and intron-exon boundaries of targeted genes using DNA samples from 510 NTD cases. These candidate genes were PCP genes, including VANGL1, VANGL2, CELSR1, SCRIB, DVL2, DVL3 and PTK7. Candidate variants were validated using Sanger sequencing. A total of 397 single nucleotide variants(SNVs) were identified with a mean depth of approximately 570×. Of these identified SNVs, 74 were predicted to affect protein function and had a minor allele frequency of < 0.01 or unknown. Among these 74 missense SNVs, 10 were identified from six NTD cases that carried two mutated genes. Of the six NTD cases, three spina bifida cases and one anencephaly case carried digenic variants in the CELSR1 and SCRIB gene; one anencephaly case carried variants in the CELSR1 and DVL3 gene; and one spina bifida case carried variants in the PTK7 and SCRIB genes. Three cases that parental samples were available were confirmed to be compound heterozygous. None of the digenic variants were found in the 1000 genome database. The findings imply that genetic variation might interact in a digenic fashion to generate the visible NTD phenotypes and emphasize the importance of these genetic interactions in the development of NTDs in humans.
登录
查看更多内容
DOI：
10.1007/s12031-012-9871-9
发表时间：
2013-03
期刊：
Journal of molecular neuroscience : MN
影响因子：
--
作者：
De Marco P;Merello E;Consales A;Piatelli G;Cama A;Kibar Z;Capra V
通讯作者：
Capra V
影响因子：
6.7
作者：
LECK, I
通讯作者：
LECK, I
影响因子：
64.8
作者：
Lu, XW;Borchers, AGM;Tessier-Lavigne, M
通讯作者：
Tessier-Lavigne, M
影响因子：
158.5
作者：
Kibar, Zoha;Torban, Elena;Gros, Philippe
通讯作者：
Gros, Philippe
影响因子：
11.8
作者：
Gray, Ryan S.;Roszko, Isabelle;Solnica-Krezel, Lilianna
通讯作者：
Solnica-Krezel, Lilianna