Department of Genetics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico.
Birth Defects Res. 2021 Mar;113(4):371-381. doi: 10.1002/bdr2.1872. Epub 2021 Jan 19.
Myelomeningocele (MMC) is the most severe and frequent type of spina bifida. Its etiology remains poorly understood. The Hedgehog (Hh), Wnt, and planar cell polarity (PCP) signaling pathways are essential for normal tube closure, needing a structural-functional cilium for its adequate function. The present study aimed to investigate the impact of different gene variants (GV) from those pathways on MMC genotype-subphenotype correlations.
The study comprised 500 MMC trios and 500 controls, from 16 Telethon centers of 16 Mexican states. Thirty-four GVs of 29 genes from cilia, Hh, PCP, and Wnt pathways, were analyzed, by an Illumina on design microarray. The total sample (T-MMC) was stratified in High-MMC (H-MMC) when thoracic and Low-MMC (L-MMC) when lumbar-sacral vertebrae affected. STATA/SE-12.1 and PLINK software were used for allelic association, TDT, and gene-gene interaction (GGI) analyses, considering p value <.01 as statistically significant differences (SSD).
Association analysis showed SSD for COBL-rs10230120, DVL2-rs2074216, PLCB4-rs6077510 GVs in T-MMC and L-MMC, and VANGL2-rs120886448 in T-MMC and H-MMC, and INVS-rs7024375 exclusively in L-MMC. TDT assay showed SSD preferential transmissions of C2CD3-rs826058 in H-MMC, and LRP5-rs3736228, and BBS2-rs1373 in L-MMC. Statistically significant GGI was observed in four in T-MMC, four completely different in L-MMC, and one in H-MMC. Interestingly, no one repeated in subphenotypes.
Our results support an association of GVs in Hh, Wnt, PCP, and cilia pathways, with MMC occurrence location, although further validation is needed. Furthermore, present results show a distinctive panel of gene-variants in H-MMC and LMMC subphenotypes, suggesting a feasible genotype-phenotype correlation.
脊髓脊膜膨出（MMC）是最严重和最常见的脊柱裂类型。其病因仍知之甚少。Hedgehog（Hh）、Wnt 和平面细胞极性（PCP）信号通路对于正常的管闭合至关重要，需要一个结构功能的纤毛才能充分发挥其功能。本研究旨在探讨这些途径中的不同基因变异（GV）对 MMC 基因型-表型相关性的影响。
该研究包括来自 16 个墨西哥州的 16 个 Telethon 中心的 500 个 MMC 三体型和 500 个对照。通过设计微阵列分析了来自纤毛、Hh、PCP 和 Wnt 途径的 29 个基因的 34 个 GV。总样本（T-MMC）按胸椎高 MMC（H-MMC）和腰椎-骶椎低 MMC（L-MMC）分层。使用 STATA/SE-12.1 和 PLINK 软件进行等位基因关联、TDT 和基因-基因相互作用（GGI）分析，考虑到 p 值<.01 为统计学显著差异（SSD）。
关联分析显示，在 T-MMC 和 L-MMC 中，COBL-rs10230120、DVL2-rs2074216、PLCB4-rs6077510 GVs，在 T-MMC 和 H-MMC 中，VANGL2-rs120886448，以及在 L-MMC 中，INVS-rs7024375 存在 SSD。TDT 检测显示，在 H-MMC 中，C2CD3-rs826058 的优先传递存在 SSD，在 L-MMC 中，LRP5-rs3736228 和 BBS2-rs1373 也存在 SSD。在 T-MMC 中观察到四个统计学显著的 GGI，在 L-MMC 中观察到四个完全不同的 GGI，在 H-MMC 中观察到一个 GGI。有趣的是，没有一个在亚表型中重复。
我们的结果支持 Hh、Wnt、PCP 和纤毛途径中的 GV 与 MMC 发生部位相关，尽管需要进一步验证。此外，目前的结果显示了 H-MMC 和 LMMC 亚表型中独特的基因变异面板，表明存在可行的基因型-表型相关性。
