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Exome sequencing of cases with neural tube defects identifies candidate genes involved in one-carbon/vitamin B12 metabolisms and Sonic Hedgehog pathway

Abstract : Neural tube defects (NTD) result from complex mechanisms between genes, nutrition and environment. The identifcation of genetic predictors by genome exome sequencing and their infuence on genome methylation need further consideration. Gene variants related to 1-CM metabolism (1-CM) could infuence the methylation of genes involved in neural tube embryogenesis through impaired synthesis of S-adenosyl methionine. We performed exome sequencing of 6116 genes referenced in OMIM and NTD risk and genome-wide methylation in 23 NTD cases. We replicated the most signifcant associations in 81 other cases. The analysis of exome sequencing identifed one gene of 1-CM, LRP2, and one gene of Sonic Hedgehog (SHH), GLI3, in the 23 NTD cases. The analysis restricted to genes of 1-CM and neural tube embryogenesis identifed fve gene predictors of 1-CM (LRP2, rs137983840; MMAA, rs148142853; TCN2, rs35838082; FPGS, rs41306702; BHMT, rs763726268) and two of SHH (GLI3, rs35364414; MKS1, rs151023718). We replicated the association of TCN2, BHMT and GLI3 with NTD risk in the 81 cases. We found a signifcant hemimethylation of CFAP46 that may infuence SHH activation in one case, who carried risk alleles in BHMT, LRP2, MMAA and GLI3. In conclusion, we identifed new candidate genes and rare variants that highlight an interacting infuence of genes involved in SHH and 1-CM in the puzzle of genetic components of NTD risk.
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https://hal.univ-lorraine.fr/hal-02503888
Contributor : Philippe de Carvalho <>
Submitted on : Tuesday, March 10, 2020 - 12:22:18 PM
Last modification on : Tuesday, October 13, 2020 - 10:47:29 AM

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Émeline Renard, Céline Chery, Abderrahim Oussalah, Thomas Josse, Pascal Perrin, et al.. Exome sequencing of cases with neural tube defects identifies candidate genes involved in one-carbon/vitamin B12 metabolisms and Sonic Hedgehog pathway. Human Genetics, Springer Verlag, 2019, 138 (7), pp.703-713. ⟨10.1007/s00439-019-02015-7⟩. ⟨hal-02503888⟩

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