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Cystathionine β-synthase genetic variant rs2124459 is associated with a reduced risk of cleft palate in French and Belgian populations
  1. Laetitia Goffinet1,2,
  2. Abderrahim Oussalah1,3,4,
  3. Rosa-Maria Guéant-Rodriguez1,3,4,
  4. Céline Chery1,3,4,
  5. Mirta Basha5,
  6. Patrice Hodonou Avogbe1,
  7. Thomas Josse1,3,4,
  8. Elise Jeannesson1,3,4,
  9. Pierre Rouyer1,
  10. Justine Flayac1,
  11. Philippe Gerard1,
  12. Anne Le Touze6,
  13. Béatrice Bonin-Goga7,
  14. Dominique Goga7,
  15. Etienne Simon8,9,
  16. François Feillet1,
  17. Miikka Vikkula5,
  18. Jean-Louis Guéant1,3,4
  1. 1Faculty of Medicine of Nancy, INSERM U954, NGERE—Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France
  2. 2Department of Pediatric Surgery, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France
  3. 3Department of Molecular Medicine and Personalized Therapeutics, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France
  4. 4Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France
  5. 5Human Molecular Genetics (GEHU), de Duve Institute—Université catholique de Louvain, Brussels, Belgium
  6. 6Department of Pediatric Visceral Surgery, Francois Rabelais University, and University Hospital of Tours, Tours, France
  7. 7Department of Maxillofacial Surgery, Hospital Trousseau, CHRU Tours, Tours, France
  8. 8Department of Maxillofacial, Plastic, Reconstructive and Cosmetic Surgery, University Hospital of Nancy, Nancy, France
  9. 9University of Lorraine, Vandoeuvre-lès-Nancy, Lorraine, France
  1. Correspondence to Professor Jean-Louis Guéant, Faculty of Medicine of Nancy, INSERM U954, NGERE—Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy F-54000, France; jean-louis.gueant{at}


Background Orofacial cleft (OFC) is the most prevalent craniofacial birth defect. Genes involved in one-carbon, folate and vitamin B12 metabolisms have been associated with OFC but no study performed a concomitant assessment on genes involved in these three pathways.

Objective We looked for potential genetic variants associated with OFC using an exhaustive gene panel of one-carbon metabolism.

Methods We performed a case–control discovery study on children with OFC (236 cases, 145 controls) and their related mothers (186 cases, 127 controls). We performed a replication study on the top significant genetic variant in an independent group from Belgium (248 cases, 225 controls).

Results In the discovery study on ‘mothers’, the CBS locus reached array-wide significance (p=9.13×10−6; Bonferroni p=4.77×10−3; OR 0.47 (0.33 to 0.66)) among the 519 haplotypes tested for their association with OFC risk. Within the CBS haplotype block (rs2124459, rs6586282, rs4920037, rs234705, rs234709), the rs2124459 was the most significantly associated with a reduced risk of OFC (p=1.77×10−4; Bonferroni p=2.00×10−2; OR 0.53 (0.38 to 0.74), minor allele). The rs2124459 was associated with a reduced risk of cleft palate (CP) (p=6.78×10−5; Bonferroni p=7.80×10−3; OR 0.40 (0.25 to 0.63)). In the ‘children’ group, the rs2124459 was associated with a reduced risk of CP (p=0.02; OR 0.61 (0.40 to 0.93), minor allele). The association between rs2124459 and reduced risk of CP was replicated in an independent children population from Belgium (p=0.02; OR 0.64 (0.44 to 0.93), minor allele).

Conclusions The CBS rs2124459 was associated with a reduced risk of CP in both French and Belgian populations. These results highlight the prominent involvement of the vitamin B6-dependent transsulfuration pathway of homocysteine in OFC risk and the interest for evaluating vitamin B6 status in further population studies.

  • one-carbon metabolism
  • orofacial cleft
  • cleft palate
  • cystathionine beta-synthase
  • homocysteine transsulfuration pathway

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  • Contributors LG and AO contributed equally to this article. LG and CC conducted research, analysed data, performed genotyping analyses and wrote paper. AO conducted research, analysed data, performed statistical analysis and wrote paper. R-MG-R conducted research, provided essential materials, participated in genotyping analyses and analysed data; MB conducted research. PA, TJ and PR conducted research and performed genotyping analyses. EJ, JF and PG conducted research and performed biochemical assays. ALT, BB-G, DG and ES conducted research and recruited subjects. FF conducted research and analysed data. MV conducted research, analysed data and provided essential materials. J-LG designed and coordinated research, provided essential materials, analysed data, wrote paper and had primary responsibility for final content.

  • Funding This work was supported by grants from the French National Institute for Health and Medical Research (INSERM) and the French Direction for Research (Hospital Program for Clinical Research PHRC FePA, Study No. 2008-A00924-51).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The Nancy University Hospital ethics committee and the institutional review board of Université Catholique de Louvain.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data gathered resulted in this publication.