Maternal genotypes of folate/one-carbon metabolism gene variants and nonsyndromic cleft lip with or without cleft palate risk in Chile

Eur J Oral Sci. 2021 Oct;129(5):e12813. doi: 10.1111/eos.12813. Epub 2021 Jul 21.


The aim of this study was to evaluate, in a case-control design, the association between maternal genotypes for variants in 23 genes involved in folate/one-carbon metabolism and nonsyndromic cleft lip with or without cleft palate (NSCL/P) in a Chilean population. After applying several filters to an Illumina array, we extracted 175 single nucleotide polymorphisms (SNPs) from 150 mothers of NSCL/P cases and 150 control women. Association was evaluated using computed odds ratio (OR) with a 95% confidence interval (95% CI) in additive, recessive, and dominant models. After multiple comparison correction, only SNP rs4451422 (A>C), located 237 bp downstream of the gene encoding the human folylpolyglutamate synthetase (FPGS), maintained a significant association with NSCL/P in the offspring (OR 3.03; 95% CI 1.69-5.26). The variant rs4451422 is associated with a decrease in FPGS expression according to database annotation. Our results lead to a new hypothesis that a lower activity of FPGS enzyme reduces intracellular folate levels and increases the risk of an offspring having NSCL/P.

Keywords: cleft lip/palate; folate; folic acid; folylpolyglutamate synthetase; one-carbon metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbon
  • Chile
  • Cleft Lip* / genetics
  • Cleft Palate* / genetics
  • Folic Acid
  • Genotype
  • Humans


  • Carbon
  • Folic Acid