Allelic spectrum of formiminotransferase-cyclodeaminase gene variants in individuals with formiminoglutamic aciduria

Mol Genet Genomic Med. 2017 Nov;5(6):795-799. doi: 10.1002/mgg3.333. Epub 2017 Sep 11.


Background: Elevated plasma and urine formiminoglutamic acid (FIGLU) levels are commonly indicative of formiminoglutamic aciduria (OMIM #229100), a poorly understood autosomal recessive disorder of histidine and folate metabolism, resulting from formiminotransferase-cyclodeaminase (FTCD) deficiency, a bifunctional enzyme encoded by FTCD.

Methods: In order to further understanding about the molecular alterations that contribute to FIGLU-uria, we sequenced FTCD in 20 individuals with putative FTCD deficiency and varying laboratory findings, including increased FIGLU excretion.

Results: Individuals tested had biallelic loss-of-function variants in protein-coding regions of FTCD. The FTCD allelic spectrum comprised of 12 distinct variants including 5 missense alterations that replace conserved amino acid residues (c.223A>C, c.266A>G, c.319T>C, c.430G>A, c.514G>T), an in-frame deletion (c.1373_1375delTGG), with the remaining alterations predicted to affect mRNA processing/stability. These included two frameshift variants (c.990dup, c.1366dup) and four nonsense variants (c.337C>T, c.451A>T, c.763C>T, c.1607T>A).

Conclusion: We observed additional FTCD alleles leading to urinary FIGLU elevations, and thus, providing molecular evidence of FTCD deficiency in cases identified by newborn screening or clinical biochemical genetic laboratory testing.

Keywords: Formiminoglutamic acid; formiminotransferase-cyclodeaminase; inborn errors of metabolism.

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Ammonia-Lyases / genetics*
  • Codon, Nonsense
  • Frameshift Mutation
  • Gene Deletion
  • Genotype
  • Glutamate Formimidoyltransferase / deficiency*
  • Glutamate Formimidoyltransferase / genetics
  • Humans
  • Metabolism, Inborn Errors / diagnosis
  • Metabolism, Inborn Errors / genetics*
  • Mutation, Missense
  • Open Reading Frames / genetics
  • Polymorphism, Single Nucleotide


  • Codon, Nonsense
  • Glutamate Formimidoyltransferase
  • Ammonia-Lyases
  • formiminotetrahydrofolate cyclodeaminase

Supplementary concepts

  • Glutamate formiminotransferase deficiency

Associated data

  • GENBANK/NM_206965.1