Carrier frequency of guanidinoacetate methyltransferase deficiency in the general population by functional characterization of missense variants in the GAMT gene

Mol Genet Genomics. 2015 Dec;290(6):2163-71. doi: 10.1007/s00438-015-1067-x. Epub 2015 May 24.


Guanidinoacetate methyltransferase (GAMT) deficiency is a neurodegenerative disease. Although no symptomatic patients on treatment achieved normal neurodevelopment, three asymptomatic newborns were reported with normal neurodevelopmental outcome on neonatal treatment. GAMT deficiency is therefore a candidate for newborn screening programs, but there are no studies for the carrier frequency of this disease in the general population. To determine carrier frequency of GAMT deficiency, we studied the variants in the GAMT gene reported in the Exome Variant Server database and performed functional characterization of missense variants. We used previously cloned GAMT transcript variant 1 (7 missense variants) and cloned a novel GAMT transcript variant 2 (5 missense variants). The latter was used in Exome Variant Server database according to recommendations of the Human Genome Variation Society. There were 4 missense variants (1 previously reported and 3 novel) with low GAMT enzyme activity indicating pathogenicity. Additionally, there was one novel frameshift and one novel nonsense variant likely pathogenic. There was no measurable GAMT enzyme activity in the wild type of GAMT transcript variant 2. We concluded that GAMT transcript variant 2 is not involved in GAMT protein synthesis. For this reason, Human Genome Variation Society should use mutation nomenclature according to the coding region of the GAMT transcript variant 1. The carrier frequency of GAMT deficiency was 0.123 % in the general population. As early diagnosis results in normal neurodevelopmental outcome, GAMT deficiency should be included in newborn screening programs to diagnose individuals at the asymptomatic stage of the disease to prevent permanent neurodevelopmental disability.

Keywords: Carrier frequency; Exome Variant Server; GAMT deficiency; Missense variants; Site-directed mutagenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Genetic Carrier Screening*
  • Guanidinoacetate N-Methyltransferase / chemistry
  • Guanidinoacetate N-Methyltransferase / deficiency*
  • Guanidinoacetate N-Methyltransferase / genetics*
  • HeLa Cells
  • Humans
  • Infant, Newborn
  • Language Development Disorders / genetics*
  • Molecular Sequence Data
  • Movement Disorders / congenital*
  • Movement Disorders / genetics
  • Mutation, Missense*
  • Neonatal Screening
  • Sequence Homology, Amino Acid


  • Guanidinoacetate N-Methyltransferase

Supplementary concepts

  • Guanidinoacetate methyltransferase deficiency