title: Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene.
abstract: Guanidinoacetate methyltransferase deficiency (GAMT-D) is an autosomal recessively inherited disorder of creatine biosynthesis. Creatine deficiency on cranial proton magnetic resonance spectroscopy, and elevated guanidinoacetate levels in body fluids are the biomarkers of GAMT-D. In 74 patients, 50 different mutations in the GAMT gene have been identified with missense variants being the most common. Clinical and biochemical features of the patients with missense variants were obtained from their physicians using a questionnaire. In 20 patients, 17 missense variants, 25% had a severe, 55% a moderate, and 20% a mild phenotype. The effect of these variants on GAMT enzyme activity was overexpressed using primary GAMT-D fibroblasts: 17 variants retained no significant activity and are therefore considered pathogenic. Two additional variants, c.22C>A (p.Pro8Thr) and c.79T>C (p.Tyr27His) (the latter detected in control cohorts) are in fact not pathogenic as these alleles restored GAMT enzyme activity, although both were predicted to be possibly damaging by in silico analysis. We report 13 new patients with GAMT-D, six novel mutations and functional analysis of 19 missense variants, all being included in our public LOVD database. Our functional assay is important for the confirmation of the pathogenicity of identified missense variants in the GAMT gene.
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada; Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Saadet
authors.initials: S
authors.lastname: Mercimek-Mahmutoglu
authors.forename: Joseph
authors.initials: J
authors.lastname: Ndika
authors.forename: Warsha
authors.initials: W
authors.lastname: Kanhai
authors.forename: Thierry Billette
authors.initials: TB
authors.lastname: de Villemeur
authors.forename: David
authors.initials: D
authors.lastname: Cheillan
authors.forename: Ernst
authors.initials: E
authors.lastname: Christensen
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dorison
authors.forename: Vickie
authors.initials: V
authors.lastname: Hannig
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hendriks
authors.forename: Floris C
authors.initials: FC
authors.lastname: Hofstede
authors.forename: Laurence
authors.initials: L
authors.lastname: Lion-Francois
authors.forename: Allan M
authors.initials: AM
authors.lastname: Lund
authors.forename: Helen
authors.initials: H
authors.lastname: Mundy
authors.forename: Gaele
authors.initials: G
authors.lastname: Pitelet
authors.forename: Miquel
authors.initials: M
authors.lastname: Raspall-Chaure
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Scott-Schwoerer
authors.forename: Katalin
authors.initials: K
authors.lastname: Szakszon
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.forename: Monique
authors.initials: M
authors.lastname: Williams
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D050937:Guanidinoacetate N-Methyltransferase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007805:Language Development Disorders / Q000235:genetics* / Q000473:pathology*; D008297:Male; D009069:Movement Disorders / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D020125:Mutation, Missense; D011795:Surveys and Questionnaires; D055815:Young Adult
chemical_list: C494506:GAMT protein, human; D050937:Guanidinoacetate N-Methyltransferase
keywords: GAMT; GAMT-D; missense variants; site-directed mutagenesis