Variability of Creatine Metabolism Genes in Children with Autism Spectrum Disorder

Jessie M. Cameron,Valeriy Levandovskiy,Stephen Scherer,Alvin Loh,Wendy Roberts,Andreas Schulze,Evdokia Anagnostou

doi:10.3390/ijms18081665

Abstract

Creatine deficiency syndrome (CDS) comprises three separate enzyme deficiencies with overlapping clinical presentations: arginine:glycine amidinotransferase (GATM gene, glycine amidinotransferase), guanidinoacetate methyltransferase (GAMT gene), and creatine transporter deficiency (SLC6A8 gene, solute carrier family 6 member 8). CDS presents with developmental delays/regression, intellectual disability, speech and language impairment, autistic behaviour, epileptic seizures, treatment-refractory epilepsy, and extrapyramidal movement disorders; symptoms that are also evident in children with autism. The objective of the study was to test the hypothesis that genetic variability in creatine metabolism genes is associated with autism. We sequenced GATM, GAMT and SLC6A8 genes in 166 patients with autism (coding sequence, introns and adjacent untranslated regions). A total of 29, 16 and 25 variants were identified in each gene, respectively. Four variants were novel in GATM, and 5 in SLC6A8 (not present in the 1000 Genomes, Exome Sequencing Project (ESP) or Exome Aggregation Consortium (ExAC) databases). A single variant in each gene was identified as non-synonymous, and computationally predicted to be potentially damaging. Nine variants in GATM were shown to have a lower minor allele frequency (MAF) in the autism population than in the 1000 Genomes database, specifically in the East Asian population (Fisher’s exact test). Two variants also had lower MAFs in the European population. In summary, there were no apparent associations of variants in GAMT and SLC6A8 genes with autism. The data implying there could be a lower association of some specific GATM gene variants with autism is an observation that would need to be corroborated in a larger group of autism patients, and with sub-populations of Asian ethnicities. Overall, our findings suggest that the genetic variability of creatine synthesis/transport is unlikely to play a part in the pathogenesis of autism spectrum disorder (ASD) in children.

Highlights

Autism spectrum disorder (ASD) can be present in children with inborn errors of metabolism, the latter having a prevalence of 1 in every 800 live births [1]
Sequence data was compared with NCBI reference genes, and genetic variations were compared to three variation databases: the 1000 Genomes phase 3 dataset, the National Heart, Lung and Blood Institute Grand Opportunity Exome Sequencing Project (NHLBI GO ESP) and the Exome Aggregation Consortium (ExAC)
We hypothesized that genetic variability in the three genes associated with Creatine deficiency syndrome (CDS) could impact the health of children and result in an autistic phenotype

Summary

Introduction

Autism spectrum disorder (ASD) can be present in children with inborn errors of metabolism, the latter having a prevalence of 1 in every 800 live births [1]. Less than 5% of ASD cases can be attributed to routinely-screened-for inborn errors of metabolism [2,3]. Creatine deficiency syndrome (CDS) is an inherited metabolic disorder that is not included in routine newborn screening panels or in standard ASD diagnostic work up. We recently ascertained the prevalence of CDS in children with non-syndromic autism in a large, prospective, multicentre study by screening for creatine metabolites in urine and sequencing GAMT, GATM and SLC6A8 genes (glycine amidinotransferase, guanidinoacetate methyltransferase and solute carrier family 6 member 8) for pathogenic mutations (443 children with ASD). The estimated prevalence of CDS was less than 7 in 1000 and there was no obvious correlation between pathogenic CDS gene mutations and ASD, the chances of a child with ASD having a CDS were very low [5]

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