Identification of two pathogenic guanidinoacetate methyltransferase variants in patients with intellectual disability: clinical and molecular insights

Background Intellectual disability (ID) is a genetically heterogeneous neurodevelopmental disorder with diverse underlying causes. Guanidinoacetate methyltransferase (GAMT) deficiency is a rare autosomal recessive disorder of creatine biosynthesis characterized by cerebral creatine depletion and accumulation of guanidinoacetate (GAA), resulting in a spectrum of neurodevelopmental manifestations, including intellectual disability. This study aimed to investigate the molecular basis of ID in individuals with suspected genetic etiologies and to characterize pathogenic GAMT variants. Methods Whole-exome sequencing (WES) was performed in 50 unrelated Iranian individuals with idiopathic ID. Variants were prioritized based on population allele frequency, predicted functional impact, and genotype–phenotype correlation. Candidate variants were confirmed by Sanger sequencing, and segregation analysis was performed to establish their inheritance patterns. Biochemical and cerebral magnetic resonance spectroscopy findings were also evaluated in individuals with pathogenic GAMT variants. Results Pathogenic biallelic GAMT variants were identified in two unrelated families. Patient 1 harbored the homozygous nonsense variant NM_000156.6:c.134G > A (p.Trp45Ter), whereas Patient 2 carried a novel homozygous four-base-pair deletion, NM_000156.6:c.373_376del (p.Pro125ThrfsTer35), predicted to result in premature protein truncation. Both variants were absent from the population databases examined and were classified as pathogenic according to ACMG/AMP criteria. Sanger sequencing confirmed homozygosity in the affected individuals and heterozygosity in their parents, consistent with autosomal recessive inheritance. Both patients exhibited global developmental delay, intellectual disability, severe speech impairment, behavioral/autistic features, and a history of seizures. Elevated plasma GAA concentrations and reduced cerebral creatine levels further supported the diagnosis of GAMT deficiency. Conclusions This study expands the molecular spectrum of GAMT -related disease by identifying a novel pathogenic frameshift variant and provides additional clinical and biochemical characterization of GAMT deficiency in Iranian individuals with ID. The findings highlight the importance of considering GAMT deficiency among the potentially treatable causes of unexplained intellectual disability, particularly when neurodevelopmental manifestations are accompanied by biochemical evidence of disturbed creatine metabolism. Early molecular and biochemical recognition may facilitate appropriate clinical management and genetic counseling.