A novel splice GCDH variant and analysis of splicing variants in glutaric aciduria type I

Abstract Objectives Glutaric aciduria type I (GA-I) is an inborn error of metabolism caused by biallelic variants in the GCDH gene, disrupting lysine and tryptophan catabolism. While exonic variants are well-characterized, the clinical and molecular consequences of intronic splice-site variants remain poorly understood, especially in underrepresented populations. Here, we report a novel homozygous intronic variant in GCDH in a 5-year-old Iranian girl. Methods We investigated a 5-year-old Iranian patient with severe GA-I symptoms (macrocephaly, seizures, developmental delay) using Gas chromatography–mass spectrometry (GC–MS) for biochemical profiling, Targeted GCDH sequencing (Sanger) and segregation analysis and Computational splice prediction tools (MutationTaster, SpliceAI). Twenty-one splice-site variants from 77 GA-I patients were also analyzed in silico. Results Genetic testing identified a novel intronic variant (c.957-1G>C) in the GCDH gene in our patient, who presented with severe neurological symptoms including seizures, macrocephaly, and developmental delay. Biochemical analysis revealed elevated levels of glutaric acid (560 µmol/mol creatinine) and 3-hydroxyglutaric acid (18 µmol/mol creatinine). Parental testing confirmed carrier status for this variant. Seventy-six patients with intronic variants were also investigated from the previous reported patients; splice variants account for 27% (21/77) of cases. The most common clinical manifestations included neurological disorders (40%), macrocephaly (16%), and seizures (15%). Geographically, most affected individuals were of North American (50%) or Asian (32%) descent. Conclusions The c.957-1G>C variant expands the mutational spectrum of GA-I and underscores the importance of intronic analysis in diagnostic workflows. Splice-site variants demonstrate significant phenotypic heterogeneity, necessitating early surveillance for neurological sequelae. Population-specific variant patterns suggest founder effects in high-risk groups.