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Objectives <p>Glutaric aciduria type I (GA-I) is an inborn error of metabolism caused by biallelic variants in the <i>GCDH</i> 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 <i>GCDH</i> in a 5-year-old Iranian girl.</p> Methods <p>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 <i>GCDH</i> 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.</p> Results <p>Genetic testing identified a novel intronic variant (c.957-1G&gt;C) in the <i>GCDH</i> 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.</p> Conclusions <p>The c.957-1G&gt;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月6日

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  • Nasrin Zamani,
  • Mohammadi Sarband,
  • Mirab Samiee,
  • Amirhassan Rabbani,
  • Bahman Akbari,
  • Nejat Mahdieh,
  • Bahareh Rabbani

摘要

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.