Exome sequencing and molecular dynamics simulation characterizes a compound heterozygous GCDH missense variant leading to glutaric aciduria type 1 in a paediatric patient from Jammu and Kashmir, India

Glutaric Aciduria Type 1 (GA1) is a rare autosomal recessive metabolic disorder caused by mutations in the gene GCDH, leading to deficiency of the enzyme glutarylCoA dehydrogenase. This study reports a case of GA1 in a 3-year-old male from Jammu and Kashmir, India, presenting with a compound heterozygous mutation in the GCDH. Whole exome sequencing (WES) and molecular dynamics simulations were employed to investigate the genetic and structural basis of GA1 in the proband. Clinical evaluation, MRI, and tandem mass spectrometry were conducted to assess the patient's metabolic profile and neurological status. The pathogenic impact of the identified mutations (c.881G > A; p.Arg294Gln and c.481C > T; p.Arg161Trp) was analyzed using computational tools and molecular dynamics simulations. Molecular dynamics simulations indicated significant dynamic changes in the mutant protein structures. The R161W mutation increased flexibility, while the R294Q mutation caused notable conformational instability at the catalytic site, reducing its normal protein function and stability. The RMSD, RMSF, and SASA analyses supported these findings, correlating well with experimental observations. The molecular dynamics simulations provided valuable insights into the structural implications of the R161W and R294Q mutations and might contribute to a deeper understanding of GA1 molecular mechanisms. •Two rare compound heterozygous mutations p.Arg294Gln and p.Arg161Trp lead to Glutaric Aciduria Type 1 in a patient J&K, India.•Molecular dynamics reveal structural changes in wild type and mutant GCDH, explaining their role in GA1.•Highlights genotype-clinical features and call for neonatal genetic screening in India for inborn metabolic errors.