Early onset classic isovaleric aciduria caused by two novel <i>IVD</i> variants identified by whole exome sequencing (WES)

Abstract Objectives Isovaleric acidemia (IVA) disrupts leucine metabolism and can lead to life-threatening neonatal metabolic crises. Biallelic IVD gene variants cause IVA. This case report describes two novel IVD variants in an Iranian neonatal case. Methods A 5-day-old Iranian male neonate was referred to the Children Medical Center due to poor feeding, lethargy, and progressive encephalopathy. A comprehensive clinical evaluation was performed. Isovalerylcarnitine (C5) quantification was performed from dried blood spots (DBS) using flow injection analysis tandem mass spectrometry (FIA-MS/MS), and urine organic acid analysis was conducted via gas chromatography‒mass spectrometry (GC‒MS). Metabolic screening was applied followed by whole IVD gene sequencing, parental segregation analysis, and in silico structural pathogenicity assessments. Results The child was presented with metabolic acidosis, hyperammonemia (&gt;700 μmol/L), and elevated C5 (11.5 μmol/L). Two novel variants were detected: c.883A&gt;T (p.M295L) and c.1138+6T&gt;G, alongside four benign SNPs. Parental testing confirmed autosomal recessive inheritance. Structural modeling predicted that p.M295L may alter the enzyme’s α-helical configuration and surface solvent accessibility (C-score: −0.57), potentially impairing catalytic activity. Conclusions This case expands the IVD mutational spectrum and highlights two novel variants, underscoring the critical role of molecular diagnostics in confirming diagnosis and guiding genetic counseling. Although newborn screening (NBS) is generally effective, the early neonatal symptoms in this case occurred before NBS results were available, precluding any direct screening benefit. Prompt recognition and tailored metabolic management remain essential to improve clinical outcomes.