Whole-exome sequencing reveals the molecular diagnoses of pediatric patients presenting with hyperammonemia

Hyperammonemia (HA) is a life-threatening metabolic emergency with diverse genetic etiologies. While classical causes include the urea-cycle and organic acid disorders, the complete mutational spectrum remains incompletely defined. This study aimed to identify the underlying molecular diagnoses in pediatric patients presenting with hyperammonemia as a prominent metabolic manifestation, using whole-exome sequencing (WES). Five pediatric patients with hyperammonemia were retrospectively analyzed using WES followed by Sanger sequencing. Variants were classified according to the ACMG guidelines, and clinical data were reviewed to establish genotype–phenotype correlations. WES identified variants in five genes: FBXL4, GLDC , FUCA1 , BSND , and COL6A2 . Three novel variants, FBXL4 c.1702G>A; p. (Gly568Arg), BSND c.85G>T; p. (Asp29Tyr), and COL6A2 c.1999C>T; p. (His667Tyr), were identified. The affected genes were related to mitochondrial function, glycine cleavage, lysosomal degradation, renal tubular transport, and extracellular matrix organization. All variants were biallelic or homozygous and were confirmed by segregation analysis. This study highlights the diagnostic power of WES in identifying unexpected molecular causes of pediatric hyperammonemia and expanding the spectrum of implicated genes. The identification of these three novel variants emphasizes the genetic heterogeneity of HA and supports early genomic testing in patients with unexplained or atypical biochemical profiles.