Clinical and genetic analysis of Liver-Predominant ornithine transcarbamylase deficiency caused by a novel de novo OTC sequence variant in a female child.

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. Although the classical presentation is dominated by hyperammonemia-related neurological manifestations, some patients may present with atypical liver-predominant phenotypes, which can delay early diagnosis. Here, we identified a 3-year-6-month-old female patient who presented primarily with liver dysfunction, characterized by elevated transaminases, mild coagulation abnormalities, and increased hepatic parenchymal echogenicity, without overt jaundice or typical neurological symptoms. Metabolic mass spectrometry screening revealed elevated urinary uracil, whereas amino acid and acylcarnitine profiles were unremarkable. Trio whole-exome sequencing followed by Sanger validation identified a novel de novo heterozygous missense sequence variant in exon 6 of OTC, c.541G > A (p.Glu181Lys), which was absent in both parents. According to OTC/UCD-specific curation recommendations, this sequence variant was classified as pathogenic. Structural modeling and mature-trimer molecular dynamics simulations suggested that the p.Glu181Lys substitution may modestly alter OTC conformational dynamics, including local flexibility around residues 120-150 and the variant site. Together with the liver-predominant clinical presentation and supportive metabolic screening findings, these results indicate that OTC c.541G > A (p.Glu181Lys) is the most likely genetic basis of disease in this patient. This study expands the variant spectrum of OTC and highlights the importance of considering OTCD in children with otherwise unexplained liver dysfunction, even in the absence of classical hyperammonemic encephalopathy.