Ornithine transcarbamylase deficiency: identification of mutations, computational validation, and phenotypic correlation in argentinian patients

Abstract

Ornithine transcarbamylase deficiency (OTCD; Online Mendelian Inheritance in Man [OMIM] 311250) is an urea cycle defect with Xlinked inheritance. In hemizygous males, neonatal or late onset depends on the degree of residual enzymatic activity. In heterozygous females, symptom presentation depends on Xchromosome inactivation. Mutation identification in OTC gene allows diagnostic confirmation and carrier detection. Objective: To identify mutations causing OTCD in Argentinian patients, to validate those changes, and to correlate them with phenotype. Methods: A total of 11 patients belonging to 8 families, 6 male patients, 2 with severe presentation and death during the neonatal period and 4 with late-onset (0.5-10 years) and 5 symptomatic women (0.8 to 4 years), 3 of them died and were diagnosed with OTCD. Molecular analysis of OTC gene was performed by polymerase chain reaction/multiplex ligation-dependent probe amplification/ Single-strand conformation polymorphism analysis and/ or sequencing, and missense changes validation was made using computational methods, PolyPhen, SIFT, and PopMusic 2.0. Results: We identified mutations in all patients; 2 were not previously described: 1 of splicing (c.540þ1G>A) and a deletion (delExon 2-10) and 6 were already reported: 1 of splicing (c.216þ1G>A) and 5 missense (p.Arg129His, p.Leu151Arg, p.Thr178Met, p.Ala208Thr, and p.Arg277Trp). Result validation was consistent with the applied computational programs and the patients presentation form. Conclusion: This analysis provides a better understanding of alterations responsible for the phenotypic expression. This work expands carrier detection capability allowing appropriate genetic counseling. Early detection of patients with OTCD is essential to reduce morbidity and mortality in affected individuals.