Canonical splice variant c.298+2T>C in OTC associated with attenuated ornithine transcarbamylase deficiency
Biochemical/Metabolic and Therapeutics
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Introduction
Ornithine transcarbamylase (OTC) deficiency is a severe inborn error of metabolism caused by pathogenic variants in the X-linked OTC gene. OTC encodes ornithine transcarbamylase, which catalyzes an early step in the urea cycle. OTC deficiency is associated with a phenotypic continuum of hyperammonemia, ranging from neonatal-onset to mild and subclinical. Pathogenic variants in OTC that significantly impair enzyme catalytic function or folding, or that result in absent OTC transcript have been reported in association with neonatal-onset OTC. Thus, canonical splice variants are empirically deemed pathogenic due to predicted alternative splicing and degradation of the transcript. Here, however, we present the case of two individuals who carry a canonical splice-site variant in OTC (c.298+2T>C), associated with a mild, post-neonatal phenotype.
Case Presentation
A healthy mother was identified as an OTC deficiency heterozygote on carrier screening. On subsequent amniocentesis, her male fetus was found to be hemizygous for the c.298+2T>C variant. The variant was deemed pathogenic due to presumed deleterious effect on RNA splicing, however it had not previously been reported in an affected individual. Delivery and the neonatal period were managed conservatively with ammonia scavengers and protein restriction.
Diagnostic Workup
However, at 12 months, the infant appears to be mildly affected. Motor milestones have been slightly delayed, and labs are notable for mild elevations in glutamine and orotic acid, and normal citrulline.
Treatment and Management
To date, he has not experienced a metabolic decompensation, and he continues to tolerate increases in daily protein allowance. His mother has been well throughout her life, with the exception of migraines associated with excess protein intake.
Conclusion
This case adds to the growing body of evidence that the +2T>C splice variant is compatible with a variable degree of wildtype splicing.
Ornithine transcarbamylase (OTC) deficiency is a severe inborn error of metabolism caused by pathogenic variants in the X-linked OTC gene. OTC encodes ornithine transcarbamylase, which catalyzes an early step in the urea cycle. OTC deficiency is associated with a phenotypic continuum of hyperammonemia, ranging from neonatal-onset to mild and subclinical. Pathogenic variants in OTC that significantly impair enzyme catalytic function or folding, or that result in absent OTC transcript have been reported in association with neonatal-onset OTC. Thus, canonical splice variants are empirically deemed pathogenic due to predicted alternative splicing and degradation of the transcript. Here, however, we present the case of two individuals who carry a canonical splice-site variant in OTC (c.298+2T>C), associated with a mild, post-neonatal phenotype.
Case Presentation
A healthy mother was identified as an OTC deficiency heterozygote on carrier screening. On subsequent amniocentesis, her male fetus was found to be hemizygous for the c.298+2T>C variant. The variant was deemed pathogenic due to presumed deleterious effect on RNA splicing, however it had not previously been reported in an affected individual. Delivery and the neonatal period were managed conservatively with ammonia scavengers and protein restriction.
Diagnostic Workup
However, at 12 months, the infant appears to be mildly affected. Motor milestones have been slightly delayed, and labs are notable for mild elevations in glutamine and orotic acid, and normal citrulline.
Treatment and Management
To date, he has not experienced a metabolic decompensation, and he continues to tolerate increases in daily protein allowance. His mother has been well throughout her life, with the exception of migraines associated with excess protein intake.
Conclusion
This case adds to the growing body of evidence that the +2T>C splice variant is compatible with a variable degree of wildtype splicing.