Welcome to the Gene Scene! Each week, we will explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. Here, we focus on the condition that led to the gene’s inclusion on the list, providing clear, relevant information that supports your clinic. To subscribe to the Gene Scene, contact your local GSL or send a request to info@ambrygen.com. 

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Clinical Phenotype Summary: 

The OTC gene is located on chromosome Xp11.4 and encodes ornithine carbamoyltransferase. Pathogenic variants in this gene are known to cause ornithine transcarbamylase (OTC) deficiency, which is inherited in an X-linked fashion. 

OTC deficiency is characterized by plasma hyperammonemia, which if left untreated can lead to seizures, lethargy, respiratory distress, and eventual coma. Diagnostic criteria has been proposed to include <20% of OTC activity in the liver and elevated urinary orotate after allopurinol challenge test (Tuchman, 2008). 

OTC deficiency is further delineated as neonatal onset with patients presenting in the first week of life or late onset which can present within the first few months of life into adulthood. The severity and age of presentation is related to the levels of plasma ammonia, with acute episodes occurring after a high protein meal, fasting, infections, invasive medical procedures, chemotherapy, or other environmental insults that results in increased protein catabolism. 

Other features seen in a minority of patients include developmental delay, learning difficulties, impaired consciousness, vomiting, and drowsiness. Loss of function has been reported as the mechanism of disease for OTC deficiency.

OTC deficiency is an inborn error of metabolism, and is characterized by:

• Lab Findings:
  • Plasma hyperammonemia
  • <20% OTC activity in liver
  • Elevated urinary orotate (following allopurinol challenge)
• Seizures, Lethargy, Respiratory Distress (metabolic crisis)
• Developmental Delay, Learning Difficulties, Impaired Consciousness, Vomiting, Drowsiness

Unique Considerations: 
1. Heterozygous individuals are typically unaffected; however, 20% of carriers have been reported to be symptomatic due to X-chromosome inactivation, typically presenting with late onset disease and a milder course.

2. Pathogenic alterations that severely impair or completely abolish the OTC enzyme activity typically result in neonatal onset disease in hemizygous males, while hemizygous males with alterations that decrease the OTC enzyme activity may present later.

Clinical Resources:

Understanding Your Result – Secondary Findings on Exome/Genome

Citations: 

Batshaw ML, et al. (2014) Mol Genet Metab 113(1-2):127-30.

Caldovic L, et al. (2015) J Genet Genomics 42(5):181-194.

Mendez-Figueroa H, et al. (2010) Am J Perinatol 27(10):775-84.

Ambry Genetics Gene-Disease Validity Scheme

Each week, we explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. 

To learn more about the ACMG Secondary Findings list, click here. 

To read all previous Gene Scene emails, click here.