This study focused on two OTC gene variants—p.(Arg40Cys) and p.(Phe354Cys)—that are often found incidentally during genetic testing. Researchers reviewed medical records, the UCDC database, and published reports to understand what these variants mean for health. They also tested the variants in a lab yeast model to measure enzyme activity. The goal was to help doctors to appropriately counsel people who carry these variants. The study included 28 individuals (14 with each variant), both males and females, from newborns to adults.
Key Takeaways
Late-Onset Risk in Males: Neither variant has been reported to cause neonatal-onset hyperammonemia in males. However, 6 of 8 males with p.(Arg40Cys) and 2 of 9 males with p.(Phe354Cys) had hyperammonemia later in life at ages ranging from 9 to 68 years.
Females Rarely Affected: None of the females with these variants had documented hyperammonemia. Most were identified through carrier screening or family testing.
Functional Testing Shows Reduced Activity: Lab tests using yeast showed both variants reduce OTC enzyme function to a “hypomorphic” level (about 28–36% of normal growth), which matches late-onset disease risk.
Triggers and Outcomes: Common triggers included fasting, illness, and high-protein diets. Some crises were fatal—3 deaths in the p.(Arg40Cys) group and 1 in the p.(Phe354Cys) group—often due to delayed diagnosis.
Counseling Is Essential: People with these variants should know warning signs and avoid triggers like fasting, certain medications (e.g., valproic acid), and high-protein diets. Emergency letters and medical ID bracelets are recommended.
Why This Matters
As genetic testing becomes more common, more people with these OTC variants might be detected. This research helps explain what these findings mean and highlights the importance of education and emergency planning to prevent life-threatening crises.
Lang SH, Lo RS, Cromie GA, Dudley AM, Mew NA, Simpson K, Sutton VR, Darilek S, Ali S, Snyder MT, Lee B, Marom R, Nagamani SCS, Burrage LC. Two commonly reported incidental variants in OTC are associated with late-onset disease. HGG Adv. 2025 Oct 16;7(1):100531. doi: 10.1016/j.xhgg.2025.100531. Epub ahead of print. PMID: 41108081.
