OTC Gene Variants Explained: From Testing to Care 

PNRI study helps clarify how OTC gene variants affect health and risk

Advances in genetic testing have made it easier than ever to find answers, but sometimes, those answers arrive without a clear next step. Around the world, people are learning they carry genetic variants linked to potentially life-threatening rare diseases—yet sometimes show no symptoms at all. Because these conditions affect so few people and vary so widely, it’s often unclear how a specific variant will influence disease severity or when symptoms might appear. As a result, families and clinicians are often left asking the same questions: Will symptoms ever develop? How serious could they be? What can we do to prepare?

These variants are often discovered incidentally — through family testing after a relative’s diagnosis, secondary findings from genome-wide sequencing, or carrier screening before or during pregnancy — leaving families with unexpected results and a pressing need for clear, data-driven guidance.

That’s the challenge researchers, including  PNRI’s Dudley Lab, set out to address. Their latest study, published in Human Genetics and Genomics Advances (Cell Press), takes a closer look at two specific variants in the OTC gene and what those variants mean for individuals who carry them.

What happens when the OTC gene malfunctions

Variants in the OTC gene cause ornithine transcarbamylase deficiency (OTCD), a rare, X-chromosome-linked disorder that affects the body’s ability to clear ammonia – a natural but toxic byproduct produced when protein is broken down. The OTC gene normally provides instructions for making an enzyme that helps remove ammonia from the bloodstream. When this enzyme doesn’t work properly, ammonia can accumulate to dangerous levels, damaging the brain and leading to confusion, seizures, or even coma and death if untreated.

Decoding the variants: from enzyme function to clinical insight

The study focused on two of the most frequently reported OTC variants—p.(Arg40Cys) and p.(Phe354Cys) — which are increasingly being identified in genetic testing but have lacked clear clinical guidance.

The study was led by clinicians at Baylor College of Medicine, Texas Children’s Hospital, Children’s National Hospital, and the University of Virginia. These clinical teams had seen that patients with the same OTC variants could present very differently — from mild symptoms to life-threatening metabolic crises.

By reviewing clinical data from 28 individuals and testing how each variant affects OTC enzyme activity, researchers confirmed that both are hypomorphic, meaning the enzyme still functions, but less efficiently. This partial activity explains why individuals with these variants typically develop late-onset rather than neonatal OTCD. In other words, their enzyme function is sufficient under normal conditions but may fail during periods of metabolic stress, such as illness, fasting, or when taking certain medications.

The Dudley Lab contributed a crucial piece of the puzzle: functional yeast-based assays that isolated the genetic impact of each variant under controlled conditions.

“Yeast gives us a uniquely clear window into how a genetic change affects enzyme function,” explained Dr. Aimée Dudley, PNRI’s Chief Scientific Officer and Senior Investigator. “Unlike humans, yeast cells can be engineered to be genetically identical except for one difference. That lets us see exactly what the variant does without interference from environmental factors.”

Together, these lab and clinical findings confirmed that both variants cause disease but tend to produce milder, later-onset forms in males and variable effects in females. The study underscores the importance of early identification and anticipatory care for people who carry these variants — even if they appear asymptomatic — so that potentially dangerous ammonia buildup can be prevented or managed promptly.

Why early awareness matters

Understanding the potential consequences of OTC variants gives families and clinicians a clearer roadmap for managing risk before symptoms appear. In people with OTCD, illness, fasting, surgery, pregnancy, or sudden increases in protein intake can overwhelm the body’s ability to clear ammonia. If recognized quickly, this buildup can be treated with medications or emergency interventions that remove ammonia from the bloodstream — but timing is critical.

Knowing about an OTC variant in advance can allow families and doctors to recognize warning signs early and take preventive steps, such as maintaining balanced protein intake, being cautious during illness or recovery, and seeking care immediately if symptoms appear. For clinicians, these findings provide an evidence-based framework for counseling and tailoring care to each person’s true level of risk — transforming genetic uncertainty into informed prevention.

From research to real-world impact

The OTC study is one example of how PNRI researchers collaborating with clinicians to  bridge that gap — turning data into guidance that changes how rare diseases are understood, diagnosed, and managed. It’s part of PNRI’s ongoing work to ensure that genetic discoveries lead not only to knowledge, but to better outcomes for patients and families living with rare diseases.