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DNA Today podcast features NUCDF voices plus new research

Promotional image for podcast featuring photos of three experts in urea cycle disorders.

How are new genetic screening tools offering hope to babies born with life-threatening metabolic disorders? Check out this podcast from DNA Today to learn about new research into faster and more accurate diagnosis of urea cycle disorders (UCD), variants of uncertain significance, life with a UCD, and more.

In the podcast, host Kira Dineen talks with Aimée Dudley, Ph.D., a senior investigator at the Pacific Northwest Research Institute,  Andrea Gropman, M.D., the Division Chief of Neurodevelopmental Pediatrics and Neurogenetics at Children’s National Medical Center, and Tresa Warner, the executive director of NUCDF. Warner is also the parent of a child with ornithine transcarbamylase deficiency (OTC), the most common of the urea cycle disorders.

Dr. Gropman set the stage for the discussion, offering an overview of urea cycle disorders and highlighting the importance of early diagnosis and intervention. She also provided an overview of a range of treatments available to UCD patients. She serves as the principal investigator of the Urea Cycle Disorders Consortium (UCDC), which has been leading UCD research for more than 20 years, and as a brain researcher, using advanced imaging to determine the effects of UCD on cognitive function.

One family’s diagnostic, treatment odyssey

Tresa Warner shares the story of her daughter’s experiences with late-onset OTC starting with a diagnostic journey that began 25 years ago.

“Lexi was developing normally until about nine months of age, when we started to introduce whole foods,” Warner says. Her daughter then developed symptoms including lethargy, irritability, failure to thrive, uncontrollable crying, and sleeping for long periods of time.

“It took us about five months to get her diagnosed, after going to hospital after hospital. She was misdiagnosed with an array of things,” she says. A sharp resident who took the time to look at the whole picture finally helped diagnose her with OTC deficiency.

Even with the right diagnosis in hand, getting the right care for Lexi was still challenging. “They told us that we don’t have low-protein formula and we don’t have a way to get the medication. It was a scary time 25 years ago. Thankfully, it’s not as scary as it used to be,” says Warner.

"It was a scary time 25 years ago. Thankfully, it’s not as scary as it used to be"

—Tresa Warner, NUCDF executive director and OTC mom

For many years, the Warner family focused on medical management of Lexi’s condition. New medications were developed over that time, but each came with its own challenges. “It was a real struggle," she says. "There were many crises. Hospital stays and ICU visits were all just part of life.”

Lexi chose to have a liver transplant in 2019, in part to be able to attend college independently. She graduated from college this year.

“The transplant option worked out for us,” says Warner. “It’s not for every family. Every family must consider what’s best for them. We did medical management for 19 years. And coming soon, UCD patients may have a new genetic treatment option.”

UCD treatment is not one size fits all, Warner says. “At NUCDF, our focus is on helping families navigate their version, so they can personalize their healthcare to their family’s needs.”

Improving diagnosis with the awesome power of yeast genetics

A fortuitous introduction of Dr. Aimée Dudley to Dr. Gropman led to a collaboration between the Dudley lab and investigators in the UCDC. Together, they are aiming to shorten the diagnostic odyssey for many OTC patients. Their work may also help individualize patient care.

“One real game changer that did not exist 25 years ago was the ability to do rapid and cheap whole exome and genome sequencing,” says Dudley.

For many UCD patients, such sequencing can provide a definitive diagnosis. For others though, sequencing may identify “variants of unknown significance”—genetic changes that are not yet well understood, where it’s not clear whether a particular variant found on testing is connected to a health condition. Better understanding these variants would help many patients find a definitive diagnosis more quickly.

In the new study, the Dudley lab and their UCDC colleagues used what is literally known as the “awesome power of yeast genetics” to learn more about these variants of unknown significance.

“One of the reasons we use yeast so frequently is that it’s a simple, but powerful model system,” says Dudley. “Many of the biological processes that happen in human cells also happen in yeast cells. However, we can rapidly, quickly and cheaply manipulate yeast cells to study thousands of variants and test how they function.”

"We can rapidly, quickly and cheaply manipulate yeast cells to study 
thousands of variants and test how they function."

—Aimée Dudley, Ph.D.

With this rapid system, they assessed the impact of 1,570 human OTC variants.  Dr. Dudley’s team worked with Dr. Gropman and other clinicians, scientists, and rare disease experts from the UCDC to verify and correlate their work with the experiences of patients.

Study authors report that a large proportion of the variants tested (27%) showed little to no OTC function and that these variants were associated with the most severe form of the disease.

The results were also consistent with the hypothesis that late onset disease may not appear in people with moderately functioning variants until they experience an environmental trigger. Triggering events are known to include dietary changes, surgeries, infections, pregnancy, or exposure to specific prescription drugs.

Thus, a better understanding of which variants are impaired enough to potentially cause disease could help these individuals avoid environmental triggers and allow physicians to more rapidly diagnose metabolic crises should they occur.

Information gained through Dudley’s work may also help clinicians individualize treatment for UCD patients.

“In the past, treatment was more of a one size fits all. 
Now we know more about these patients."

—Andrea Gropman, M.D.

“In the past, treatment was more of a one size fits all,” says Gropman. “Now we know more about these patients. We’ve studied them, through our work with UCDC and our work with Aimée to really understand how particular variants influence the enzyme capability and potentially the prognosis. Each patient is an individual, and the diagnosis will confer some individual differences in the therapeutic pathway.”


DNA Today is a weekly genetics podcast that educates the public on genetic and public health topics.


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A summary of the scientific paper described here is available at this link: The functional impact of 1,570 individual amino acid substitutions in human OTC. To request the full paper, email

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