When Vicki Tennant came to Mayo Clinic for answers about her heart condition, she never expected to be at the center of a medical breakthrough. But her case led Mayo Clinic researchers to identify a previously undetectable genetic phenomenon.

Most genetic diseases are linked to protein-coding regions, which is also where standard testing has been focused. The discovery based on Tennant's case, published in Circulation: Heart Failure, was that disease-causing variants can hide in areas of DNA that don't make proteins.

Specifically, a tiny glitch in one of these regions, combined with a known mutation, was enough to cause Tennant's disease. 

"The level of care and expertise at Mayo Clinic is something I've never experienced," Tennant says. "It’s amazing to think that what they found in me could change how doctors diagnose others."

A clue hidden in the heart

In her home state of Iowa, Tennant had been diagnosed with hypertrophic cardiomyopathy, a genetic condition that thickens the heart muscle and increases the risk of heart failure. But her case didn't follow the usual pattern.

She had an irregular heartbeat that required several procedures to restore a normal rhythm, and she had also had a stroke. Her cardiologist in Iowa referred her to Mayo Clinic for further evaluation.

At Mayo Clinic, what began as a closer look at Tennant's heart tissue by cardiologist Jeffrey Geske, M.D., quickly turned into full-scale scientific pursuit. Dr. Geske identified microscopic abnormalities in her heart muscle during a biopsy that indicated the need for further investigation.

Around the same time, Tennant underwent a routine gallbladder surgery in Iowa. A liver biopsy performed during that procedure also revealed abnormalities, prompting Tennant to ask her Mayo team to review the findings. That request helped deepen the investigation into the underlying cause of her health issues.

When standard clinical genetic testing did not yield an answer, Dr. Geske asked Naveen Pereira, M.D., a cardiovascular genomicist, to take a closer look at Tennant's DNA. Dr. Pereira searched Tennant's genome for hidden patterns and anomalies.

"This discovery highlights the strength of integrating advanced genomic science with clinical expertise to solve some of medicine's most complex mysteries."

Naveen Pereira, M.D.

He found that Tennant had one known disease-causing mutation in a gene responsible for producing an enzyme that prevents substances from accumulating in the cell. Normally, two mutations are needed to cause a genetic condition called mucopolysaccharidosis type IIIA. But something still didn't add up — besides having only one variant, Tennant lacked some of the typical symptoms of the disease.

Dr. Pereira conducted additional lab tests to check for signs of the condition in her cells, however, which led to confirming it as her diagnosis.

Mucopolysaccharidosis type IIIA usually appears in early childhood and causes progressive neurological decline. But Tennant, in her 40s, had no signs of neurological issues. In her, the condition showed up as heart disease — an unexpected and atypical presentation that added to the mystery.

A genetic mystery unfolds

With unanswered questions remaining, Dr. Pereira expanded the team, bringing in experts from Mayo Clinic's Center for Individualized Medicine: Filippo Pinto e Vairo, M.D., Ph.D., medical director of Mayo Clinic’s Program for Rare and Undiagnosed Diseases; Eric Klee, Ph.D., the Everett J. and Jane M. Hauck Midwest Associate Director of Research and Innovation; and Laura Lambert, Ph.D., director of the Functional Omics Resource Laboratory.

The team applied advanced sequencing and analysis methods to search beyond the usual areas of the genome. That's when they made another discovery.

"We found a variant in a stretch of DNA located between two genes — it's a region often missed by standard genetic testing because it doesn't code for proteins," says Dr. Pinto e Vairo. "Now we had to prove it was actually disrupting how the gene worked and contributing to the disease in our patient."

To validate the finding, Dr. Lambert and the Functional Omics Resource Laboratory team used innovative, light-based methods to test whether the DNA change was interfering with how the gene worked.

"This gave us the functional proof we needed to confirm that this variant was actually causing disease," Dr. Lambert says.

Combined with the known mutation previously identified by Dr. Pereira, this hidden change provided the missing explanation for Tennant's condition.

"This finding is a testament to the transformative potential of looking beyond the expected," Dr. Klee says. "It underscores how advancements in genomics and technology are enhancing our ability to understand the impact of an increasing number of genetic changes."

Together, these insights revealed an entirely new way genetic disease can emerge and take shape.

"This discovery highlights the strength of integrating advanced genomic science with clinical expertise to solve some of medicine's most complex mysteries," says Dr. Pereira. "This finding could help change our approach and diagnose other patients with unexplained conditions, and expand the scope of precision medicine."

A long-awaited answer

For Tennant, the discovery has provided long-sought clarity. She enjoys working on her farm, spending time outdoors and operating her tractor — all activities she now approaches with a deeper understanding of her health.

While there is no cure for Mucopolysaccharidosis type IIIA with cardiac involvement, her diagnosis allows for more precise monitoring and offers hope for potential future treatments, including gene therapy.

"I also hope this helps someone else," Tennant says. "If sharing my story means someone gets diagnosed sooner, then it's all worth it."

For a complete list of authors, disclosures and funding, review the study.

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