February 28, 2023

Mayo Clinic investigators put genomics into action to diagnose patients’ mysterious illnesses

By Susan Murphy

February 28 is designated Rare Disease Day to raise awareness that, collectively, rare diseases are relatively common. A rare disease is defined as a disease or condition that affects less than 200,000 people. As many as 30 million people in the U.S. have a rare disease, and many people search an average of eight to 10 years for answers while being propelled through a marathon of health care visits and tests. Rare diseases are chronic, debilitating and even deadly. Over 80% of rare diseases are caused by genetic variations that can strike at any age.  

"Rare is not rare to us," says Konstantinos Lazaridis, M.D., the Carlson and Nelson Endowed Executive Director for Mayo Clinic's Center for Individualized Medicine. "Mayo Clinic, across its three campuses, has several hundred researchers who relentlessly pursue discoveries relevant to rare diseases that will deliver hope and healing to patients today and for generations to come."   

Mayo Clinic's A-team of genomics experts

When patients' illnesses are rare or present as a mystery and their symptoms have defied a diagnosis, they are often referred to Mayo Clinic for an evaluation. The Program for Rare and Undiagnosed Diseases, which launched in 2019 in the Center for Individualized Medicine, provides a team of genomics-oriented physicians and researchers to pursue every possible novel methodology to solve these complex cases in collaborations with clinicians from different divisions or departments.   

Using sophisticated genomic and other omics tests, along with worldwide research, this A-team of genomics experts within the program investigated nearly 650 patients with rare disease in 2022 and provided a genetic cause for an undiagnosed disease patient in nearly 30% of cases.  

"For patients who have an illness but do not have a diagnosis, we never give up," says Filippo Pinto e Vairo, M.D., Ph.D., the program's medical director.  

Dr. Pinto e Vairo is involved in investigating nearly every patient's rare disease case that comes through the program. It starts usually when a Mayo Clinic provider suspects a patient's confounding symptoms could be caused by a genetic variant.  

"First, we develop a test called a multigene panel that analyzes a set of genes at once to look for variations," Dr. Pinto e Vairo explains. "So, for example, if the patient's illness is related to kidney failure, instead of looking at the 20,000 genes, we can start with a focused analysis and look at 300 to 400 genes that are broad in scope but highly expressed in the kidney."  

When the clinical genetic report is complete, revealing any genetic variants, Dr. Pinto e Vairo and his team scour the data.   

After a thorough investigation, which sometimes includes comparing genetic data to other patient cases with similar symptoms and variants, Dr. Pinto e Vairo and his team of genetic experts meet with the patient's providers.  

"We discuss these data, we review the results and then we propose next steps," he says. "Sometimes that means more clinical tests, more comprehensive genetic testing or even research options."  

Throughout the process, genetic counselors provide the patient with ongoing education and information about their genetic data.  

For patients who receive a diagnosis, the results can be life-changing, or even lifesaving, including for their family members who may also carry the genetic variant. A diagnosis is key to determining a potential treatment — usually an existing drug that is used to treat another condition. 

For patients who do not initially come away with a treatment or diagnosis, work at the Center for Individualized Medicine continues.  

Accelerating rare disease diagnoses with new worldwide tracking system

The Center for Individualized Medicine has created a new automated system that tracks scientific knowledge from around the world of pathogenic genetic variants and applies it to Mayo Clinic patients with rare and undiagnosed diseases.  

The launch of RENEW comes at a pivotal time when advancements in genomic sequencing technologies and bioinformatics tools are leading to a greater understanding of the links between genes and disease. RENEW stands for REanalysis of NEgative Whole-exome/genome data.    

Last year alone, researchers within Mayo Clinic and across the globe documented nearly twice as many newly discovered gene-disease variants, compared to five years ago.   

"We're seeing dramatic growth in knowledge around what causes genetic disease, so we wanted to create a system to consistently track these discoveries,” says Eric Klee, Ph.D., director of the Omics Data Platform within the Center for Individualized Medicine. 

Dr. Klee says, with RENEW, the latest worldwide gene-disease findings are automatically downloaded every three months from a hub of published discoveries. New findings are then compared to Mayo Clinic's database of patient sequencing results to identify potentially important developments.    

"We're able to identify any differences within minutes and then apply those differences to patient data to see if any patients have these new emerging findings," Dr. Klee says. "As scientific understanding continues to expand, my hope is that by reanalyzing data periodically, we can potentially help more people find answers." 

Pursuing every path to help patients with rare diseases

Mayo Clinic has developed a rare disease biobank to serve as a deep research resource for scientists to study and compare variants and patient data. The hope is, as cohorts of patients with similar phenotypes are obtained, researchers can solve those rare disease cases by identifying the genetic mutations causing the disease and provide answers to patients whose cases have not yet been resolved.  

Mayo Clinic also recently joined the Rare Disease Centers of Excellence Network that consists of 31 medical centers across the U.S. This network seeks to promote knowledge-sharing; connect patients to appropriate specialists; and improve the pace of progress in rare disease diagnosis, treatment and research. 

Rare disease patient stories

Months after young Maggie Carmichael started taking an experimental drug for her ultra-rare genetic disease, she was able to trade in her wheelchair for a walker. The 9-year-old Mayo Clinic patient even took a few of her first-ever steps on her own. She also became better at feeding herself, her speech improved and she started coloring in the lines. Read more.

Araeya Sell spent much of her childhood enduring countless blood draws, scans, procedures and a surgery ― all in the search for answers to her complex symptoms. After an exhaustive, nearly seven-year diagnostic odyssey, the Sells turned to Mayo Clinic, where Araeya received a diagnosis and a life-changing therapy. Read more.

Patti Schultz's life was defined by mysterious and debilitating health conditions that caused her to feel isolated and discouraged. After 50 years of searching for answers, Patti finally had a definitive diagnosis: a disease-driving gene variation that affects just 200 people worldwide. Read more.

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Tags: Biomedical research, center for individualized medicine, Dr. Eric Klee, Dr. Konstantinos Lazaridis, Dr. Pinto e Vairo, genetic testing, genomic medicine, medical research, Rare diseases, Research, undiagnosed diseases

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