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Science Saturday: Mayo Clinic researchers use new innovative technology to diagnose teen brothers with ultra-rare genetic disorder
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When Emery Diffendorfer was a baby, he couldn't hold his head up or babble like other infants his age. His rare genetic disorder enlarged his tongue and head, and he had weakened muscle tone, brittle bones, sleep apnea, poor eyesight and persistent infections in his tonsils and adenoids.
By six months old, the tiny Mayo Clinic patient was in the intensive care unit with severe pneumonia.
That's when Cheryl Diffendorfer and Amy Honsey — both Mayo Clinic nurses at the time — opened their hearts and their home to Emery as his foster parents. They knew they had the necessary expertise, as well as the love and patience, to care for him.
"We brought him home with all of his tubes and breathing equipment," Honsey says. "And we cared for him around the clock."
A few years later, they officially adopted Emery, along with his older brother, Aiden, who shared some of the same symptoms, but on a much milder scale.
Meanwhile, doctors remained baffled by the boys' perplexing conditions. They suspected a hereditary abnormality in their DNA — the blueprint of life that guides the development and function of cells, tissues and organs. But even extensive genomic sequencing failed to pinpoint the boys' disease-causing gene mutation.
"Out of the blue they called and said they found a diagnosis. They didn't forget about our kids. They didn't give up."Cheryl Diffendorfer
"They did every test under the sun, and everything came back negative," Diffendorfer recalls. "They couldn't find the answer."
Determined to provide a diagnosis, Emery and Aiden's doctor made a promise at that time. "She told us, 'Somewhere down the road, you will get a phone call that we have identified Emery and Aiden's disorder,'" Honsey says.
That phone call came nearly 12 years later in August 2022.
"Out of the blue they called and said they found a diagnosis," Diffendorfer says. "They didn't forget about our kids. They didn't give up."
From discovery to diagnosis
Emery, now 15 years old, and Aiden, 16, were among the first to receive a diagnosis with the help of Mayo Clinic's new automated system called RENEW, which launched in 2022. RENEW stands for reanalysis of negative whole-exome/genome data.
RENEW tracks newly published discoveries of disease-causing genetic variants from around the world. The scientific findings are automatically uploaded into Mayo's system every three months.
"Then the findings are compared to Mayo Clinic Center for Individualized Medicine’s database of unsolved patient sequencing results to identify potentially important developments," explains Eric Klee, Ph.D., the center’s Everett J. and Jane M. Hauck Midwest Associate Director, Research and Innovation, and the creator of RENEW..
Dr. Klee says Emery and Aiden's disease-causing genetic variant was discovered by researchers in Norway in 2021. The boys are now among 15 people worldwide who have been diagnosed with the ultra-rare genetic disorder.
"We're seeing dramatic growth in the knowledge around what causes genetic diseases, and that is reflected every time we run RENEW and answers are revealed," Dr. Klee says. "The overall percentage of the answers may be small, but the impact of giving a diagnosis to patients is immense."
A key part of the innovative technology is a special set of filters that whittles down the new genetic information available since the last analysis. This helps zero in on what could be causing a patient's disorder.
Dr. Klee says it takes less than a minute per patient for RENEW to analyze and compare the new discoveries with the data, and for his team to review the results for the nearly 2,000 Mayo Clinic patients in the system.
"My hope is that someday down the road, maybe in another few years, we'll be able to call the Diffendorfer family back saying we've identified a therapy." Dr. Eric Klee
Every time RENEW flags a match, as it did with the Diffendorfer boys, a team of genomic researchers launches an in-depth investigation.
"We're leveraging a wealth of new genetic knowledge to aid in our efforts to identify the genetic cause of patients’ diseases," says Rory Olson, Ph.D., a clinical variant scientist at Mayo Clinic's Center for Individualized Medicine.
Dr. Olson says the new knowledge may describe a new disorder or widen the clinical spectrum for an existing disorder.
"We review the patient’s medical records, clinical history and DNA alterations, and correlate this information with new genetic findings," explains Dr. Olson. "Our role is to ask, 'What is this gene’s function and what is the gene-disease mechanism? And is this finding potentially relevant for this patient’s disorder?'"
Providing answers and hope
So far, nearly 20 Mayo Clinic patients with rare and undiagnosed diseases have received a definitive diagnosis with the help of RENEW.
Like most rare diseases, Emery and Aiden's diagnosis has not yet resulted in a targeted therapy.
"But providing patients with an answer to the cause of their disease is the most important first step toward finding a treatment," Dr. Klee emphasizes.
"RENEW embodies the spirit of what Mayo is all about — the needs of the patient come first. This is a lifelong pursuit for us," Dr. Klee says.
"My hope is that someday down the road, maybe in another few years, we'll be able to call the Diffendorfer family back saying we've identified a therapy," he says.
This article was first published on the blog of the Mayo Clinic Center for Individualized Medicine.
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