The IU Impact: We bring hope to families by providing answers for their ultra-rare medical mysteries and use cutting-edge medical science to help doctors around the world address these complex health challenges.
Sarah Hardman, left, finally got answers for her daughter Madison's rare disease from Dr. Erin Conboy, right, and the IU Undiagnosed Rare Disease Clinic. The clinic solves "cold cases" involving ultra-rare syndromes that often require gene discovery before they can be cracked. Photo by Wendi Chitwood, Indiana University
Ten-year-old Madison Hardman's medical odyssey began in infancy. She had feeding issues and started falling behind on developmental milestones. By age 3, she was still nonverbal and wasn't walking on her own. While doctors suspected a genetic disorder was the cause, years of bloodwork, scans and DNA testing left Madison's family with no answers.
In 2020 - two years after Madison's initial genetic testing - the Indiana University School of Medicine launched its Undiagnosed Rare Disease Clinic to help families like Madison's search for answers to mysteries that modern medicine hasn't yet solved. Patients from throughout Indiana and surrounding states are turning to the IU clinic for answers they can't get anywhere else. Luckily for Madison, an Indianapolis resident, this invaluable resource was right in her backyard.
The clinic consistently solves "cold cases" involving ultra-rare syndromes that often require gene discovery before they can be cracked. IU is one of just 24 sites in the nation comprising the federally funded Undiagnosed Diseases Network. The IU School of Medicine, in partnership with the IU Health system, is the only site in Indiana designated as a National Organization for Rare Disorders Center of Excellence.
"Our patients have already been on a long diagnostic odyssey," said Dr. Erin Conboy, a clinical and metabolic geneticist who co-directs IU's rare disease clinic. "They've had the best genetic test out there, but still they have no answers. That's when they come to our clinic."
Finally hearing: 'We have an answer'
For Madison's mother, Sarah Hardman, visiting IU's Undiagnosed Rare Disease Clinic was a "last-ditch effort." She remembers thinking, "If anybody's going to find the answers, it's going to be them."
After Madison's initial genetic testing failed to provide a diagnosis, her parents decided to take a break from all the tests and do what they could to help Madison through physical therapy, occupational therapy and speech language therapy.
Dr. Erin Conboy, left, co-direct's IU's rare disease clinic, which discovered that variants on Madison Hardman's DOCK3 gene, inherited from both parents, explained her neurodevelopmental disorder. Photo by Wedndi Chitwood, Indiana University
"They ran so many tests, scans and bloodwork, but everything came back normal," Hardman said. "She probably saw 10 different types of doctors. It was frustrating."
It wasn't until age 9 that Madison returned to her pediatric neurologist at Riley Hospital for Children at IU Health and was given a glimmer of hope for diagnosis: the newly opened Undiagnosed Rare Disease Clinic. Clinic co-directors Conboy and Francesco Vetrini are the cold-case investigators of genetic disease.
"We are examining direct evidence, indirect evidence, supporting evidence - and then maybe there's the smoking gun," Vetrini said. "It's very exciting when you can solve it. I feel this 'eureka' sensation when we can turn to a family and say, 'We have the smoking gun; this is the causative gene mutation in your family.'"
Although diagnosis might not immediately change a patient's treatment path, it does provide a sense of relief. It can also pave the way for insurance coverage or federal assistance programs, and it can ultimately lead to new therapies.
In Madison's case, whole genome sequencing - the most comprehensive DNA testing available - turned up variants on the DOCK3 gene inherited from both parents. But when Madison's initial genetic testing was done, scientists didn't know if defects on DOCK3 could result in a specific syndrome.
Madison is now on the cutting edge of medical science, part of a tiny cohort identified with a DOCK3-related neurodevelopmental disorder that causes intellectual disability, weak muscle tone and lack of coordination. Her case will help medical geneticists worldwide to understand the disease's traits and progression over time.
"I always knew she was destined for greatness," Hardman said. "She's part of something bigger than herself."
That fits perfectly with the now 10-year-old Madison's personality. Her mom calls her "the most caring, empathetic child I've ever known." She loves music of all types, from Prince to Taylor Swift, and enjoys helping others.
Having a diagnosis doesn't change Madison's daily struggles, but there is peace that comes from knowing the cause of Madison's developmental delays, Hardman said.
She will never forget the day genetic counselor Kayla Treat called from the IU rare disease clinic to say, "We have an answer."
"I just started bawling my eyes out," Hardman said. "To finally have an answer that explains everything was mind-blowing."
IU's genetic detectives: 'We keep looking for clues'
There are more than 20,000 genes in the human genome, but scientists only know what roughly 7,500 of them do. In Madison's case, scientific knowledge about the DOCK3 gene had to catch up before a diagnosis could be made.
Clinic co-directors Francesco Vetrini and Erin Conboy, from right, gave Sarah Hardman and her daughter, Madison, peace of mind when the IU Undiagnosed Rare Disease Clinic provided the answer they had sought for years. Photo by Wendi Chitwood, Indiana University
"This case underscores how our commitment to long-term patient follow-up, coupled with the periodic re-evaluation of clinical and genomic data, was crucial in diagnosing this and other challenging cases," Vetrini said.
Getting to that exhilarating moment of a diagnosis takes a dedicated, multidisciplinary team. IU's Undiagnosed Rare Disease Clinic presents tough cases to its Genome Board, consisting of IU biomedical geneticists, genetic counselors, disease and genomics experts, lab directors, analysts, rare disease postdocs, and other interested researchers and learners.
IU researchers also connect with colleagues nationally and globally through the Undiagnosed Diseases Network and through GeneMatcher, a platform connecting researchers, clinicians and patients who share an interest in the same gene.
"As the knowledge about variants and genes evolves and improves over time, we keep reanalyzing the data of patients and looking for new clues that lead, eventually, to definitive answers," Vetrini said.
That persistence means the world to families like Madison's.
"Everyone at the rare disease clinic has been so caring and answered every question as I try to understand Madison's gene anomaly," Hardman said. "They are learning things as we are learning."
