Sarah Hardman saw “genetics” pop up on her phone and thought she better answer. Probably just another call from another doctor’s office. After 10 years, Hardman was accustomed to fielding calls related to her daughter’s medical care.
But this call would be the one she had been longing for — and never expected to receive. It was Kayla Treat, genetic counselor with the Undiagnosed Rare Disease Clinic at the Indiana University School of Medicine.
“I have some news for you,” Treat said. “We have an answer.”
Odyssey to a diagnosis
Madison’s medical odyssey began in infancy. She had feeding issues, and by 9 months, it was obvious she was falling behind on developmental milestones. By 20 months, Madison was seeing a pediatric neuromuscular specialist for regressing motor skills. By age 3, she was still nonverbal and wasn’t walking on her own.
“They ran tests for numerous things — so many tests, scans and bloodwork — but everything came back normal,” Hardman said. “She probably saw 10 different types of doctors. It was frustrating.”
A genetic disorder was suspected, but whole exome sequencing in 2018 delivered no answers. Madison’s family decided to take a break from all the testing and do what they could to help Madison through physical therapy, occupational therapy and speech language therapy.
It wasn’t until age 9 that Madison returned to her pediatric neurologist at Riley Hospital for Children and was given a glimmer of hope for diagnosis. In 2020 — two years after Madison’s initial genetic testing — the IU School of Medicine launched its Undiagnosed Rare Disease Clinic (URDC) for unsolved cases like Madison’s.
“Our patients have already been on a long diagnostic odyssey,” said Erin Conboy, MD, a clinical and metabolic geneticist who is co-director of the URDC. “They’ve had the best genetic test out there, but still, they have no answers. That’s when they come to our clinic.”
For Hardman, it was a “last-ditch effort.” She remembers thinking, “If anybody’s going to find the answers, it’s going to be them.”
Conboy and the clinic’s other co-director, Francesco Vetrini, PhD, MSc, 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.’”
In Madison’s case, whole genome sequencing turned up variants on the DOCK3 gene inherited from both parents. When Madison’s initial genetic testing was done, DOCK3 had not yet been “discovered,” meaning scientists didn’t know if defects on that gene could result in a specified syndrome.
Madison is now on the cutting-edge of medical science, part of a tiny cohort identified with a DOCK3-related neurodevelopmental disorder. Her case will help medical geneticists understand the disease’s phenotype 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, which include instability when walking, toileting issues and a moderate intellectual disability. But there is peace that comes from knowing the cause of Madison’s developmental delays, Hardman said.
When she got that call from Treat breaking the news of a diagnosis, she was overcome with emotion.
“I just started bawling my eyes out,” Hardman said. “To finally have an answer that explains everything was mind-blowing.”
How genetic detectives solve medical cold cases
The URDC has successfully solved 20% of its “cold cases” involving ultrarare syndromes that sometimes require gene discovery before they can be cracked. Vetrini recently led an international team of researchers who “discovered” the DDX39B gene, which causes a novel neurodevelopmental syndrome when it carries defects.
In Madison’s case, scientific knowledge about the DOCK3 gene had to catch up before a diagnosis could be made. There are more than 20,000 genes in the human genome, but scientists only know what roughly 7,000-8,000 of them do.
“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.
Khurram Liaqat, PhD, a postdoctoral fellow genomic scientist under the supervision of Vetrini and Conboy, worked closely with the clinical team to identify the mutations in DOCK3 which ended Madison’s diagnostic journey.
Getting to that exhilarating moment of a patient diagnosis takes a dedicated, multidisciplinary team. The URDC Genome Board consists 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 — a research study funded by the National Institutes of Health that aims to solve the most challenging medical mysteries — and through GeneMatcher, a platform enabling connections between 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.
“Finally, we have a name for this,” Hardman said of the relief that comes with diagnosis. “Dr. Conboy and everyone at the rare disease clinic have been so caring and answered every question as I try to understand Madison’s gene anomaly. They are learning things as we are learning.”
