Erin Conboy, MD, and Francesco Vetrini, PhD, co-directors of the URDC. Photo by Indiana University School of Medicine.

News Release

INDIANAPOLIS — An international team of researchers led by the Indiana University School of Medicine has recently linked a previously uncharacterized gene to a human disorder for the first time. This breakthrough led to the diagnosis of an ultrarare neurodevelopmental disorder for a patient of the Undiagnosed Rare Disease Clinic, located at Riley Hospital for Children.

“Novel gene discovery in human clinical genetics refers to identification and characterization of a gene that was already there in the genome but was previously not associated with a disorder or disease,” explained Francesco Vetrini, PhD, MSc, the clinic’s co-director and an assistant professor of clinical medical and molecular genetics at the IU School of Medicine. “This process is complex and can take years and it involves cutting-edge genomic technologies.”

The team recently published their findings in BRAIN.

“It’s exciting because this is an ultrarare disease — so rare that there is not even a name to call it yet,” Vetrini said. “There were just six known patients that we found through GeneMatcher who were involved in the study. Additional cases are now being found.”

The search began with a patient who was referred to IU’s rare disease clinic in 2021. The cause of the patient’s short stature, small head, low muscle tone and developmental delays was suspected to be genetic. However, genomic testing did not reveal any gene mutations known to cause disease.

The URDC specializes in solving these complex “cold cases” of undiagnosed diseases, Vetrini said. The search began with GeneMatcher, a platform designed to enable connections between researchers, clinicians and patients who share an interest in the same gene.

“This is a game changer in our field,” Vetrini said. “It’s a data sharing and collaborative approach that connects anyone interested in a specific gene around the world.”

Using the tool, Vetrini was able to identify five additional patients in the United Kingdom and one in Hong Kong with mutations in the DDX39B gene — a protein-coding gene involved in messenger RNA processing and other cellular functions. All six patients had similar clinical presentations and ranged in age from 1 to 36 years old.

“These patients have short stature and some facial differences; two have had seizures, one has autism and another has mild intellectual disability,” Vetrini said of the small cohort. “This is a neurodevelopmental disorder with variable presentation. In the future, the more patients we discover with a mutation in this gene, the better picture we will have of what this syndrome is and how it progresses.”

Identifying a novel disease-associated gene and understanding its function is not only the first step toward developing targeted therapeutic strategies for affected patients but also has a profound “snowball effect.”

Once a gene is discovered, it enables the diagnosis of additional patients who may have remained undiagnosed for years. As more cases are identified, the clinical spectrum of the disease becomes clearer, leading to improved management strategies and potential treatment options. Over time, this knowledge drives further research, ultimately benefiting a growing number of patients worldwide while expanding scientific understanding of the human genome.

There are more than 20,000 genes in the human genome, but scientists only know what roughly 7,000-8,000 of them do and how they relate to human health and disease.

“Every time we link a new gene to a phenotype, it’s a window into new mechanisms that were not known before,” Vetrini said. “It’s another piece of the puzzle about how the genes interact. From our publication, there will be other research and publications to reinforce the gene-disease association. This is just a start.”

Kevin Booth, PhD, a fellow with the American Board of Medical Genetics and Genomics who is now on faculty at IU, was one of the publication’s lead authors. He played a critical role in data analysis, predictive models of the mutated proteins and manuscript preparation. Booth also introduced the term “TREX-opathy” to describe a group of related disorders affecting proteins within the same complex as DDX39B, providing a unifying framework for understanding their shared molecular mechanisms.

“The discovery of DDX39B exemplifies the transformative power of global collaboration,” Booth said. “Linking novel genes to disease not only advances diagnostics and provides long-sought answers for families but also offers a critical window into fundamental biology — shedding light on cellular mechanisms and pathways that govern human health.”

Other IU researchers involved with the study were Kayla Treat, Kerry White, Celanie Christensen, MD, Erin Conboy, MD and Lili Mantcheva. The IU team worked with colleagues at Baylor College of Medicine and globally in Hong Kong, Italy, Ireland, England and Scotland.

IU researchers with the URDC have collaborated on three other gene discoveries since the clinic’s founding at the IU School of Medicine in 2020 through a grant from IU’s Precision Health Initiative, but this was the first one led by IU.

The URDC gained acceptance in September 2024 to the Undiagnosed Diseases Network, a national research network funded by the National Institutes of Health to bring together clinical and research experts from across the United States to solve the most challenging medical mysteries. The URDC, in partnership with Indiana University Health, is also a designated NORD Rare Disease Center of Excellence.