Yale researchers have discovered the underlying genetic cause of a rare childhood disorder that mimics inflammatory bowel disease, a finding that may help researchers uncover the roots of a host of other inflammatory and autoimmune disorders.

For the study, a team of Yale researchers investigated a mysterious case of a young boy who was treated at Yale New Haven Hospital for abdominal pain, intermittent bouts of fever, and diarrhea over multiple days, and canker sores in his mouth. Using genome sequencing of the child and his healthy parents, they revealed that the boy had a genetic defect that blocked ELF4, a transcription factor on the X chromosome that regulates expression of a large number of other genes.

Then, after reaching out to colleagues in the field of rare diseases, the research team identified two other male children with similar symptoms who also had ELF4 gene variants. This disorder is now termed “Deficiency in ELF4, X-linked,” or DEX for short. And an increasing number of cases are being identified. 

“It is very exciting to start with patients who are sick and discover an unexpected new gene with a fundamental role in regulating inflammation.” said Carrie Lucas, an assistant professor of immunobiology at Yale School of Medicine and senior author of the paper published July 29 in the journal Nature Immunology.

The study was headed by Paul Tyler, Molly Bucklin, and Mengting Zhao, all of whom are members of Lucas’s lab.

Inflammatory diseases caused by a single gene mutation affect about 1 out of every 5,000 children.

According to the researchers, the symptoms experienced by the children in the study were similar to those associated with other inflammatory bowel diseases, including ulcerative colitis and Crohn’s Disease, thought to be caused by an overactive immune system response that damages tissues of the host.

After identifying the ELF4 variant, Lucas’s lab then studied its effects in cultured cells from patients, as well as in mice using CRISPR gene-editing to introduce patient-derived ELF4 mutations. They confirmed that the variant disrupted ELF4 function, and resulted in elevated inflammatory responses of a variety of immune cell types.

The widespread effects of the variant suggest ELF4 and its target genes likely play a role in regulating inflammation in multiple diseases, Lucas said.

“This gives us the opportunity to identify and study the effects not only of ELF4 but also the genes it regulates across immune cell types and inflammatory disease phenotypes,” she said. “This will help us create a new molecular roadmap relevant to understanding and treating human disease.”