Multi-center study uncovers genetic underpinnings of congenital diarrhea and enteropathies

A new multi-center study co-led by scientists from UCLA Health has uncovered critical genetic insights into a group of rare disorders affecting intestinal epithelial cell function, paving the way for targeted therapies that could significantly improve patient outcomes. The study is published in the New England Journal of Medicine(Link is external).

The study was made possible by funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH), which supported funding of the PediCODE Consortium(Link is external) (Link opens in new window). The work was also supported through the California Center for Rare Diseases(Link is external), a program of the UCLA Institute of Precision Health.

Congenital Diarrhea and Enteropathies (CODE) are rare disorders that primarily affect intestinal epithelial cell function, leading to infantile onset diarrhea and poor growth. These disorders have substantial morbidity and mortality, often requiring lifelong fluid and nutritional management.

Previously identified genetic causes of CODE include mutations in several specific genes, such as MYO5B, EPCAM, NEUROG3, DGAT1, and SLC9A3. Understanding these genetic causes has led to some targeted therapies, including special diets and experimental drugs.

For the new work, an international team of researchers analyzed the genetic material of 129 infants with suspected genetic diarrhea disorders. They found genetic causes in nearly half (48%) of these cases, a remarkable improvement from the 4% seen in similar studies of other genetic disorders. 

"This study highlights the transformative potential of next-generation sequencing in uncovering both known and novel genetic causes of congenital diarrhea and enteropathies,” said Dr. Martín G. Martín, co-lead of the study, a pediatric gastroenterologist at UCLA Health and a member of the Eli and Edythe Broad Center of Regenerative Medicine(Link is external). “By identifying these genetic underpinnings, we can develop more targeted and effective treatments, ultimately improving patient outcomes.”

Martín G. Martín, MD

One variant, in the NEUROG3 gene is a newly identified mutation that likely originated in a Bedouin population in Israel. The variant is significant because it helps researchers understand the genetic basis of CODE disorders in this specific group and can lead to more targeted and effective treatments.

They also identified three new genes related to CODE: GRWD1, MYO1A, and MON1A. The researchers used cell and zebrafish models to study these genetic variants and understand their effects.

The study represents a significant advancement in understanding the genetic basis of CODE disorders. The identification of novel genes and variants offers potential pathways for developing targeted therapies, improving outcomes for affected patients.

The study was co-led by Dr. Martín G. Martín at the University of California, Los Angeles, Dr. Aleixo Muise at The Hospital for Sick Children, and Drs. Jay Thiagarajah. Dr. Wayne Lencer at Boston Children’s Hospital, and Dr. James Goldenring at Vanderbilt University Medical Center also played instrumental roles in the study.

Article(Link is external) (Link opens in new window): The Genetic Architecture of Congenital Diarrhea and Enteropathy, NEJM 2025 DOI: 10.1056/NEJMoa2405333

Funding: DK118640 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).