A research consortium co-led by Vanderbilt University Medical Center and supported in part by the National Institutes of Health has identified three previously unknown genes that cause severe congenital diarrheal disorders in infants.
The findings, published April 4 in The New England Journal of Medicine, represent a significant advance toward development of more effective, targeted therapies for congenital diarrhea and enteropathies (CODEs). These disorders, though rare, are often life-threatening.
“This manuscript details one of the largest cohorts of CODE patients,” said James Goldenring, MD, PhD, the Paul W. Sanger Professor of Experimental Surgery and vice chair for Surgical Research in the Section of Surgical Sciences at VUMC.
Goldenring is co-principal investigator with Izumi Kaji, PhD, of VUMC’s participation in the Pediatric Congenital Diarrhea and Enteropathy (PediCODE) Consortium and Repository. They are professor and assistant professor, respectively, of Surgery and of Cell & Developmental Biology in the Vanderbilt University School of Medicine.
In collaboration with the other centers in the consortium, “our ongoing work, especially in Dr. Kaji’s laboratory, is seeking to identify novel therapeutic approaches to ameliorate the pathological diarrhea in CODE patients,” Goldenring said.
CODEs are monogenic disorders (caused by a single genetic mutation) that primarily affect the function of the epithelial lining of the intestine.
They are characterized by persistent diarrhea beginning in infancy, poor growth due to malabsorption of nutrients and other defects. Usually, total parenteral nutrition therapy must be started immediately to prevent dehydration and long-term complications.
For most CODE disorders, treatment options are limited. Patients often require lifelong fluid and nutritional management in the form of specialized formulas, restrictive diet or parenteral nutrition (via intravenous catheter). Fortunately, some CODE-associated genes have been identified, and drugs that target some of them are under development.
To identify more mutations and determine how these genetic alterations disrupt normal intestinal function, in 2019 the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH awarded a five-year, $9.4-million grant to establish the PediCODE Consortium and Repository. NIH funding for the consortium was renewed in 2024.
In addition to VUMC, the School of Medicine, and Monroe Carell Jr. Children’s Hospital at Vanderbilt, the consortium includes the Department of Pediatrics at the University of California, Los Angeles, The Hospital for Sick Children in Toronto, and Boston Children’s Hospital.
In this study, next-generation sequencing (NGS) was used to analyze DNA samples from 139 infants with suspected congenital diarrheal disorders who were treated at the medical centers in the consortium or referred from other institutions. NGS facilitated identification of genetic causes of CODE in over 50% of patients.
Using other analytical methods, the researchers identified variations in eight genes that, by altering protein function and cell development in the intestinal epithelium, were responsible for about half of the confirmed cases of CODEs.
They also discovered three new disease-associated genes, including myosin-1a, which has been investigated for several years as a critical component of intestinal function in the laboratory of one of Vanderbilt’s consortium members, Matthew Tyska, PhD, the Cornelius Vanderbilt Chair and professor of Cell and Developmental Biology.
While further study is needed, the findings — what the researchers described as the “genetic architecture” of CODE — “demonstrate the usefulness of next-generation sequencing as a powerful tool to identify known and novel pathogenic variants that cause congenital diarrhea,” Goldenring said.
In addition to Goldenring and Tyska, other Vanderbilt contributors to the study were Sari Acra, MD, MPH, chief of Pediatric Gastroenterology, Hepatology and Nutrition; Hernán Correa, MD, associate professor of Pathology, Microbiology and Immunology; and Suli Mao, research assistant II in the Tyska lab.
The study was supported in part by NIH grants RC2DK118640 and RC2DK122532, the Helmsley Charitable Trust, the Canadian Institutes of Health Research, Canada Research Chairs, the Lassonde Family Precision IBD Initiative, the California Center for Rare Diseases at the UCLA Institute for Precision Health, and the UCLA Clinical Genomics Center.
