Novel genes linked to rare childhood diarrhea

At only two days old, Sophie was losing too much weight, and too quicky.

Further genetic testing would show that Sophie has one of a group of rare conditions called CODE (congenital diarrhea and enteropathies) that disrupts the function of cells in the intestine, causing diarrhea and preventing infants from absorbing the nutrients they need to grow and thrive. For Sophie’s parents, Samantha and Kyle, this meant a complete re-envisioning of the life they had expected as a family.  

“Suddenly, our days were filled with medical treatments and frequent hospital visits, requiring us to adjust to being not only parents, but also home health-care providers to our first child,” says Samantha.  

Now, research led by Dr. Aleixo Muise at The Hospital for Sick Children (SickKids) has identified new genes responsible for CODE experienced by children like Sophie. 

The study, published in The New England Journal of Medicine, is an international collaboration that conducted genome sequencing on 129 infants with suspected CODE. The analysis was remarkably successful, providing a diagnosis for 48 per cent of cases – a striking improvement from the 20 per cent rate Muise typically sees in his work leading the Precision IBD and Monogenic Intestinal Diseases clinic at SickKids. Not long ago, diagnostic rates were as low as three per cent. 

The study findings uncovered three new genes associated with CODE (GRWD1, MYO1A and MON1A) and provided answers to 62 families. 

“Undiagnosed infantile diarrhea can be fatal, but even when it isn’t, early diagnosis of rare conditions can help provide much-needed answers for families,” explains Muise, Staff Gastroenterologist and Senior Scientist in the Cell & Systems Biology program. “As a result of this study, we can now provide a diagnosis to more families and move closer to precision treatments tailored to their child’s specific genetic variant.” 

Developing precision therapies for children with CODE 

Sophie and her parents were referred to the Group for Improvement of Intestinal Function Treatment (GIFT) program at SickKids a few short weeks after her birth, where she began total parenteral nutrition (TPN), a specialized solution delivered through a vein to supply the essential nutrients her gut couldn’t absorb. Genetic test results also confirmed Sophie had microvillus inclusion disease (MVID) caused by variation in the MYO5B gene, the second most common cause of CODE.  

“When we got Sophie’s genetic test results back it was a relief, like finally having another piece of the puzzle,” says Samantha. “Having the official genetic report meant that we would have the support we need to move forward and connect with other families.” 

A genetic diagnosis alone can provide relief to many families but understanding the genetic and functional underpinnings of the conditions, including three new pathways, can also move scientists closer to targeted treatments. In collaboration with co-leads Drs. Jay Thiagarajah and Wayne Lencer at Boston Children’s Hospital, Dr. James Goldenring at Vanderbilt University Medical Center and Dr. Martín Martín at the University of California, Los Angeles, the scientists characterized the function of novel CODE genes using advanced computational methods and zebrafish models developed at SickKids.  

“This is Precision Child Health in action,” says Muise, Co-Director of the Inflammatory Bowel Disease (IBD) Centre. “While the journey towards understanding and treating these rare conditions is ongoing, better understanding of the genetic pathways that impact CODE brings us one step closer to developing drugs to target those pathways and change the trajectory of patients with these conditions.” 

Research provides hope for children with rare genetic conditions 

At SickKids, Sophie’s care team taught Samantha and Kyle how to manage her condition using TPN, and though her early years were marked by frequent diaper changes and slowed growth, she began to gain weight and get the nourishment she needed.   

Sophie, now six years old, requires ongoing monitoring and TPN treatment, but a novel surgical approach to CODE detailed by co-senior author Dr. Yaron Avitzur, Interim Division Head of Gastroenterology, Hepatology and Nutrition and Director of the GIFT program, significantly improved her health and quality of life, with her parents noting a marked increase in her comfort and happiness.  

“We hope that there is more research like this, that could move us closer to treatments that will continue to improve Sophie’s quality of life and transform the lives of children like her,” explains Samantha. 

This study was funded by the Canadian Institutes of Health Research (CIHR), National Institutes of Health (NIH), The Leona M. and Harry B. Helmsley Charitable Trust, the Lassonde Family Precision IBD Initiative, and the California Center for Rare Disease (CCRD).