Defying all the textbooks: How SickKids used whole exome sequencing to diagnose a patient’s rare condition

Isla’s journey

This journey began when Isla was brought to the neonatal intensive care unit (NICU) at The Hospital for Sick Children (SickKids) at just one week old. She had severe jaundice, high levels of inflammation markers in her blood, skin rashes, extremely low energy and difficulty feeding.

During her first eight months spent in and out of SickKids, Isla experienced high fevers, infections, breathing issues and extreme acid reflux. Her clinical team addressed the symptoms, with the ultimate goal of finding out the underlying cause. Isla had a variety of tests done to check her blood, bone marrow, immunity, genetics and more, all to rule out more common conditions.

Although there was no clear diagnosis, the Rheumatology team suspected that treating the high levels of inflammation might help many of Isla’s health issues. In discussion with the rest of Isla’s clinical team, a biologic drug, which helps block inflammation proteins, was prescribed for Isla in the form of a daily injection.

Once Isla began her treatment, the effect was dramatic, says Isla’s mother, Miki Simmons. “Isla started to have more energy and began smiling and even laughing.”

At this point, while Isla’s condition was improving considerably, Isla still had complications from the symptoms she endured for the first eight months of her life. Her challenges with eating persisted and she received a feeding tube, called a gastrostomy (G) tube, for nutrition.

Isla had a complicated relationship with food, which was particularly challenging for the Simmons family. Her father, Bryan, is a professional chef and family dinners were always a special time for Isla’s parents and four older siblings. But when it came time to reintroduce solid food, Isla had extreme physical and psychological reactions.

A diagnosis through whole exome sequencing

At one year of age, although significantly better, Isla was still experiencing symptoms requiring visits to SickKids, such as fevers and breathing problems, and she was still having difficulty gaining weight. The clinical team suspected a genetic condition, but initial tests did not lead to a diagnosis. This prompted the team to arrange whole exome sequencing, one of the most comprehensive types of genetic testing currently available.

Whole exome sequencing is typically done when a genetic cause of the patient’s disease is suspected, but all other genetic tests have not been able to determine the diagnosis. The test looks at the protein-coding regions of the genome (called the exome) to identify possible disease-causing mutations.

“Isla was defying all the textbooks. Arranging whole exome sequencing was one of the last options we had to truly uncover what was going on,” says Isla’s physician, Dr. Ronald Laxer, Staff Rheumatologist in the Division of Rheumatology at SickKids and Professor, Departments of Medicine and Paediatrics at the University of Toronto.

The results showed Isla had a mutation in a gene called CDC42, responsible for a protein involved in regulation of multiple pathways in cells. When there is a mutation in the gene, severe inflammation can result.

“Finding a mutation was crucial because at this point, we wanted to ensure the treatment we were offering was the right course of action and we were relieved to see that the treatment not only worked clinically, but made sense given the genetic test result,” adds Laxer.

Isla’s genetic mutation meant she had a very rare condition, one that had never been described before in the medical literature. Uncovering the specific gene also meant that Isla’s clinical team could more precisely understand the disease mechanisms and potentially change treatments should new therapies become available.

Laxer consulted with his colleagues and discovered only three other children in North America with the same gene mutation. In 2019, he published the findings of the similarities of the four children with the CDC42 gene mutation in The Journal of Allergy and Clinical Immunology. At the same time, a group from Italy identified four children with the same mutation and called the condition NOCARH syndrome in a publication in the Journal of Experimental Medicine.

“With genetic testing, clinical teams are realizing the opportunity we have to get to the diagnosis sooner. Rare diseases are slowly making their way to the forefront, after being on the back-burner for so long,” Laxer said. “Early recognition and treatment are vital to surviving and thriving.”
While Isla received genetic testing and a diagnosis when she was still very young, even earlier intervention likely would have meant she wouldn’t have needed a feeding tube at all, adds Laxer.

Isla’s story is an example of how SickKids is championing Precision Child Health, a movement at SickKids to shift medicine from a one-size-fits-all approach to health care that is individualized to each unique patient. Clinical teams are using tests like whole exome sequencing to pinpoint genetic causes of symptoms and help find potential interventions that are most appropriate for a child’s unique differences.

Raising awareness of diagnostic genetic testing

With ongoing treatment and close follow-up, Isla reached a significant milestone in the spring of 2020. Two years after receiving her feeding tube, she was able to have it removed. Today, Isla is the least-picky eater among all her siblings and can frequently be found in the kitchen, helping with the cooking alongside her siblings and dad.

Isla’s family and her clinical team hope her story will raise awareness of the importance of early genetic testing for children with unexplained medical conditions.

“We don’t think Isla ever felt left out of family events that included food, like birthday parties or the holidays, because we always made sure she was at the table with a plate in front of her. But early on, being around food would cause a lot of distress and fear for Isla given her earlier difficulties with eating,” Miki says. “As she improved, she began to steal her siblings’ Halloween candy and ask her siblings to feed her some soup, which was wonderful for us to see as a family."