SickKids researchers show whole genome sequencing should be standard diagnostic test for children with medical complexity

Children with medical complexity often have to embark on a diagnostic odyssey that can mean several years of tests before getting a diagnosis. A new study from researchers and clinicians at The Hospital for Sick Children (SickKids) shows whole genome sequencing could provide the diagnostic answers families are seeking and open up new avenues for treatment in a shorter period of time. The study was published on September 22, 2020 in JAMA Network Open. 

Diagnostic process for children with medical complexity can last several years 

Children with medical complexity typically have at least one chronic medical condition, are dependent on technology to support their day-to-day lives, are followed by multiple subspecialists and spend a lot of time in hospital. They make up less than one per cent of children in Ontario but account for 33 per cent of all paediatric health-care spending. A genetic cause is suspected in many of these children but conventional genetic testing often falls short, as these methods typically only test a small proportion of a patient’s genetic data. Families generally go through several rounds of genetic testing, at great personal cost to them and financial cost to the health-care system. 

The study team recruited 49 patients followed by the Complex Care Program at SickKids. The patients all had a suspected but undiagnosed genetic cause for their symptoms, despite undergoing conventional genetic testing in the past. The team performed whole genome sequencing for the participants at The Centre for Applied Genomics (TCAG) operated by SickKids. Where possible, family members also underwent whole genome sequencing to provide a complete picture of the family’s genetic characteristics. 

A case for whole genome sequencing as a cornerstone for diagnostics 

Through the study, 15 of the 49 participants (30 per cent) received a new primary molecular genetic diagnosis and seven of these patients received a diagnosis that had immediate implications for their care plans. All 15 patients had experienced a long diagnostic process, ranging from five to 17 years. For each of the study participants, whole genome sequencing identified any variants in their genetic code that their previous, conventional genetic testing had shown. 

“Our results show one test could replace years of time-consuming, emotional and costly genetic testing for all children with medical complexity and their families,” says Dr. Gregory Costain, study co-lead, Staff Physician in the Division of Clinical and Metabolic Genetics, and Scientist-Track Investigator in the Genetics & Genome Biology program at SickKids. “With this study, we’ve made the case for whole genome sequencing as a standard-of-care test for children with medical complexity who have a suspected, undiagnosed genetic condition. 

Costain says he suspects study participants who did not receive a new diagnosis through whole genome sequencing may see that change in the future as researchers learn more about the human genome. 

Currently, whole genome sequencing is available in Canada through research studies such as this one but has not yet been implemented clinically. The researchers argue in the paper that their findings support a role for whole genome sequencing as a “cornerstone” for use in clinical programs following paediatric patients with undiagnosed diseases. SickKids is striving to enable and expand patient access to precision health technology, such as whole genome sequencing, so all children and youth can receive an individualized care plan. 

The value of having a diagnosis 

Uncovering the genetic cause for a child’s medical complexity could mean targeted, more efficient treatments that help these patients stay healthier and out of hospital. This means a better quality of life for the patient and their family as well as reduced health-care system costs. However, the researchers explain simply having a diagnosis can be invaluable to families. 

“Many of our families want to know why their children have these conditions as they often worry they might have done something to cause their children’s symptoms,” says Costain, who is also an Assistant Professor in the Department of Paediatrics at the University of Toronto. “When we’ve been able to identify a genetic cause for a child’s condition, the relief on their family’s faces is palpable.” 

The researchers hope their study will bring some of this relief even to families who didn’t participate in the study, as the data generated from their research also contributed to the discovery of three new genetic conditions. These discoveries could potentially unlock diagnoses for children with medical complexity around the world. 

Costain says the next phase of this research is to expand the study to include more families and new cutting-edge genomic tests. Their long-term goal is to understand and develop best practices for the translation of genomic medicine into clinical care at SickKids and beyond. 

The study team would like to acknowledge Dr. M. Stephen Meyn, study co-lead who is now at the University of Wisconsin, as well as the patients and families who enabled this work. 

The study was supported by Norman Saunders Complex Care Initiative, SickKids Centre for Genetic Medicine, University of Toronto McLaughlin Centre and SickKids Foundation.