20 years later, doctor uncovers cause of syndrome that bears his name

TORONTO – After two decades of searching for answers, a multidisciplinary group of researchers at The Hospital for Sick Children (SickKids) has uncovered the genetic cause of Roifman syndrome. This rare congenital disorder was discovered 20 years ago by Dr. Chaim Roifman, who is co-principal investigator of a new study published November 2 in Nature Communications.

Roifman Syndrome is characterized by immune deficiency, abnormal growth and formation of bones and joints, vision problems and cognitive delay. It is typically diagnosed based on clinical signs and symptoms between the ages of three and five, after the child has experienced recurrent infections.

This study demonstrates the importance of perseverance and questioning assumptions in medical science. Because most reported cases of Roifman Syndrome are among boys, it was always suspected that this was an X-linked disorder. For years, researchers around the world tried to determine the underlying molecular and genetic causes of this syndrome without success. As the technology advanced so did science’s ability to solve the puzzle.

“I have always promised families that so long as I am working I will try to find the cause of this condition, and my greatest achievement is to now be able to tell the families that we not only have discovered the cause, but we can provide a genetic explanation for many of the key features of Roifman Syndrome. This is a major leap forward in our pursuit of treatment,” says Dr. Chaim Roifman, co-principal investigator of the study, and Clinician-Scientist in Immunology & Allergy at SickKids.

In this study, the team used whole genome sequencing and found that the gene responsible for Roifman Syndrome actually regulates more than 800 other genes, explaining why the condition affects many systems in the body. To the researchers’ surprise, the gene was found hidden in the non-coding segments of DNA that comprise 99 per cent of the genome, which is now accessible using the whole genome sequencing. Essentially, Roifman explains in earlier attempts to uncover the genetic cause, the medical community had been looking under the proverbial lamp post, and we found it at the back of very crowded garage amongst decades of evolutionary junk.

Children with rare genetic conditions like Roifman Syndrome often undergo a long diagnostic odyssey. The discovery of the gene will afford earlier diagnosis that will help prevent medical complications like recurrent infections and lung disease. This finding is also important for genetic counseling for families.

A novel ‘molecular map’ developed by Dr. Daniele Merico and other members of the research team helped to define and assess the impact of the genetic alteration on the function of the gene. “What is so fascinating about the Roifman syndrome gene is that the mutations have effects on hundreds of other genes in the body,” says Dr. Maian Roifman, co-lead author on the study, Clinician-Investigator in Clinical and Metabolic Genetics at SickKids and, the Prenatal Diagnosis and Medical Genetics Program at Mount Sinai Hospital, as well as Chaim Roifman’s daughter. “What this means for a condition like Roifman syndrome, which affects many body systems including the brain, heart, eyes, bones and immune system, is that we have an opportunity to tease out the individual genes that cause each feature of Roifman syndrome. In doing that, we may discover new genetic causes of more common disorders that overlap with Roifman syndrome like congenital heart disease, eye disorders, immune deficiency and mental retardation, potentially helping many more patients with a variety of medical disorders.”

“I remember when the first case of Roifman Syndrome was described,” she says. “My passion for uncovering the mechanisms of disease has definitely been inspired by my dad. To be collaborating on the pursuit of the cause of the syndrome that bears our family name has truly been an honour, both personally and professionally.”

This study highlights the value of collaboration across different disciplines; immunology, clinical genetics, and genome science. This diverse array of expertise made this discovery possible. Dr. Chaim Roifman adds, “while it may be some time before we can correct the global defect, we are now poised to begin a new era of treatment for these patients, who before now, had no answers.”

Daniele Merico, Manager of the Informatics Research Core Facility of The Centre for Applied Genomics (TCAG) at SickKids, and Maian Roifman were co-lead authors on this paper; Stephen Scherer, Senior Scientist and Director of TCAG at SickKids, and Chaim Roifman were co-principal investigators.

The research was supported by Genome Canada, Ontario Genomics Institute, Canadian Institutes for Health Research, the University of Toronto McLaughlin Centre, the Canadian Center for Primary Immunodeficiency, the Jeffrey Modell Foundation, Immunodeficiency Canada and SickKids Foundation.

This paper is an example of how SickKids is contributing to making Ontario Healthier, Wealthier and Smarter www.healthierwealthiersmarter.ca.    

About The Hospital for Sick Children

The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally.  Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is proud of its vision for Healthier Children. A Better World. For more information, please visit www.sickkids.ca.

Media contacts

Matet Nebres
The Hospital for Sick Children
Phone: 416-813-6380
email: matet.nebres@sickkids.ca

Caitlin McNamee-Lamb
The Hospital for Sick Children
Phone: 416-813-7654 ext. 201436
email: caitlin.mcnamee-lamb@sickkids.ca