CFRI investigator Dr. Bill Gibson and his colleagues have discovered a new genetic disorder in two young men who have suffered from a range of debilitating symptoms since birth. In addition to finally providing conclusive answers for these patients and their families, this research may ultimately help scientists better understand the root causes of certain forms of cancer.

This work builds on Dr. Gibson's previous research on a class of genetic disorders known as overgrowth syndromes that increase head size, height and weight. In 2011, Dr. Gibson led the group that identified the gene that causes Weaver syndrome, an overgrowth syndrome characterized by high birth weight, tall stature and developmental delays. 

Now Dr. Gibson's research team, in collaboration with researchers at Canada's Michael Smith Genome Science Centre at the BC Cancer Agency, has discovered a new mutation in a second gene that works closely with the Weaver syndrome gene. This new mutation causes a genetic overgrowth syndrome very similar to Weaver syndrome. Last year, Ana Cohen, a doctoral student supervised by Dr. Gibson, diagnosed a second young man with the new syndrome after meeting him at the first International Conference on Weaver Syndrome, which was organized and hosted by the Gibson Lab in November of 2014.

The study was published on March 19, 2015 in the Journal of Human Genetics. Ana Cohen is the lead author and Dr. Gibson is the senior author. 

How did you discover this new syndrome?

Dr. Bill Gibson: We offer free research-grade testing to families, and we were asked to test a young man in Turkey who had signs and symptoms that seemed to indicate Weaver syndrome. However, when we tested him, he didn't have any mutations in the Weaver syndrome gene. We then sequenced the protein-coding portion of his DNA and discovered a never-before-seen mutation in a gene that codes for a protein called EED. EED sticks together with EZH2, the protein that is mutated in Weaver syndrome, and helps it to work properly.

How did you find the second known patient with this syndrome?

BG: In November 2014, our team organized the first International Conference on Weaver Syndrome to bring together families affected by Weaver syndrome with scientists, doctors and students who specialize in studying and treating the disorder. We were very pleased to have Dr. David Weaver as our keynote speaker. At the conference, Ana Cohen met a thirty-year-old man who had been diagnosed with Weaver syndrome as a child but didn't actually have a mutation Weaver syndrome gene. She noticed that his facial features and large hands were very similar to those of the young man profiled in our paper, so she tested him and discovered he also has a mutation in this newly-discovered overgrowth gene. We're delighted that the Weaver syndrome conference was instrumental in finally providing a conclusive diagnosis for this young man.

Connecting families affected by rare disorders with scientists who study those diseases can make a real difference – both to the lives of patients and to the state of medical research. 

How will this discovery help children?

BG: Discovering this genetic mutation is the first step towards directly improving the lives of children who have this disorder. When patients don't have a definitive diagnosis, they are often subjected to many unnecessary tests. Sometimes they even have invasive procedures like muscle and liver biopsies, and they may also try multiple treatments that have little or no effect. Now we'll be able to give families of children with this syndrome the certainty of a diagnosis and work towards developing more effective care protocols and treatments.

What are the implications of this discovery for cancer research?

BG: Both EED, the protein involved in this new syndrome, and EZH2, the protein involved in Weaver syndrome, form part of a complex called Polycomb Repressive Complex 2 (PRC2). This complex is responsible for gene silencing – that is, turning genes off at the right time. When the function of PRC2 is impaired, certain genes stay active for too long, leading to the overgrowth seen in Weaver syndrome and this new disorder. PRC2 malfunction has also been implicated in the development of certain cancers, particularly leukemia, lymphomas and other blood cancers.

By studying this new syndrome, we can learn more about the role EED plays in the human body and how impaired EED function affects the way genes controlled by EED are expressed. Understanding these molecular processes will improve our knowledge of EED's involvement in cancer and may open the door to developing new treatments and preventative therapies. 

What are the next steps?

BG: We're hoping to find more people with this new disorder, and we're available to provide genetic sequencing to any patients who may be affected. We'd also like to collect more DNA samples so we can further research the underlying genetic causes of this disease.

We have plans to develop a registry to track patients with overgrowth syndromes over the course of their lives. These disorders are so rare that no single medical centre sees enough affected patients to study them systematically without collecting specific referrals. A registry will help scientists and doctors understand how these conditions usually progress and which therapies are most effective. Families affected by rare diseases often feel isolated and are eager to connect with other people who have faced the same diagnosis. A registry would serve as a platform to bring families together and give them access to the latest research developments. 

We believe there are more overgrowth syndromes that have yet to be discovered, and we continue to search for mutations in other genes that cause disease. In addition to furthering our understanding of the genetic roots of overgrowth syndromes and cancer, this research makes a real difference in the lives of people with these rare conditions. Every time we find a new syndrome, we're able to finally provide answers to a new group of patients and their families.

Dr. Bill Gibson is a CFRI investigator at BC Children's Hospital and an Associate Professor in the Department of Medical Genetics at the University of British Columbia. 

This research was made possible by support from BC Children's Hospital Foundation and Operating Grants from the Canadian Institute of Health Research. Ana Cohen holds a Doctoral Grant from the Fundação para a Ciência e a Tecnologia.


Read more: 
Cohen AS, Tuysuz B, Shen Y, Bhalla SK, Jones SJ, Gibson WT. A novel mutation in EED associated with Overgrowth in Journal of Human Genetics, March 19, 2015.