Genome Sequencing Identifies Some Forms of Potentially Treatable Intellectual Disabilities Interview with:

Dr. Clara van Karnebeek PhD Certified Pediatrician and Biochemical Geneticist at the BC Children’s Hospital Principal Investigator, University of British Columbia

Dr. Clara van Karnebeek

Dr. Clara van Karnebeek PhD
Certified Pediatrician and Biochemical Geneticist at the BC Children’s Hospital
Principal Investigator, University of British Columbia What is the background for this study?

Dr. van Karnebeek: The goal of the study was to diagnose patients with genetic conditions and discover and describe new diseases with potential for treatment. The study included patients with neurodevelopmental conditions that doctors suspected were genetic or metabolic in origin but had not been diagnosed using conventional methods. Our team tested the children and their parents using a combination of metabolomic (large scale chemical) analysis and a type of genomic sequencing called whole exome sequencing. With this state-of-the-art technique, experts analyze and interpret the portion of DNA called genes that hold the codes for proteins.

Some people’s intellectual disability is due to rare genetic conditions that interfere with the processes the body uses to break down food. Because of these metabolic dysfunctions, there is an energy deficit and build-up of toxic substances in the brain and body leading to symptoms such as developmental and cognitive delays, epilepsy, and organ dysfunction. Some of these rare diseases respond to treatments targeting the metabolic dysfunction at the cellular level and range from simple interventions like dietary modifications, vitamin supplements and medications to more invasive procedures like bone marrow transplants. Because the right treatment can improve cognitive functioning or slow or stop irreversible brain damage, early intervention can improve lifelong outcomes for affected children and their families. What are the main findings?

Dr. van Karnebeek: The researchers diagnosed 68 per cent of the 41 families in the study with the precise underlying genetic condition and, based on this, were able to offer targeted treatments to more than 40 per cent of cases. They also discovered 11 new disease genes and described new physical traits and symptoms associated with a number of known diseases.

This research is very encouraging because it shows for a subset of patients we can identify the genetic underpinning of their intellectual disability and then determine the right intervention. What should readers take away from your report?

Response: This is one of the first studies to show the life-changing benefits of genome-wide sequencing for children with certain kinds of intellectual disability. There’s a bright future ahead for personalized medicine informed by genetic diagnosis. By carefully studying disease mechanisms and pathways, we can identify treatment targets. Genome-wide sequencing is a powerful diagnostic tool that can shorten the diagnostic odyssey. What recommendations do you have for future research as a result of this study?

Dr. van Karnebeek: We propose to increase awareness and diagnosis of treatable forms of intellectual disability among clinicians, to perform similar –omics studies in larger sample numbers and to continue to discover novel disease genes and develop and implement therapies based on genomic diagnosis. This form of genomic medicine may well be applicable to other neurologic conditions with a genetic basis (e.g. atypical cerebral palsy, epilepsy). Is there anything else you would like to add?

Dr. van Karnebeek: This research was conducted as part of the Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC, TIDE-BC is a Collaborative Area of Innovation Project based at BC Children’s Hospital that launched in 2011, the focus of which is improving early diagnosis and treatment of intellectual disability. A diagnosis ends the diagnostic odyssey for patients, provides information and improves genetic counseling along with access to community services and, in some cases, the opportunity to improve patient management.

In previous research, the TIDE-BC team developed a mobile app that helps clinicians review the intellectual disability patient’s symptoms and arrive at the diagnosis of a treatable form of intellectual disability (in 2015 there were 90 such diseases know as early as possible, based on the best available evidence. Thank you for your contribution to the community.


Exome Sequencing and the Management of Neurometabolic Disorders
Maja Tarailo-Graovac, Ph.D., Casper Shyr, Ph.D., Colin J. Ross, Ph.D., Gabriella A. Horvath, M.D., Ph.D., Ramona Salvarinova, M.D., Xin C. Ye, M.Sc., Lin-Hua Zhang, Ph.D., Amit P. Bhavsar, Ph.D., Jessica J.Y. Lee, B.Sc., Britt I. Drögemöller, Ph.D., Mena Abdelsayed, Ph.D., Majid Alfadhel, M.D., Linlea Armstrong, M.D., Matthias R. Baumgartner, M.D., Ph.D., Patricie Burda, Ph.D., Mary B. Connolly, M.D., Jessie Cameron, Ph.D., Michelle Demos, M.D., Tammie Dewan, M.D., Janis Dionne, M.D., A. Mark Evans, Ph.D., Jan M. Friedman, M.D., Ph.D., Ian Garber, M.D., Suzanne Lewis, M.D., Ph.D., Jiqiang Ling, Ph.D., Rupasri Mandal, Ph.D., Andre Mattman, M.D., Margaret McKinnon, M.D., Aspasia Michoulas, M.D., Daniel Metzger, M.D., Oluseye A. Ogunbayo, Ph.D., Bojana Rakic, Ph.D., Jacob Rozmus, M.D., Peter Ruben, Ph.D., Bryan Sayson, B.Sc., Saikat Santra, M.D., Kirk R. Schultz, M.D., Kathryn Selby, M.D., Paul Shekel, Ph.D., Sandra Sirrs, M.D., Cristina Skrypnyk, M.D., Andrea Superti-Furga, M.D., Ph.D., Stuart E. Turvey, M.D., Ph.D., Margot I. Van Allen, M.D., David Wishart, Ph.D., Jiang Wu, Ph.D., John Wu, M.D., Dimitrios Zafeiriou, M.D., Ph.D., Leo Kluijtmans, Ph.D., Ron A. Wevers, Ph.D., Patrice Eydoux, Ph.D., Anna M. Lehman, M.D., Hilary Vallance, M.D., Sylvia Stockler-Ipsiroglu, M.D., Ph.D., Graham Sinclair, Ph.D., Wyeth W. Wasserman, Ph.D., and Clara D. van Karnebeek, M.D., Ph.D.
May 25, 2016DOI: 10.1056/NEJMoa1515792

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