“Medical detectives” use genomics to move from diagnosis to treatment

15 June 2016

Dr. Clara van Karnebeek, a 2014 MSFHR Scholar, is the lead author on a study published in the New England Journal of Medicine last month that shows how genome-wide sequencing for children with certain kinds of intellectual disability can go beyond diagnosis and actually target treatments.

Her international, multi-disciplinary research team also includes Dr. Suzanne Lewis (2005 Scholar), Dr. Colin Ross (2016 Scholar and 2001 Trainee), and Dr. Wyeth Wasserman (2004 Scholar).

Dr. van Karnebeek is a clinician-scientist based at BC Children’s Hospital. She is the co-founder of TIDE-BC, a collaborative care & research initiative with a focus on prevention and treatment of intellectual disability. The most recent study involved sequencing the full trio exome for children with an undiagnosed cause of their intellectual disability and metabolic abnormalities. By doing this, the research team was able to successfully find the genetic cause in 90 per cent of the individuals who participated.

“This work would not have been possible without the very close collaboration between physicians, laboratory scientists and bio-informaticians,” said Dr. van Karnebeek. “In particular, I want to single out Dr. Maja Tarailo-Graovac. She and the bioinformatics team were able to analyze the huge amounts of data generated by this work and find the causal mutation in nine out of the 10 cases studied. That’s like finding a needle in a haystack.”

The diagnosis is critical. Many of Dr. van Karnebeek’s patients are among a handful of people in the world with these illnesses. To date, medical research has not been able to offer families much in the way of treatment options.

“I am greatly impressed by the resilience and strength of these families,” says Dr. van Karnebeek. “They are full partners in this process and often drive the research forward by connecting with other families suffering the same rare disease.”

Some intellectual disabilities are 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. Dr. van Karnebeek’s team discovered 11 novel human disease genes, one of which is NANS deficiency. This work, published recently in Nature Genetics, provides insight into brain functioning.

For four out of 10 participants in the study, the research team was able to go beyond diagnosis. Using the genomic data, they studied the affected metabolic pathways and disease mechanisms and developed a targeted treatment for the individual. Treatments ranged from simple interventions like dietary modifications, vitamin supplements and medications to more invasive procedures like bone marrow transplants. Early intervention is key. The right treatment can improve cognitive functioning, lessen the symptoms of epilepsy and autism, or minimize irreversible brain damage.

“This research shows us what can be possible with personalized medicine — the precise genomic diagnosis gives us the potential to treat these diseases,” says Dr. van Karnebeek. “As physicians, we don’t have to view the patient’s current condition as fixed, and we have the potential to improve outcomes.”

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