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Personalized Genomics Dramatically Aids Intellectual Disability Diagnostics

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    New findings from clinical studies lead by scientists at British Columbia Children’s Hospital, an agency of the Provincial Health Services Authority, and the University of British Columbia, show the life-altering benefits of genome-wide sequencing for children with certain kinds of intellectual disabilities. The results from this study were published recently in the New England Journal of Medicine through an article entitled “Exome Sequencing and the Management of Neurometabolic Disorders.”


    The researchers found a precise underlying genetic condition for almost 70% of the patients they studied and were able to offer targeted treatments to more than 40% of those cases. Moreover, the research team 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 for a subset of patients we can identify the genetic underpinning of their intellectual disability and then determine the right intervention,” explained senior study author Clara van Karnebeek, M.D., Ph.D., a pediatrician and biochemical geneticist at BC Children’s Hospital, and principal investigator in the Centre for Molecular Medicine and Therapeutics at the University of British Columbia. “There’s a bright future ahead for personalized medicine informed by genetic diagnosis.”


    Some 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 buildup of toxic substances in the brain and body, leading to symptoms such as developmental and cognitive delays, epilepsy, and organ dysfunction. A few 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.


    Since the appropriate treatment can improve cognitive functioning or slow or stop irreversible brain damage, early intervention can improve lifelong outcomes for affected children and their families. This new study should help to change the paradigm for diagnosing and treating these conditions.


    The goal of the current 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. The researchers tested the children and their parents using a combination of metabolomic analysis and whole-exome sequencing. Using this next-generation sequencing technique, the investigators were able to analyze and interpret the portion of DNA that codes for proteins.


    “Deep phenotyping and whole-exome sequencing in 41 probands (patients) with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%,” the authors wrote.


    Interestingly, during the study, researchers discovered a new genetic disease called carbonic anhydrase VA deficiency that presents during early childhood with life-threatening sleepiness and coma due to hyperammonemia (the build-up of a toxin if the body’s cells cannot properly break down proteins into energy). Researchers found that a drug called carglumic acid could prevent brain damage in children with this condition.


    Additionally, the BC Children’s Hospital team discovered a new metabolic disease called glutamic oxaloacetic transaminase 2 deficiencies that affects the brain and is characterized by small head size, seizures, and developmental delays. Treatment with an amino acid called serine and vitamin B6 improved the symptoms.


    “Our findings open the door to life-changing treatments for a small yet meaningful percentage of patients,” noted Dr. van Karnebeek. “We’re learning more about brain function and the mechanisms underlying intellectual disability. These results are meaningful to individuals around the world who suffer these rare conditions.”

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