• Recruiting Patients
    Now recruiting patients meeting the following eligibility criteria
    1. confirmed intellectual disability (ID) or potential for cognitive impairment
      ± seizures, neurologic and/or systemic abnormalities
    2. biochemical phenotype of unknown cause
      abnormal metabolites in urine, blood, CSF
    3. extensive clinical and metabolic phenotyping performed (+preferably chromosome micro-array) with normal results
    4. age: 0-18 years preferred
      but > 18 years also accepted
    5. minimally blood / DNA on patient and parents
      if available: affected and non-affected siblings
  • Workflow
    Workflow: from unexplained phenotype to validated gene discovery
    1. Patient / family eligibility determined > consenting under the TIDEX study at UBC
    2. Phenotype form filled out & candidate gene hypothesis formulated
    3. DNA collected and trio sent out for whole exome sequencing
    4. For consanguineous families: regions of homozygosity determined
    5. Bio-informatics interpretation & report generated by our Team
    6. Candidate variants / genes identified
    7. Validation via Sanger sequencing
    8. Metabolomics according to genes / pathways (Dr. Wishart, Edmonton)
    9. Plan for functional studies outlined & executed to prove causality
    10. Publication…(and ongoing research…targets for treatment & diagnosis)
  • First Results
    Introduction: Intellectual disability (ID) is a lifelong, debilitating condition affecting 2.5% of children and adults worldwide. Our TIDEX project aims to identify novel, potentially treatable ID genes employing the utility of the metabolic phenotype.
    Methods: Criteria were applied to select patients for whole exome sequencing (WGS): patient with unexplained, Mendelian ID plus metabolic abnormalities. Whole exome sequencing was performed for trio’s with customized bio-informatics and subsequent validation.
    Results: In 12 families meeting the selection criteria, we discovered 5 novel genetic defects, including a new treatable disorder Mitochondrial carbonic anhydrase VA (CA-VA) deficiency identified in two siblings with neonatal lethargy, hyperammonemia, hyperlactatemia, hypoglycemia. CA-VA deficiency impairs bicarbonate provision to four mitochondrial enzymes with a central role in the urea cycle and intermediary metabolism. CA-VA deficiency is amenable to preventive and emergency treatment, and expands the number of treatable IDs. The other discovered genes (in various phases validation and publication) include nuclear mitochondrial disease (COX7A2L, RMNDN1), biotin responsive (ACACB), neuronal arborization (DSCAML1), early endosomal recycling (ZFYVE20), presynaptic neurotransmitter transport (BSN). Two novel phenotypes were also unraveled including dystonia with disturbances of intermediary metabolism (UCQCR2), and neurotransmitter disturbances in a channelopathic epilepsy (SCN2A) the latter offering new insights into pathophysiology and targets for treatment. Bio-informatics interpretation for the remaining 3 families is still ongoing. Also, another 15 families has been recruited for this study.
    Conclusions: Our high success rate (75%) emphasizes the importance of the metabolic phenotype for gene discovery using WES. Advantages include: facilitation candidate gene hypothesis, validation causality identified variants, and targets for treatment. Most important, such discoveries can be directly translated into improved patient care. We will expand the TIDEX study to enroll more patients with unexplained across Canada and include metabolomics as for validation and identification of targets for diagnosis and treatment.
  • About the Team
    Principal Investigators:
    Clara van Karnebeek, MD PhD
    Sylvia Stockler, MD PhD
    Wyeth Wasserman, PhD
    Validation Studies:
    Amit Bhavsar, PhD
    Marion Coulter-Mackie
    Colin Ross, PhD
    Graham Sinclair, PhD
    Hilary Vallance, MD
    Linhua Zhang, PhD
    Research support staff:
    Michelle Higginson
    Ruth Giesbrecht
    Marion Thomas, PhD
    Bio-informatics Team (genomics)
    Wasserman Lab:
    Maja Tarailo-Graovac, PhD
    Casper Shyr
    Cynthia Ye
    Robert Burgess, PhD (Maine USA)
    Elizabeth Conibear, PhD
    Eric Shoubridge, PhD (Montreal CA)
    William, Sly, MD PhD (St. Louis USA)
    Abdul Waheed, MD PhD (St Louis USA)
    Clinical Team (phenomics):
    Mary Connolly, MD
    Michelle Demos, MD
    Gabriella Horvath, MD
    Anna Lehman, MD
    Andre Mattman, MD
    Ramona Salvarinova, MD
    Sandra Sirrs, MD
    Margot Van Allen, MD
    Ron Wevers, PhD (Nijmegen NL)
    David Wishart, PhD (Edmonton CA)

    unless otherwise indicated: affiliated with the TIDE, University of British Columbia, Vancouver CA

To enroll patients, please contact Dr. C. van Karnebeek (PI) at cvankarnebeek@cw.bc.ca

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Omics 2 Treat ID

A combined genomics and metabolomics approach to discover novel inborn errors of metabolism with potential for treatment
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Seeking collaborators across Canada

You as clinician or scientist submitting the patient / family remain closely involved throughout the study
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This study is funded by

BC Children's Hospital Foundation & Genome BC and part of the TIDE BC project
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