van Karnebeek Lab

Clara van Karnebeek

 “The goal of my personalized medicine research program ‘Omics2TreatID’ is to harness ‘-omics’ technologies to identify and treat genetic defects that lead to intellectual disability, and to develop tools to assist physicians with the diagnosis and treatment of these conditions before permanent brain damage occurs.”

Early recognition of rare but treatable genetic diseases in children is the key to preventing certain forms of intellectual disability.

“Intellectual disabilities are no longer necessarily an unchangeable fate,” says Dr. van Karnebeek. “Today, new tools allow us to diagnose and treat specific genetic conditions causing developmental delay and intellectual disability, previously thought to be permanent.”

Dr. van Karnebeek’s research is aimed at discovering new inborn errors of metabolism, a class of genetic diseases that is particularly amenable to treatment. Her team uses a multidisciplinary approach involving the study of three “-omics” in patients: phenomics, their physical and biochemical properties, genomics, their genetic information, and metabolomics, their metabolite profiles. She established two large collaborative efforts, the Treatable Intellectual Disability Endeavor in BC (TIDEBC.org), and the international TIDEX Study aimed at harnessing these new technologies for the discovery of genetic defects in children who present with intellectual disabilities and providing clinicians the tools for early recognition and management.

Dr. van Karnebeek and her team already successfully identified a number of these defects, developed new treatments and were able to enhance identification of these diseases in BC Children’s Hospital. Over the past 4 years, more than 500 children with intellectual disability were systematically screened and 5% were identified to have treatable condition; treatment in these cases improved behavior, cognition and often changed the lives of the whole family.

These diagnostic tools – a protocol supported by the Treatable-ID.org App – are now used by physicians around the world, allowing them to recognize diseases in newborns and treat these vulnerable patients before they suffer important brain damage.Dr. van Karnebeek’s team has discovered more than 15 novel human diseases, including carbonic anhydrase VA deficiency (presenting with a life-threatening hyperammonemia amenable to treatment with carglumic acid and medical diet) as well as NANS deficiency (a sialic acid metabolism defect presenting with skeletal and brain abnormalities and brain, for which therapy is being developed). In May 2016, the TIDEX genomics discovery study was published in the New England Journal of Medicine, the major medical journal reporting a diagnostic yield of 90% in 41 families with unexplained neurometabolic phenotypes; most importantly the study demonstrates personalized medicine as a genomic diagnosis enables targeted therapy for improved outcomes in 44%.

Dr. van Karnebeek established and chairs the International Pyridoxine Dependent Epilepsy Consortium (www.pdeonline.org). This program of research spans model organism research, a patient registry, novel treatment studies and outcomes.

In 2017, Dr. van Karnebeek in collaboration with the Academic Medical Centre in Amsterdam, established a new research study focused on the identification of phenotypic modifiers in degenerative metabolic diseases such as Adrenoleukodystrophy and Gaucher disease. Applying a systems biology approach with integrated multi-omics analysis, discordant siblings with extreme and differing clinical outcomes will be studied. The results will not only prove insights into pathophysiology but also facilitate prognostication and timing of therapeutic interventions (e.g. stem cell therapy), increasingly important with the inclusion of conditions in newborn screening programs.

MAJOR ACHIEVEMENTS & PUBLICATIONS

Nomination for YWCA Woman of Distinction Award – 2017

Canadian Organization for Rare Diseases Scientific Award – 2016

UBC Faculty of Medicine Early Career Excellence Award – 2016

Michael Smith Foundation for Health Research Scholar Award – 2014

IG Maud Menten New Principal Investigator Finalist Prize (CIHR) – 2013

Digital Health Innovation Summit Award – 2012

Bluma Tischler Fellowship Research Award – 2011

Laura McRae Award for Excellence in Pediatrics – 2011

Tarailo-Graovac M, Wasserman W, van Karnebeek CD. Impact of next-generation sequencing on diagnosis and management of neurometabolic disorders: current advances and future perspectives Expert Review of Molecular Diagnostics: dx.doi.org/10.1080/14737159.2017.1293527dx.doi.org/10.1080/14737159.2017.1293527

van Karnebeek CD, Bowden K, Berry-Kravis E. Treatment of Neurogenetic Developmental Conditions: From 2016 into the Future. Pediatr Neurol. 2016 Dec;65:1-13. doi: 10.1016/j.pediatrneurol.2016.07.010.

Van Karnebeek CD. GLUT1 deficiency: progress in unraveling its genetic basis. Dev Med Child Neurol. 2016 Dec;58(12):1210-1211. doi: 10.1111/dmcn.13220

van Karnebeek CD, Bonafé L, Wen XY et al.NANS-mediated synthesis of sialic acid is required for brain and skeletal development. Nature Genetics 2016,doi:10.1038/ng.3578

Tarailo-Graovac M, Shyr C, Ross C, et al, van Karnebeek CD.Exome sequencing and the management of neurometabolic disorders. New Engl J Med 2016:May 25th

Cameron JM, Shyr C, Zhang L, Drögemöller B, Ross CJ, Wasserman WW, Wevers RA, Rodenburg RJ, Gupte G, Preece MA, van Karnebeek CD. Cytosolic phosphoenolpyruvate carboxykinase deficiency presenting with acute liver failure following gastroenteritis. Molec Genet Metab 2016 Mar 4. pii: S1096-7192(16)30021-X. doi: 10.1016/j.ymgme.2016.03.001

Horvath G, Demos M, Shyr C, Matthews A, Zhang L, Race S, Stockler-Ipsiroglu S, Van Allen MI, Mancarci O, Toker L, Pavlidis P, Ross CJ, Wasserman WW, Trump N, Heales S, Pope S, Cross JH, van Karnebeek CDMSecondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: a potential treatment target?Molec Genet Metab 2016 Jan;117:42-48 (IF 2.6).

Langlois S, Tarailo-Graovac M, Sayson B, Drögemöller B, Swenerton A, Ross CJ, Wasserman WW, van Karnebeek CD. De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome.Eur J Hum Genet.2015 Oct 21. doi: 10.1038/ejhg.2015.217. [Epub ahead of print] (IF 4.3).

Jaggumantri S, Dunbar M, Edgar V, Mignone C, Newlove T, Elango R, Collet JP, Sargent M, Stockler-Ipsiroglu S, van Karnebeek CD. Treatment of Creatine Transporter (SLC6A8) Deficiency With Oral S-Adenosyl Methionine as Adjunct to L-arginine, Glycine, and Creatine Supplements.Pediatr Neurol.2015 Oct;53(4):360-363.e2. doi:

Boycott K, Hartley T, Adam S, Francois Bernier3, Karen Chong4,5, Bridget A. Fernandez6, Jan M. Friedman2, Michael T. Geraghty1, Stacey Hume7, Bartha Knoppers8, Anne-Marie Laberge9, Jacek Majewski10, Roberto Mendoza-Londono4, M. Stephen Meyn4,11, Jacques L. Michaud9, Tanya N. Nelson12, Julie Richer1, Bekim Sadikovic13, David L. Skidmore14, Tracy Stockley15, Sherry Taylor7, van Karnebeek CD, Zawati M, Lauzon J, Armour C (on behalf of the Canadian College of Medical Geneticists) The clinical application of genome-wide sequencing for monogenic diseases in Canada Position Statement of the Canadian College of Medical Geneticists. J Med Genet.2015 Jul;52(7):431-7. doi: 10.1136/jmedgenet-2015-103144

Sirrs S, van Karnebeek CD, Peng X, Shyr C, Tarailo-Graovac M, Mandal R, Testa D, Dubin D, Carbonetti G, Glynn SE, Sayson B, Robinson WP, Han B, Wishart D, Ross CJ, Wasserman WW, Hurwitz TA, Sinclair G, Kaczocha M. Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms.Orphanet J Rare Dis.2015 Mar 28;10(1):38

van Karnebeek CD, Sly WS et al. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am J Hum Genet.2014;94:453-61.

“UBC scientist helps physicians diagnose a life-threatening disease in newborns”, Feature by UBC Faculty of Medicine, February 14 2014. http://www.med.ubc.ca/ubc-scientist-helps-physicians-diagnose-a-life-threatening-disease-in-newborns/

Stockler-Ipsiroglu S, Nahdi S, van Karnebeek C. Introduction of the Tide Protocol to screen children for treatable intellectual disability: first evaluation of protocol use by community pediatricians in British Columbia. BCMJ (http://www.bcmj.org).2015 Nov, 57(9):387-393.

van Karnebeek, CDM, Shevell M, Zschocke J, Moeschler JB, Stockler S. The metabolic evaluation of the child with an intellectual developmental disorder: Diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab.2014 (ePub ahead of print).

Michelle K Demos, Clara DM van Karnebeek, Colin JD Ross, Shelin Adam, Yaoqing Shen, Shing Hei Zhan, Casper Shyr, Gabriella Horvath, Mohnish Suri, Alan Fryer, Steven JM Jones and Jan M Friedman. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet Journal of Rare Diseases 2014, 9:15 doi:10.1186/1750-1172-9-15

van Karnebeek CD, Stockler S.Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab 2012 Mar;105(3):368-81.

van Karnebeek C, Houben R, Lafek M, Giannasi W, Stockler S. The treatable intellectual disability APP www.treatable-id.org: a digital tool to enhance diagnosis and care for rare diseases.Orphanet Journal of Rare Diseases. 2012, 7:47.

Exome sequencing and the management of neurometabolic disorders. New Engl J Med 2016:May 25th

Cameron JM, Shyr C, Zhang L, Drögemöller B, Ross CJ, Wasserman WW, Wevers RA, Rodenburg RJ, Gupte G, Preece MA, van Karnebeek CD. Cytosolic phosphoenolpyruvate carboxykinase deficiency presenting with acute liver failure following gastroenteritis. Molec Genet Metab 2016 Mar 4. pii: S1096-7192(16)30021-X. doi: 10.1016/j.ymgme.2016.03.001

Horvath G, Demos M, Shyr C, Matthews A, Zhang L, Race S, Stockler-Ipsiroglu S, Van Allen MI, Mancarci O, Toker L, Pavlidis P, Ross CJ, Wasserman WW, Trump N, Heales S, Pope S, Cross JH, van Karnebeek CDMSecondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: a potential treatment target?Molec Genet Metab 2016 Jan;117:42-48 (IF 2.6).

Langlois S, Tarailo-Graovac M, Sayson B, Drögemöller B, Swenerton A, Ross CJ, Wasserman WW, van Karnebeek CD. De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome.Eur J Hum Genet.2015 Oct 21. doi: 10.1038/ejhg.2015.217. [Epub ahead of print] (IF 4.3).

Jaggumantri S, Dunbar M, Edgar V, Mignone C, Newlove T, Elango R, Collet JP, Sargent M, Stockler-Ipsiroglu S, van Karnebeek CD. Treatment of Creatine Transporter (SLC6A8) Deficiency With Oral S-Adenosyl Methionine as Adjunct to L-arginine, Glycine, and Creatine Supplements.Pediatr Neurol.2015 Oct;53(4):360-363.e2. doi:

Boycott K, Hartley T, Adam S, Francois Bernier3, Karen Chong4,5, Bridget A. Fernandez6, Jan M. Friedman2, Michael T. Geraghty1, Stacey Hume7, Bartha Knoppers8, Anne-Marie Laberge9, Jacek Majewski10, Roberto Mendoza-Londono4, M. Stephen Meyn4,11, Jacques L. Michaud9, Tanya N. Nelson12, Julie Richer1, Bekim Sadikovic13, David L. Skidmore14, Tracy Stockley15, Sherry Taylor7, van Karnebeek CD, Zawati M, Lauzon J, Armour C (on behalf of the Canadian College of Medical Geneticists) The clinical application of genome-wide sequencing for monogenic diseases in Canada Position Statement of the Canadian College of Medical Geneticists. J Med Genet.2015 Jul;52(7):431-7. doi: 10.1136/jmedgenet-2015-103144

Sirrs S, van Karnebeek CD, Peng X, Shyr C, Tarailo-Graovac M, Mandal R, Testa D, Dubin D, Carbonetti G, Glynn SE, Sayson B, Robinson WP, Han B, Wishart D, Ross CJ, Wasserman WW, Hurwitz TA, Sinclair G, Kaczocha M. Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms.Orphanet J Rare Dis.2015 Mar 28;10(1):38

van Karnebeek CD, Sly WS et al. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am J Hum Genet.2014;94:453-61.

“UBC scientist helps physicians diagnose a life-threatening disease in newborns”, Feature by UBC Faculty of Medicine, February 14 2014. http://www.med.ubc.ca/ubc-scientist-helps-physicians-diagnose-a-life-threatening-disease-in-newborns/

Stockler-Ipsiroglu S, Nahdi S, van Karnebeek C. Introduction of the Tide Protocol to screen children for treatable intellectual disability: first evaluation of protocol use by community pediatricians in British Columbia. BCMJ (http://www.bcmj.org).2015 Nov, 57(9):387-393.

van Karnebeek, CDM, Shevell M, Zschocke J, Moeschler JB, Stockler S. The metabolic evaluation of the child with an intellectual developmental disorder: Diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab.2014 (ePub ahead of print).

Michelle K Demos, Clara DM van Karnebeek, Colin JD Ross, Shelin Adam, Yaoqing Shen, Shing Hei Zhan, Casper Shyr, Gabriella Horvath, Mohnish Suri, Alan Fryer, Steven JM Jones and Jan M Friedman. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet Journal of Rare Diseases 2014, 9:15 doi:10.1186/1750-1172-9-15

van Karnebeek CD, Stockler S.Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab 2012 Mar;105(3):368-81.

van Karnebeek C, Houben R, Lafek M, Giannasi W, Stockler S. The treatable intellectual disability APP www.treatable-id.org: a digital tool to enhance diagnosis and care for rare diseases.Orphanet Journal of Rare Diseases. 2012, 7:47.

van Karnebeek C, Hartmann H, Jaggumantri S, Bok L, Cheng B, Connolly M, Coughlin C, Das A, Gospe S, Jakobs C, van der Lee H, Mercimek-Mahmutoglu S, Meyer U, Struyst E, Sinclair G, Van Hove J, Collet JP, Plecko B, Stockler S. Lysine restricted diet for pyridoxine-dependent epilepsy: first evidence & future trials. Mol Genet Metab 2012 Nov;107(3):335-44.

Press Coverage

  • CTV: http://www.ctvnews.ca/health/breakthrough-study-pinpoints-genetic-conditions-behind-intellectual-disabilities-1.2916829
  • Health Day: https://consumer.healthday.com/kids-health-information-23/misc-learning-disabilities-health-news-441/scientists-find-new-genetic-explanations-for-some-developmental-delays-711364.html
  • MedPage: http://www.medpagetoday.com/Neurology/GeneralNeurology/58140 http://www.upi.com/Health_News/2016/05/25/Genetic-insights-may-help-kids-battling-developmental-delays/5011464222070/
  • United Press International:
  • 24 Hours Vancouver: http://vancouver.24hrs.ca/2016/05/26/dna-studied-to-solve-brain-disease
  • MedicalResearch.com: http://medicalresearch.com/author-interviews/genome-sequencing-identifies-some-forms-of-potentially-treatable-intellectual-disabilities/24754/
  • Philly.com: http://www.philly.com/philly/health/topics/HealthDay711364_20160525_Genetic_Insights_May_Help_Kids_Battling_Developmental_Delays.html
  • DoctorsLounge: http://www.doctorslounge.com/index.php/news/pb/63934
  • The Monitor Daily: http://www.themonitordaily.com/genetics/211720/
  • Pulse Headlines: http://www.pulseheadlines.com/researchers-discover-genetic-conditions-genomewide-sequencing/32717/
  • NH Voice: http://nhv.us/content/56451-researchers-find-precise-genetic-cause-70-children-suffering
  • PerfScience: http://perfscience.com/content/2144051-genome-wide-sequencing-helps-find-doctors-personalized-medicine-children
  • Tech Times: http://www.techtimes.com/articles/161044/20160526/genetic-analysis-may-help-diagnose-treat-kids-with-mysterious-developmental-delays.htm
  • BioNews: http://www.bionews.org.uk/page_653147.asp
  • Neurology Advisor: http://www.neurologyadvisor.com/neurobehavioral-disorders/genetic-analysis-offers-options-for-some-developmental-delay/article/499111/
  • Genome Web: https://www.genomeweb.com/sequencing/exome-sequencing-prompts-treatment-changes-neurometabolic-disorders-44-percent-cases