• Sinclair, Graham

    Investigator, BC Children's Hospital

    Clinical Professor, Department of Pathology & Laboratory Medicine, Faculty of Medicine, University of British Columbia
    Biochemical Geneticist, BC Newborn Screening Laboratory, BC Women's Hospital & Health Centre

    Degrees / Designations
    PhD, FCCMG
    Primary Area of Research
    Childhood Diseases
    Secondary Area(s) of Research
    604-875-2345 ext. 7450
    Lab Phone
    Mailing Address
    BC Children's Hospital
    Department of Pathology
    Room 2F24
    4480 Oak Street
    Vancouver, BC V6H 3V4
    Affiliate Websites
    Research Areas
    • Newborn screening
    • Inborn errors of metabolism
    • Fatty acid oxidation disorders
    • Mass Spectrometry
    • Aboriginal Health
    • Lysosomal storage disorders

    Newborn screening is designed to identify infants with treatable rare disorders at birth in order to start therapies before the infants get sick. These disorders can lead to developmental disability, growth failure, liver disease, seizures, and even death if untreated. The investigation of potential new candidate disorders for screening, evaluation of new screening tests or improvement of existing methods, and the measurement of the long-term effectiveness of screening to improve health are all active aspects of my research.

    We have a focus on disorders affecting the use of fats as an energy source and a variant of one of these disorders that is common to coastal BC First Nations. This variant is associated with an increased risk of infant death, but may also have benefits related to traditional diets.. Investigation of this variant will lead to a better understanding of its clinical impact and help to identify effective interventions.

    Current Projects
    CPT1a P479L Variant:
    The carnitine palmitoyltransferase 1A (CPT1a) p.P479L variant has recently been found to be common in coastal First Nations communities in BC and also in aboriginal populations in Alaska, NWT, Nunavut, and Greenland. CPT1a is a central enzyme in fatty acid oxidation and is required for import of fatty acids into the mitochondrion to be utilized as an energy source. This variant (p.P479L) was first identified in individuals with symptoms suggestive of a fatty acid oxidation disorder and has been shown to decrease CPT1a activity in vitro. We have performed a population based retrospective study in BC to confirm that the variant is common to coastal communities and is associated with a small increased risk in sudden unexpected death in infancy. Similar results have been found in Nunavut and Alaska. There is evidence, however, that this variant is also associated with improved plasma lipid profiles and obesity markers in adults suggesting a selective advantage, possibly related to alterations in the regulation of enzyme activity. We are continuing to investigate both the potential harms and benefits of this variant through prospective studies with community participants and basic biochemical investigations using in vitro methods to better understand the biochemical and clinical implications of this common variant.

    GAMT Deficiency Screening:
    Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited disorder of creatine biosynthesis that leads to severe neurological complications in affected children. Treatment with supplemental creatine and other dietary restrictions has been shown to be effective when initiated early. This makes GAMT deficiency a potential candidate for newborn screening. We are investigating the carrier frequency for GAMT deficiency in BC to determine a theoretical disease incidence and evaluating the measurement of guanidinoacetate (GAA) in bloodspots as a potential approach to population-wide newborn screening for this treatable disorder.

    Second-Tier Testing for Newborn Screening:
    The performance of newborn screening programs can be defined by the positive predictive value (PPV) of the screening tests, a major component of which is the false positive rate. Traditional approaches to screening for some disorders have an unacceptable false positive rate, but attempts to minimize this rate by raising screening cutoffs can lead to increased false negative rates and the associated devastating outcomes of a missed case. We have developed a number of second-tier screening tests, sampled from the same original newborn screening bloodspot, as an approach to reduce false positive rates without negatively affecting the sensitivity of testing. Our work involves the development of a number of mass spectrometry-based testing approaches and evaluation of the performance impacts of these tests in routine use. To date, we have implemented second-tier testing for congenital adrenal hyperplasia (CAH) and Maple Syrup Urine Disease (MSUD) and have methods in development for Propionic Acidemia (PA), Methylmalonic Acidemia (MMA), and Homocystinuria (HCY).
    Selected Publications

    Schutz PW, Struys EA, Sinclair G, Stockler S. Protective effects of D-3-hydroxybutyrate and propionate during hypoglycemia coma: Clinical and biochemical insights from infant rats. (2011) Molecular Genetics and Metabolism. In Press.

    McHugh DMS, Cameron CA, Abdenur JE, et al. Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry : A worldwide collaborative project. (2011) Genetics in Medicine. Feb 15 [EPub ahead of print] PMID: 21325949.

    Alfadhel M, Lillquist YP, Waters PJ, Sinclair G, Struys E, McFadden D, Hendson G, Hyams L, Shoffner J, Vallance HD. Infantile cardioencephalopathy due to a COX 15 gene defect: case report and review. (2011) American Journal of Medical Genetics. Mar 15 EPub ahead of print] PMID:21412973.

    Li M, Al-Sarraf A, Sinclair G, Frolich J. Exacerbation of symptoms of fish-odor syndrome by rosuvastatin. (2011) Canadian Medical Association Journal, In press.

    Zay, A., Patrick, C., Sinclair, G., Choy, FYM. Glycine cleavage enzyme complex: Molecular cloning and expression of the H-protein cDNA from cultured human skin fibroblasts. (2011) Biochemistry and Cell Biology. In Press.

    Collins SA, Sinclair G, McIntosh S, Bamforth F, Thompson R, Sobol I, Osborne G, Corriveau A, Santos M, Hanley B, Greenberg C, Vallance H, Arbour L. Carnitine palmitoyltransferase 1A (CPT1a) P479L prevalence in live newborns in Yukon, Northwest Territories, and Nunavut. (2010) Molecular Genetics and Metabolism. 101(2-3):200-4.

    Mercimek-Mahmutoglu, S., Connolly, M., Poskitt, K., Horvath, G., Lowry, N., Salomons, G., Casey, B., Sinclair, G., Davis, C., Jakobs, C., Stockler-Ipsirolgu, S. Treatment of intractable epilepsy in a female with SLC6A8 deficiency. (2010) Molecular Genetics and Metabolism. 101(4):409-412.

    Greenberg, C.R., Dilling, L.A., Thompson, J.R., Seargeant, L.E., Haworth, J.C., Phillips, S., Chan, A., Vallance, H.D., Waters, P.J., Sinclair, G., Lillquist, Y., Wanders, R.J.A, Olpin, S.A. (2009) The paradox of the carnitine palmitoyltransferase I P479L variant in Canadian aboriginal populations. MOLECULAR GENETICS AND METABOLISM, 96(4):201-7.

    Randal, D.R., Collobong, K.E., Hemmelgarn, H., Sinclair, G.B., Hetty, E., Thomas, A., Bodamer, O.A., Volkmar, B., Fernhoff, P.M., Casey, R., Chan, A.K., Mitchell, G., Stockler, S., Melancon, S., Rupar, T., Clarke, L.A. (2008) Heparin cofactor II-thrombin complex: A biomarker of MPS disease. MOLECULAR GENETICS AND METABOLISM. 94(4):456-61.

    Sinclair, G.B., Jevon, G., Colobong, K.E., Randall, D.R., Choy, F.Y.M.. and Clarke, L.A. (2007) Generation of a conditional knockout of murine glucocerebrosidase: Utility for the study of Gaucher disease. MOLECULAR GENETICS AND METABOLISM (90)2:148-156

    Randall, D.R., Sinclair, G.B., Colobong, K.E., Hetty, E. and Clarke, L.A. (2006) Heparin cofactor II-thrombin complex in MPS I: A biomarker of MPS disease. MOLECULAR GENETICS AND METABOLISM, 88(3):235-243.

    BC Children's Hospital Telethon Competition: Development of methods for screening X-linked creatine transporter deficiency (X-CRTRD) in mental retardation.; COMP; $9,910 CDN; Principal Investigator: Sylvia Stockler; Coinvestigators: Hilary Vallance, Graham Sinclair.

    BC Children's Hospital Telethon Competition; Determination of the incidence and natural history of carnitine palmitoyltransferase I deficiency in BC First Nations; COMP; $22,000CDN; Principal Investigator: Hilary Vallance; Coinvestigators: Graham Sinclair, Laura Arbour.
    Honours & Awards
    2004 Bluma Tischler Postdoctoral Fellowship; $22,500CDN
    2004 Garrod Association Biochemical Genetics Fellowship; $25,000CDN
    2003 Bertram Hoffmeister Postdoctoral Fellowship; $38,000CDN
    2002 Mining for Miracles Postdoctoral Fellowship; $35,000CDN
    2001 UVIC Graduate Student Award for Excellence in Teaching
    Research Group Members