- Investigator, BC Children’s Hospital
- Clinical Associate 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
Dr. Sinclair’s research interests focus on the laboratory diagnosis and pathophysiology of inborn errors of metabolism. This work is primarily translational in nature, using mass spectrometry approaches to apply basic research findings to the diagnosis, screening, and monitoring of patients with metabolic disorders. This work has included proteomic studies of murine models of lysosomal storage disorders for biomarker discovery and validation, along with population genetics studies of fatty acid oxidation variants and their potential clinical impact. Finally, the expansion of Newborn Metabolic screening in BC has provided a number of opportunities for the development of improved disease biomarkers and mass spectrometry-based diagnostic testing for rare diseases in BC.
- Fellowship (CCMG, Biochemical) University of British Columbia. 2007
- Postdoctoral Research Fellow, University of British Columbia. 2004
- PhD (Molecular Biology), University of Victoria. 2001
- Bachelor of Science (Genetics), University of British Columbia. 1995
- 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.
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).
- Laboratory based teaching