David E C Cole

University of Toronto, Toronto, Ontario, Canada

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Publications (246)1252.16 Total impact

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    ABSTRACT: The 22q11.2 deletion syndrome (DS) is a common multiple anomaly syndrome in which typical features include congenital heart defects, facial dysmorphism and palatal anomalies. Hypocalcemia due to hypoparathyroidism is a common endocrine manifestation resulting from variable parathyroid hypoplasia, but hypercalcemia has not previously been reported in 22q11.2 DS. Our patient is a 16-year-old adolescent male with dysmorphic facial features, delayed motor and speech development. At 2 years of age, 22q11.2 DS was confirmed by FISH. In contrast to hypoparathyroidism that is usually seen in 22q11.2 DS, this patient had early childhood-onset hypercalcemia with inappropriately high PTH levels and hypocalciuria. Genomic DNA was obtained from the proband and screened for calcium-sensing receptor (CASR) mutations with negative results. No parathyroid tissue could be localized by imaging or surgical exploration. Due to symptomatic hypercalcemia, the patient was treated with a calcimimetic (cinacalcet). During the treatment, plasma calcium normalized with mild symptoms of hypocalcemia. After discontinuation of cinacalcet, calcium returned to high pretreatment levels. Further DNA analysis of adaptor protein-2 σ subunit (AP2S1) showed a heterozygous missense mutation c.44 G>T resulting in a p.R15L substitution; the mutation was absent in the healthy parents and two siblings. Hypercalcemia in our patient with 22q11.2 DS could be explained by the de novo mutation in AP2S1. Identification of a genetic cause for hypercalcemia is helpful in guiding management and avoiding unnecessary treatment.
    The Journal of Clinical Endocrinology and Metabolism 05/2015; DOI:10.1210/jc.2015-1518 · 6.31 Impact Factor
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    ABSTRACT: Molecular diagnostics is increasingly embracing pharmagenomics. Here we discuss the role of GPCRs and their accessory proteins in disease, drawing on our experience addressing the role of the calcium sensing receptor polymorphisms/variation in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia in order to highlight the role that pharmacogenomics may play in personalized treatment.
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    ABSTRACT: Context: Glial cells missing-2 (GCM2) is key for parathyroid gland organogenesis. Its persistent expression in the adult parathyroid raises the possibility that overactive forms play a role in the evolution of parathyroid hyperactivity or tumorigenesis. A GCM2 c.844T>G; p.Y282D missense variant has been described within a transactivation inhibitory domain (amino acids 263 to 352). Objective: The aims of the study were to: 1) assess the frequency of Y282D in Italian primary hyperparathyroidism (PHPT) and control (C) populations, 2) test for association of 282D with PHPT and its phenotypic features, and 3) compare the transactivation potency of GCM2 282D relative to wild-type Y282. Subjects and Methods: A large southern Italian cohort (PHPT=310, C=433) and two replication cohorts from northern Italy. Association of 282D with PHPT was tested in all cohorts and with phenotypic features in the larger PHPT cohort. In vitro GCM promoter-luciferase reporter assay was conducted in HEK293 cells. Results: 282D was significantly increased in PHPT group [minor allele frequency (MAF)=0.066] compared to C (MAF=0.029, p=.0008) in the discovery cohort and was more prevalent in the replication cohorts. Combined analysis (PHPT=510, C=665) yielded a likelihood ratio of 2.27 (95% CI 1.50 - 3.42; p<0.0001). The 282D variant was not associated with serum calcium, phosphate, creatinine and PTH levels, nor bone mineral density (BMD), fractures or renal stones in the PHPT group. The 282D variant had significantly greater transcriptional activity than the wild-type Y282 (17x basal versus 12x basal; p<0.05). Conclusion: The higher frequency of GCM2 282D in PHPT and enhanced transcriptional activity of this variant supports the notion that it could contribute causally to parathyroid tumorigenesis.
    Journal of Clinical Endocrinology &amp Metabolism 10/2014; DOI:10.1210/jc.2014-2857 · 6.31 Impact Factor
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    ABSTRACT: Observational studies have shown that vitamin D binding protein (DBP) levels, a key determinant of 25-hydroxy-vitamin D (25OHD) levels, and 25OHD levels themselves both associate with risk of disease. If 25OHD levels have a causal influence on disease, and DBP lies in this causal pathway, then DBP levels should likewise be causally associated with disease. We undertook a Mendelian randomization study to determine whether DBP levels have causal effects on common calcemic and cardiometabolic disease.
    PLoS Medicine 10/2014; 11(10):e1001751. DOI:10.1371/journal.pmed.1001751 · 15.25 Impact Factor
  • Clinical Biochemistry 08/2014; 47(12):1149-1150. DOI:10.1016/j.clinbiochem.2014.06.048 · 2.23 Impact Factor
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    ABSTRACT: Background NSHPT is a life threatening disorder caused by homozygous inactivating calcium-sensing receptor (CASR) mutations. In some cases, the CaSR allosteric activator, cinacalcet, may reduce serum PTH and calcium levels, but surgery is the treatment of choice. Objective To describe a case of NSHPT unresponsive to cinacalcet. Patient and Results A 23-day-old girl was admitted with hypercalcaemia, hypotonia, bell-shaped chest and respiratory distress. The parents were first-degree cousins once removed. Serum Ca was 4.75 mmol/l (N: 2.10-2.62), P: 0.83 mmol/l (1.55-2.64), PTH: 1096 pg/ml (9–52) and urinary Ca/Cr ratio: 0.5 mg/mg. First, calcitonin was given (10 IU/kg x 4/day) and then two days later, pamidronate (0.5 mg/kg) for 2 days. Doses of cinacalcet were given daily from day 28 of life starting at 30 mg/m2 and increasing to 90 mg/m2 on day 43. On day 33, 6 days after pamidronate, serum Ca levels had fallen to 2.5 mmol/l, but thereafter rose to 5 mmol/l despite the cinacalcet. Total parathyroidectomy was performed at day 45. Hungry bone disease after surgery required daily Ca replacement and calcitriol for 18 days. At 3 months, the girl was mildly hypercalcemic, with no supplementation, and at 6 months, she developed hypocalcemia and has since been maintained on Ca and calcitriol. By CASR mutation analysis, the infant was homozygous and both parents heterozygous for a deletion-frameshift mutation. Conclusion The predicted nonfunctional CaSR is consistent with lack of response to cinacalcet, but total parathyroidectomy was successful. An empiric trial of the drug and/or prompt mutation testing should help minimize the period of unnecessary pharmacotherapy.
    Bone 07/2014; 64. DOI:10.1016/j.bone.2014.04.010 · 4.46 Impact Factor
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    ABSTRACT: Objective: To examine factors, in addition to bone mineral density (BMD), such as the common calcium-sensing receptor (CASR) gene polymorphisms, associated with vertebral fracture (VFx) risk in primary hyperparathyroidism (PHPT). . Design and Methods: Cross-sectional analysis of 266 Caucasian PHPT seen as outpatients. Calcium (sCa)-phosphate metabolism parameters were measured. BMD was assessed by dual-energy X-ray absorptiometry (DXA, expressed as Z-Score) at lumbar spine (Z-LS) and femoral neck (Z-FN), morphometric VFx by radiograph and CASR A986S/R990G genotypes by PCR amplification and genomic DNA sequencing. Results: Fractured patients (n=100, 37.6%) had lower sCa (10.8±0.7 mg/dL) and Z-LS BMD (-1.0±1.44), higher age (61±10 yrs) and prevalence (51%) of ≥1 S alleles of the CASR A986S single nucleotide polymorphism (SNP; AS/SS), than those not fractured (n =166, 11.2±1.0 mg/dL, -0.57±0.97, 58±13 yrs and 38% AS/SS, respectively, P<0.05 for all comparisons). Logistic regression, with VFx as dependent variable, showed independent risks associated with increased age (OR 1.03, 95% CI 1.01 - 1.06, P=0.006), decreased sCa (OR 1.86, 95% CI 1.28 - 2.7, P=0.001) and Z-LS BMD (OR 1.4, 95% CI 1.12 - 1.7, P=0.002) and presence of AS/SS (OR 1.8, 95% CI 1.1 - 2.9, P=0.05). The presence of two out of three (age ≥58 yr, sCa <10.8 and Z-LS BMD ≤ -1.0, and AS/SS genotype,) gave an overall OR of 4.2, 95% CI 2.25 - 7.85, P<0.0001). Conclusions: In PHPT, VFx is associated positively with age, negatively with sCa and spinal BMD, and presence of at least one copy of the CASR A986S SNP.
    06/2014; 171(3). DOI:10.1530/EJE-14-0343
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    ABSTRACT: Two single-nucleotide polymorphisms (SNPs) at the calcium-sensing receptor (CASR) gene were previously associated with kidney stones in patients with primary hyperparathyroidism (PHPT): rs1501899, likely associated with a decrease in CASR expression, and Arg990Gly, causing a gain of CASR function. To evaluate the interaction of these two SNPs in the stone risk, we tested the association of stones with the genotype at both SNPs in PHPT patients and the association of rs1501899 with CASR expression as messenger RNA (mRNA) in human kidney samples. Two hundred and ninety-six PHPT patients were genotyped at the rs1501899 and Arg990Gly SNPs. Minor allele frequency at tested SNPs was higher in PHPT stone formers relative to non-stone forming patients. PHPT patients carrying one or two copies of the minor allele at both rs1501899 and Arg990Gly (n = 16) had the maximal risk of stones (odds ratio, OR 8.3) and higher serum ionized calcium compared with homozygous patients for the wild-type allele at both SNPs. CASR expression as mRNA was measured by real time polymerase chain reaction (PCR) in normal kidney medulla samples from 109 subjects. CASR mRNA was significantly lower in medulla samples from homozygotes for the minor allele at rs1501899 than in subjects with other genotypes. We conclude that the simultaneous presence of the minor allele at rs1501899 and Arg990Gly may amplify the kidney stone risk in PHPT patients, despite their apparently opposite effects on CASR function in the kidney.
    Journal of nephrology 05/2014; 28(1). DOI:10.1007/s40620-014-0106-8 · 2.00 Impact Factor
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    ABSTRACT: Potential vitamin D-related influences on inflammatory diseases such as asthma are controversial, including the suggestion that vitamin D insufficiency is associated with increased asthma morbidity. Vitamin D-binding protein transports vitamin D metabolites in the circulation. Single nucleotide polymorphisms in the GC gene encoding vitamin D-binding protein are associated with circulating vitamin D metabolite levels in healthy infants and toddlers. To test the hypothesis that GC single nucleotide polymorphisms encoding the D432E and T436K variants predict subsequent development of asthma in healthy children. A retrospective medical record review was performed to determine the development of asthma in 776 children in whom GC genotype, vitamin D-binding protein concentration, and circulating 25-hydroxyvitamin D had been determined at 6 to 36 months of age. Demographic and detailed current clinical data were collected and criteria for asthma were recorded. GC genotype was available for 463 subjects. After an initial analysis of all subject data, the analysis was limited to the predominant Hispanic population (72.1%) to minimize potential confounding effects of ethnicity. Asthma was diagnosed in 87 children (26%). Subjects with the GC genotype encoding the ET/ET (Gc1s/Gc1s) variant had lower odds of developing asthma, representing a protective effect compared with subjects with the DT/DT (Gc1f/Gc1f) variant. In the Hispanic population of inner-city New Haven, Connecticut, the ET/ET (Gc1s/Gc1s) genotype of vitamin D-binding protein might confer protection against the development of asthma compared with the wild-type genotype DT/DT (Gc1f/Gc1f).
    Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 04/2014; DOI:10.1016/j.anai.2014.03.017 · 2.75 Impact Factor
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    ABSTRACT: Context: Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder with three known subtypes: FHH1, FHH2, and FHH3. About 65% of FHH cases are FHH1, caused by inactivating mutations of the calcium-sensing receptor (CASR) gene. FHH3 was recently found to be caused by codon Arg15 (p.R15) mutations in the adaptor-related protein complex 2, sigma-2 subunit that interacts with the CaSR, and is encoded by the AP2S1 gene. Objective: To assess the prevalence of AP2S1 mutations, and describe the phenotype of FHH3, in an independent cohort of FHH subjects lacking CASR mutations. Patients and Methods: Thirty-nine patients presenting with some combination of hypercalcemia, hypermagnesemia, non-suppressed serum PTH levels, and reduced urinary calcium excretion were studied. Exon 2 of the AP2S1 gene was PCR amplified from patient genomic DNA and Sanger sequenced. The presence of p.R15 mutations was confirmed by restriction enzyme analysis. Results: Five of the 39 subjects had AP2S1 p.R15 mutations - a frequency of 13%. The three recurrent mutations reported previously were all found in our cohort (p.R15C in 2, p.R15L in 2, and p.R15H in one subject). The FHH3 phenotype did not differ materially from that of FHH1 due to CASR mutations. Conclusions: The results affirm that a significant number of patients suspected of having FHH but proven negative for CASR mutation have AP2S1 p.R15 mutations. Screening for AP2S1 p.R15 mutations in such cases should be considered, given the clinical benefits (avoiding unnecessary parathyroidectomy) that have already been demonstrated for CASR screening in FHH1.
    The Journal of Clinical Endocrinology and Metabolism 04/2014; 99(7):jc20141120. DOI:10.1210/jc.2014-1120 · 6.31 Impact Factor
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    ABSTRACT: Pharmacogenetics investigates the influence of genetic variants on physiological phenotypes related to drug response and disease, while pharmacogenomics takes a genome-wide approach to advancing this knowledge. Both play an important role in identifying responders and nonresponders to medication, avoiding adverse drug reactions, and optimizing drug dose for the individual. G protein-coupled receptors (GPCRs) are the primary target of therapeutic drugs and have been the focus of these studies. With the advance of genomic technologies, there has been a substantial increase in the inventory of naturally occurring rare and common GPCR variants. These variants include single-nucleotide polymorphisms and insertion or deletions that have potential to alter GPCR expression of function. In vivo and in vitro studies have determined functional roles for many GPCR variants, but genetic association studies that define the physiological impact of the majority of these common variants are still limited. Despite the breadth of pharmacogenetic data available, GPCR variants have not been included in drug labeling and are only occasionally considered in optimizing clinical use of GPCR-targeted agents. In this chapter, pharmacogenetic and genomic studies on GPCR variants are reviewed with respect to a subset of GPCR systems, including the adrenergic, calcium sensing, cysteinyl leukotriene, cannabinoid CB1 and CB2 receptors, and the de-orphanized receptors such as GPR55. The nature of the disruption to receptor function is discussed with respect to regulation of gene expression, expression on the cell surface (affected by receptor trafficking, dimerization, desensitization/downregulation), or perturbation of receptor function (altered ligand binding, G protein coupling, constitutive activity). The large body of experimental data generated on structure and function relationships and receptor-ligand interactions are being harnessed for the in silico functional prediction of naturally occurring GPCR variants. We provide information on online resources dedicated to GPCRs and present applications of publically available computational tools for pharmacogenetic studies of GPCRs. As the breadth of GPCR pharmacogenomic data becomes clearer, the opportunity for routine assessment of GPCR variants to predict disease risk, drug response, and potential adverse drug effects will become possible.
    Methods in Molecular Biology 01/2014; 1175:189-242. DOI:10.1007/978-1-4939-0956-8_9 · 1.29 Impact Factor
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    ABSTRACT: Genetic variations in G protein-coupled receptor genes (GPCRs) disrupt GPCR function in a wide variety of human genetic diseases. In vitro strategies and animal models have been used to identify the molecular pathologies underlying naturally occurring GPCR mutations. Inactive, overactive, or constitutively active receptors have been identified that result in pathology. These receptor variants may alter ligand binding, G protein coupling, receptor desensitization and receptor recycling. Receptor systems discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone (FSH), luteinizing hormone, gonadotropin-releasing hormone (GNRHR), adrenocorticotropic hormone, vasopressin, endothelin-β, purinergic, and the G protein associated with asthma (GPRA or neuropeptide S receptor 1 (NPSR1)). The role of activating and inactivating calcium-sensing receptor (CaSR) mutations is discussed in detail with respect to familial hypocalciuric hypercalcemia (FHH) and autosomal dominant hypocalemia (ADH). The CASR mutations have been associated with epilepsy. Diseases caused by the genetic disruption of GPCR functions are discussed in the context of their potential to be selectively targeted by drugs that rescue altered receptors. Examples of drugs developed as a result of targeting GPCRs mutated in disease include: calcimimetics and calcilytics, therapeutics targeting melanocortin receptors in obesity, interventions that alter GNRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor congenital bleeding phenotype. De-orphanization projects have identified novel disease-associated receptors, such as NPSR1 and GPR35. The identification of variants in these receptors provides genetic reagents useful in drug screens. Discussion of the variety of GPCRs that are disrupted in monogenic Mendelian disorders provides the basis for examining the significance of common pharmacogenetic variants.
    Methods in Molecular Biology 01/2014; 1175:153-187. DOI:10.1007/978-1-4939-0956-8_8 · 1.29 Impact Factor
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    ABSTRACT: Background Potential vitamin D–related influences on inflammatory diseases such as asthma are controversial, including the suggestion that vitamin D insufficiency is associated with increased asthma morbidity. Vitamin D–binding protein transports vitamin D metabolites in the circulation. Single nucleotide polymorphisms in the GC gene encoding vitamin D–binding protein are associated with circulating vitamin D metabolite levels in healthy infants and toddlers. Objective To test the hypothesis that GC single nucleotide polymorphisms encoding the D432E and T436K variants predict subsequent development of asthma in healthy children. Methods A retrospective medical record review was performed to determine the development of asthma in 776 children in whom GC genotype, vitamin D–binding protein concentration, and circulating 25-hydroxyvitamin D had been determined at 6 to 36 months of age. Demographic and detailed current clinical data were collected and criteria for asthma were recorded. Results GC genotype was available for 463 subjects. After an initial analysis of all subject data, the analysis was limited to the predominant Hispanic population (72.1%) to minimize potential confounding effects of ethnicity. Asthma was diagnosed in 87 children (26%). Subjects with the GC genotype encoding the ET/ET (Gc1s/Gc1s) variant had lower odds of developing asthma, representing a protective effect compared with subjects with the DT/DT (Gc1f/Gc1f) variant. Conclusion In the Hispanic population of inner-city New Haven, Connecticut, the ET/ET (Gc1s/Gc1s) genotype of vitamin D–binding protein might confer protection against the development of asthma compared with the wild-type genotype DT/DT (Gc1f/Gc1f).
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    ABSTRACT: The identification and characterization of the genes encoding G protein-coupled receptors (GPCRs) and the proteins necessary for the processes of ligand binding, GPCR activation, inactivation, and receptor trafficking to the membrane are discussed in the context of human genetic disease. In addition to functional GPCR variants, the identification of genetic disruptions affecting proteins necessary to GPCR functions have provided insights into the function of these pathways. Gsα and Gβ subunit polymorphisms have been found to result in complex phenotypes. Disruptions in accessory proteins that normally modify or organize heterotrimeric G-protein coupling may also result in disease states. These include the contribution of variants of the regulator of G protein signaling (RGS) protein to hypertension; the role variants of the activator of G protein signaling (AGS) proteins to phenotypes (such as the type III AGS8 variant to hypoxia); the contribution of G protein-coupled receptor kinase (GRK) proteins, such as GRK4, in disorders such as hypertension. The role of accessory proteins in GPCR structure and function is discussed in the context of genetic disorders associated with disruption of the genes that encode them. An understanding of the pharmacogenomics of GPCR and accessory protein signaling provides the basis for examining both GPCR pharmacogenetics and the genetics of monogenic disorders that result from disruption of given receptor systems.
    Methods in Molecular Biology 01/2014; 1175:121-152. DOI:10.1007/978-1-4939-0956-8_7 · 1.29 Impact Factor
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    ABSTRACT: We sequenced the genomes of a ~7,000 year old farmer from Germany and eight ~8,000 year old hunter-gatherers from Luxembourg and Sweden. We analyzed these and other ancient genomes1–4 with 2,345 contemporary humans to show that most present Europeans derive from at least three highly differentiated populations: West European Hunter-Gatherers (WHG), who contributed ancestry to all Europeans but not to Near Easterners; Ancient North Eurasians (ANE) related to Upper Paleolithic Siberians3, who contributed to both Europeans and Near Easterners; and Early European Farmers (EEF), who were mainly of Near Eastern origin but also harbored WHG-related ancestry. We model these populations’ deep relationships and show that EEF had ~44% ancestry from a “Basal Eurasian” population that split prior to the diversification of other non-African lineages.
    Nature 12/2013; 513(7518). DOI:10.1038/nature13673 · 42.35 Impact Factor
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    ABSTRACT: Hyperparathyroidism Jaw-Tumour Syndrome (HPT-JT) is characterized by primary hyperparathyroidism (PHPT), maxillary/mandible ossifying fibromas and by parathyroid carcinoma in 15% of cases. Inactivating mutations of the tumour suppressor CDC73/HRPT2 gene have been found in HPT-JT patients and also as genetic determinants of sporadic parathyroid carcinoma/atypical adenomas and, rarely, typical adenomas, in familial PHPT. Here we report the genetic and molecular analysis of the CDC73/HRPT2 gene in three patients affected by PHPT due to atypical and typical parathyroid adenomas, in one case belonging to familial PHPT. Flag-tagged WT and mutant CDC73/HRPT2 proteins were transiently transfected in HEK293 cells and functional assays were performed in order to investigate the effect of the variants on the whole protein expression, nuclear localization and cell overgrowth induction. We identified four CDC73/HRPT2 gene mutations, three germline (c.679_680delAG, p.Val85_Val86del and p.Glu81_Pro84del), one somatic (p.Arg77Pro). In three cases the mutation was located within the Nucleolar Localisation Signals (NoLS). The three NoLS variants led to instability either of the corresponding mutated protein or mRNA or both. When transfected in HEK293 cells, NoLS mutated proteins mislocalized with a predeliction for cytoplasmic or nucleo-cytoplasmic localization and, finally, they resulted in overgrowth, consistent with a dominant negative interfering effect in the presence of the endogenous protein.
    PLoS ONE 12/2013; 8(12):e82292. DOI:10.1371/journal.pone.0082292 · 3.53 Impact Factor
  • Geoffrey N Hendy, David E C Cole
    The Journal of Clinical Endocrinology and Metabolism 12/2013; 98(12):4666-9. DOI:10.1210/jc.2013-3616 · 6.31 Impact Factor
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Publication Stats

6k Citations
1,252.16 Total Impact Points

Institutions

  • 1986–2014
    • University of Toronto
      • • Department of Laboratory Medicine and Pathobiology
      • • Department of Medicine
      • • Department of Obstetrics and Gynaecology
      • • Department of Paediatrics
      • • Department of Nutritional Sciences
      Toronto, Ontario, Canada
  • 1999–2013
    • Sunnybrook Health Sciences Centre
      • • Division of Medical Oncology and Hematology
      • • Department of Medicine
      • • Division of Rheumatology
      Toronto, Ontario, Canada
  • 2010
    • Women's College Hospital
      Toronto, Ontario, Canada
  • 2008
    • IRCCS Ospedale Casa Sollievo della Sofferenza
      Giovanni Rotondo, Apulia, Italy
  • 2004–2007
    • University of Verona
      • Section of Internal Medicine
      Verona, Veneto, Italy
  • 2006
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2005
    • SickKids
      • Division of Clinical and Metabolic Genetics
      Toronto, Ontario, Canada
    • UHN: Toronto General Hospital
      Toronto, Ontario, Canada
  • 2002
    • University Health Network
      Toronto, Ontario, Canada
  • 2001
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
    • Association for Clinical Biochemistry
      United Kingdom
  • 2000
    • Childcare Resource and Research Unit
      Toronto, Ontario, Canada
  • 1980–1997
    • McGill University
      • Department of Pediatrics
      Montréal, Quebec, Canada
  • 1996
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 1995
    • University of British Columbia - Vancouver
      • Department of Pediatrics
      Vancouver, British Columbia, Canada
  • 1984–1993
    • Dalhousie University
      • • Department of Mathematics and Statistics
      • • Department of Pediatrics
      Halifax, Nova Scotia, Canada
  • 1987
    • Mount Saint Vincent University
      Halifax, Nova Scotia, Canada