Patrick F Chinnery

The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-on-Tyne, England, United Kingdom

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Publications (435)3121.65 Total impact

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    ABSTRACT: Myoclonus dystonia syndrome (MDS) is a young-onset movement disorder. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. We assembled the largest cohort of MDS patients to date, and determined the frequency and type of SGCE mutations. The aim was to establish the motor phenotype in mutation carriers and utility of current diagnostic criteria. Eighty-nine probands with clinical features compatible with MDS were recruited from the UK and Ireland. Patients were phenotypically classified as "definite", "probable" or "possible" MDS according to previous guidelines. SGCE was analyzed using direct sequencing and copy number variant analysis. In those where no mutation was found, DYT1 (GAG deletion), GCH1, THAP1 and NKX2.1 genes were also sequenced. Nineteen (21.3 %) probands had an SGCE mutation. Three patterns of motor symptoms emerged: (1) early childhood onset upper body myoclonus and dystonia, (2) early childhood onset lower limb dystonia, progressing later to more pronounced myoclonus and upper body involvement, and (3) later childhood onset upper body myoclonus and dystonia with evident cervical involvement. Five probands had large contiguous gene deletions ranging from 0.7 to 2.3 Mb in size with distinctive clinical features, including short stature, joint laxity and microcephaly. Our data confirms that SGCE mutations are most commonly identified in MDS patients with (1) age at onset ≤10 years and (2) predominant upper body involvement of a pure myoclonus-dystonia. Cases with whole SGCE gene deletions had additional clinical characteristics, which are not always predicted by deletion size or gene involvement.
    Journal of neurology. 09/2014;
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    ABSTRACT: Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission but has not been previously asso-ciated with human disease. Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family. Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model. These findings indicate that Synaptotagmin 2 regulates neurotransmitter release at human peripheral motor nerve terminals. In addition, mutations in the Syn-aptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with heredi-tary motor axonopathies. Synaptotagmin 2 (SYT2), a synaptic vesicle protein, is the major isoform of the synaptotagmin family at mammalian neuromuscular junctions (NMJs) and functions as a cal-cium sensor for neurotransmission. 1,2 The C2B domain
    The American Journal of Human Genetics 09/2014; · 11.20 Impact Factor
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    ABSTRACT: Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.
    Journal of neurology. 09/2014;
  • Patrick Yu-Wai-Man, Patrick F Chinnery
    Brain : a journal of neurology. 08/2014;
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    ABSTRACT: Background Sengers syndrome is an autosomal recessive condition characterized by congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the acylglycerol kinase (AGK) gene have been recently described as the cause of Sengers syndrome in nine families.Methods We investigated the clinical and molecular features of Sengers syndrome in seven new families; five families with the severe and two with the milder form.ResultsSequence analysis of AGK revealed compound heterozygous or homozygous predicted loss-of-function mutations in all affected individuals. A total of eight different disease alleles were identified, of which six were novel, homozygous c.523_524delAT (p.Ile175Tyrfs*2), c.424-1G¿>¿A (splice site), c.409C¿>¿T (p.Arg137*) and c.877¿+¿3G¿>¿T (splice site), and compound heterozygous c.871C¿>¿T (p.Gln291*) and c.1035dup (p.Ile346Tyrfs*39). All patients displayed perinatal or early-onset cardiomyopathy and cataract, clinical features pathognomonic for Sengers syndrome. Other common findings included blood lactic acidosis and tachydyspnoea while nystagmus, eosinophilia and cervical meningocele were documented in only either one or two cases. Deficiency of the adenine nucleotide translocator was found in heart and skeletal muscle biopsies from two patients associated with respiratory chain complex I deficiency. In contrast to previous findings, mitochondrial DNA content was normal in both tissues.Conclusion We compare our findings to those in 21 previously reported AGK mutation-positive Sengers patients, confirming that Sengers syndrome is a clinically recognisable disorder of mitochondrial energy metabolism.
    Orphanet Journal of Rare Diseases 08/2014; 9(1):119. · 4.32 Impact Factor
  • Brendan Ai Payne, Kristian Gardner, Patrick F Chinnery
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    ABSTRACT: Mitochondrial DNA (mtDNA) mutations cause neurological and multi-system disease. Somatic (acquired) mtDNA mutations are also associated with degenerative diseases and with normal human ageing. It is well established that certain nucleoside analogue reverse transcriptase inhibitor (NRTI) anti-retroviral drugs cause inhibition of the mtDNA polymerase, pol γ, leading to a reduction in mtDNA content (depletion). Given this effect of NRTI therapy on mtDNA replication, it is plausible that NRTI treatment may also lead to increased mtDNA mutations. Here we review recent evidence for an effect of HIV infection or NRTI therapy on mtDNA mutations, as well as discussing the methodological challenges in addressing this question. Finally, we discuss the possible implications for HIV-infected persons, with particular reference to ageing.
    Antiviral therapy 07/2014; · 3.07 Impact Factor
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    Patrick Yu-Wai-Man, Patrick F Chinnery
    Brain : a journal of neurology. 07/2014;
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    ABSTRACT: Mitochondrial disorders have emerged as a common cause of inherited disease, but their diagnosis remains challenging. Multiple respiratory chain complex defects are particularly difficult to diagnose at the molecular level because of the massive number of nuclear genes potentially involved in intramitochondrial protein synthesis, with many not yet linked to human disease.
    JAMA The Journal of the American Medical Association 07/2014; 312(1):68-77. · 29.98 Impact Factor
  • Roger G Whittaker, Patrick F Chinnery, James A L Miller
    Neurology 06/2014; 82(24):e220-1. · 8.25 Impact Factor
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    ABSTRACT: Purpose:Mitochondrial disorders are a common cause of inherited metabolic disease and can be due to mutations affecting mitochondrial DNA or nuclear DNA. The current diagnostic approach involves the targeted resequencing of mitochondrial DNA and candidate nuclear genes, usually proceeds step by step, and is time consuming and costly. Recent evidence suggests that variations in mitochondrial DNA sequence can be obtained from whole-exome sequence data, raising the possibility of a comprehensive single diagnostic test to detect pathogenic point mutations.Methods:We compared the mitochondrial DNA sequence derived from off-target exome reads with conventional mitochondrial DNA Sanger sequencing in 46 subjects.Results:Mitochondrial DNA sequences can be reliably obtained using three different whole-exome sequence capture kits. Coverage correlates with the relative amount of mitochondrial DNA in the original genomic DNA sample, heteroplasmy levels can be determined using variant and total read depths, and-providing there is a minimum read depth of 20-fold-rare sequencing errors occur at a rate similar to that observed with conventional Sanger sequencing.Conclusion:This offers the prospect of using whole-exome sequence in a diagnostic setting to screen not only all protein coding nuclear genes but also all mitochondrial DNA genes for pathogenic mutations. Off-target mitochondrial DNA reads can also be used to assess quality control and maternal ancestry, inform on ethnic origin, and allow genetic disease association studies not previously anticipated with existing whole-exome data sets.Genet Med advance online publication 05 June 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.66.
    Genetics in medicine: official journal of the American College of Medical Genetics 06/2014; · 3.92 Impact Factor
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    ABSTRACT: Massively parallel resequencing of mitochondrial DNA (mtDNA) has led to significant advances in the study of heteroplasmic mtDNA variants in health and disease, but confident resolution of very low-level variants (<2% heteroplasmy) remains challenging due to the difficulty in distinguishing signal from noise at this depth. However, it is likely that such variants are precisely those of greatest interest in the study of somatic (acquired) mtDNA mutations. Previous approaches to this issue have included the use of controls such as phage DNA and mtDNA clones, both of which may not accurately recapitulate natural mtDNA. We have therefore explored a novel approach, taking advantage of mtDNA with a known stereotyped mutational motif (nAT>C, from patient with MNGIE, mitochondrial neurogastrointestinal encephalomyopathy) and comparing mutational pattern distribution with healthy mtDNA by ligation-mediated deep resequencing (Applied Biosystems SOLiD). We empirically derived mtDNA-mutant heteroplasmy detection limits, demonstrating that the presence of stereotypical mutational motif could be statistically validated for heteroplasmy thresholds ≥0.22% (P=0.034). We therefore provide empirical evidence from biological samples that very low-level mtDNA mutants can be meaningfully resolved by massively parallel resequencing, confirming the utility of the approach for studying somatic mtDNA mutation in health and disease. Our approach could also usefully be employed in other settings to derive platform-specific deep resequencing resolution limits.European Journal of Human Genetics advance online publication, 4 June 2014; doi:10.1038/ejhg.2014.96.
    European journal of human genetics: EJHG 06/2014; · 3.56 Impact Factor
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    ABSTRACT: Objective Polymerase gamma (POLG) mutations are a common cause of mitochondrial disease and have also been linked to neurodegeneration and aging. We studied the molecular mechanisms underlying POLG-related neurodegeneration using post-mortem tissue from a large number of patients.Methods Clinical information was available from all subjects. Formalin-fixed and frozen brain tissue from 15 patients and 23 controls were studied employing a combination of histopathology, immunohistochemistry and molecular studies of microdissected neurons.ResultsThe primary consequence of POLG mutation in neurons is mitochondrial DNA depletion. This was already present in infants with little evidence of neuronal loss or mitochondrial dysfunction. With longer disease duration, we found an additional, progressive accumulation of mitochondrial DNA deletions and point mutations accompanied by increasing numbers of complex I deficient neurons. Progressive neurodegeneration primarily affected the cerebellar systems and dopaminergic cells of the substantia nigra. Superimposed on this chronic process were acute, focal cortical lesions that correlated with epileptogenic foci and which showed massive neuronal loss.InterpretationPOLG mutations appear to compromise neuronal respiration via a combination of early and stable depletion and a progressive somatic mutagenesis of the mitochondrial genome. This leads to two distinct, but overlapping biological processes: a chronic neurodegeneration reflected clinically by progressive ataxia and cognitive impairment, and an acute focal neuronal necrosis that appears related to the presence of epileptic seizures. Our findings offer an explanation of the acute-on-chronic clinical course of this common mitochondrial encephalopathy. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 05/2014; · 11.19 Impact Factor
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    ABSTRACT: Mitochondrial DNA (mtDNA) is highly polymorphic at the population level, and specific mtDNA variants affect mitochondrial function. With emerging evidence that mitochondrial mechanisms are central to common human diseases, it is plausible that mtDNA variants contribute to the "missing heritability" of several complex traits. Given the central role of mtDNA genes in oxidative phosphorylation, the same genetic variants would be expected to alter the risk of developing several different disorders, but this has not been shown to date. Here we studied 38,638 individuals with 11 major diseases, and 17,483 healthy controls. Imputing missing variants from 7,729 complete mitochondrial genomes, we captured 40.41% of European mtDNA variation. We show that mtDNA variants modifying the risk of developing one disease also modify the risk of developing other diseases, thus providing independent replication of a disease association in different case and control cohorts. High-risk alleles were more common than protective alleles, indicating that mtDNA is not at equilibrium in the human population, and that recent mutations interact with nuclear loci to modify the risk of developing multiple common diseases.
    PLoS Genetics 05/2014; 10(5):e1004369. · 8.52 Impact Factor
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    ABSTRACT: Identifying the genetic basis for mitochondrial diseases is technically challenging given the size of the mitochondrial proteome and the heterogeneity of disease presentations. Using next-generation exome sequencing, we identified in a patient with severe combined mitochondrial respiratory chain defects and corresponding perturbation in mitochondrial protein synthesis, a homozygous p.Arg323Gln mutation in TRIT1. This gene encodes human tRNA isopentenyltransferase, which is responsible for i6A37 modification of the anticodon loops of a small subset of cytosolic and mitochondrial tRNAs. Deficiency of i6A37 was previously shown in yeast to decrease translational efficiency and fidelity in a codon-specific manner. Modelling of the p.Arg323Gln mutation on the co-crystal structure of the homologous yeast isopentenyltransferase bound to a substrate tRNA, indicates that it is one of a series of adjacent basic side chains that interact with the tRNA backbone of the anticodon stem, somewhat removed from the catalytic center. We show that patient cells bearing the p.Arg323Gln TRIT1 mutation are severely deficient in i6A37 in both cytosolic and mitochondrial tRNAs. Complete complementation of the i6A37 deficiency of both cytosolic and mitochondrial tRNAs was achieved by transduction of patient fibroblasts with wild-type TRIT1. Moreover, we show that a previously-reported pathogenic m.7480A>G mt-tRNASer(UCN) mutation in the anticodon loop sequence A36A37A38 recognised by TRIT1 causes a loss of i6A37 modification. These data demonstrate that deficiencies of i6A37 tRNA modification should be considered a potential mechanism of human disease caused by both nuclear gene and mitochondrial DNA mutations while providing insight into the structure and function of TRIT1 in the modification of cytosolic and mitochondrial tRNAs.
    PLoS Genetics 04/2014; 10(6):e1004424. · 8.52 Impact Factor
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    ABSTRACT: Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygous SPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis.
    Brain 04/2014; · 10.23 Impact Factor
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    ABSTRACT: GNE myopathy is a rare recessive myopathy associated with inclusion bodies on muscle biopsy. The clinical phenotype is associated with distal muscle weakness with quadriceps sparing. Most of the current information on GNE myopathy has been obtained through studies of Jewish and Japanese patient cohorts carrying founder mutations in the GNE gene. However, little is known about GNE myopathy in Europe where the prevalence is thought to be very low. Patients were referred through the National Specialist Commissioning Team service for limb-girdle muscular dystrophies at Newcastle (UK). All patients harbouring mutations in the GNE gene were recruited for our study. Detailed clinical and genetic data as well as muscle MRIs and muscle biopsies were reviewed. We identified 26 patients harbouring mutations in the GNE gene. Two previously reported mutations (c.1985C>T, p.Ala662Val and c.1225G>T, p.Asp409Tyr) were prevalent in the Scottish, Northern Irish and Northern English populations; with 90% of these patients carrying at least one of the two mutations. Clinically, we confirmed the homogenous pattern of selective quadriceps sparing but noted additional features like asymmetry of weakness at disease onset. GNE myopathy is an important diagnosis to consider in patients presenting with distal leg muscle weakness. We report, for the first time, two common mutations in the north of Britain and highlight the broader spectrum of clinical phenotypes. We also propose that the prevalence of GNE myopathy may be underestimated due to the frequent absence of rimmed vacuoles in the muscle biopsy.
    Journal of neurology, neurosurgery, and psychiatry 04/2014; · 4.87 Impact Factor
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    PLoS Genetics 04/2014; 10(4):e1004315. · 8.52 Impact Factor
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    ABSTRACT: Valproic acid (VPA) is a widely used antiepileptic drug and also prescribed to treat migraine, chronic headache and bipolar disorder. Although it is usually well tolerated, a severe hepatotoxic reaction has been repeatedly reported after VPA administration. A profound toxic reaction on administration of VPA has been observed in several patients carrying POLG mutations, and heterozygous genetic variation in POLG has been strongly associated with VPA-induced liver toxicity. Here we studied the effect of VPA in fibroblasts of five patients carrying pathogenic mutations in the POLG gene. VPA administration caused a significant increase in the expression of POLG and several regulators of mitochondrial biogenesis. It was further supported by elevated mtDNA copy numbers. The effect of VPA on mitochondrial biogenesis was observed in both control and patient cell lines, but the capacity of mutant POLG to increase the expression of mitochondrial genes and to increase mtDNA copy numbers was less effective. No evidence of substantive differences in DNA methylation across the genome was observed between POLG mutated patients and controls. Given the marked perturbation of gene expression observed in the cell lines studied, we conclude that altered DNA methylation is unlikely to make a major contribution to POLG-mediated VPA toxicity. Our data provide experimental evidence that VPA triggers increased mitochondrial biogenesis by altering the expression of several mitochondrial genes; however, the capacity of POLG-deficient liver cells to address the increased metabolic rate caused by VPA administration is significantly impaired.
    Molecular Genetics and Metabolism 03/2014; · 2.83 Impact Factor
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    P Yu-Wai-Man, M Votruba, A T Moore, P F Chinnery
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    ABSTRACT: Bilateral visual loss secondary to inherited optic neuropathies is an important cause of registrable blindness among children and young adults. The two prototypal disorders seen in clinical practice are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 90% of LHON cases are due to one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A, and m.14484T>C, which affect critical complex I subunits of the mitochondrial respiratory chain. The majority of patients with DOA harbour pathogenic mutations within OPA1, a nuclear gene that codes for a multifunctional inner mitochondrial membrane protein. Despite their contrasting genetic basis, LHON and DOA share overlapping pathological and clinical features that serve to highlight the striking tissue-specific vulnerability of the retinal ganglion cell (RGC) layer to disturbed mitochondrial function. In addition to severe visual loss secondary to progressive optic nerve degeneration, a subgroup of patients will also develop a more aggressive syndromic phenotype marked by significant neurological deficits. The management of LHON and DOA remains largely supportive, but major advances in our understanding of the mechanisms underpinning RGC loss in these two disorders are paving the way for novel forms of treatment aimed at halting or reversing visual deterioration at different stages of the disease process. In addition to neuroprotective strategies for rescuing RGCs from irreversible cell death, innovative in vitro fertilisation techniques are providing the tantalising prospect of preventing the germline transmission of pathogenic mtDNA mutations, eradicating in so doing the risk of disease in future generations.Eye advance online publication, 7 March 2014; doi:10.1038/eye.2014.37.
    Eye (London, England) 03/2014; · 1.97 Impact Factor
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    Gerald Pfeffer, Patrick F Chinnery
    Brain 02/2014; · 10.23 Impact Factor

Publication Stats

11k Citations
3,121.65 Total Impact Points


  • 1997–2014
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      • • Institute of Genetic Medicine
      • • Department of Neurology
      Newcastle-on-Tyne, England, United Kingdom
  • 1996–2014
    • Newcastle University
      • • Institute of Genetic Medicine
      • • Institute for Ageing and Health
      • • Faculty of Medical Sciences
      • • School of Mathematics and Statistics
      Newcastle-on-Tyne, England, United Kingdom
  • 2009–2013
    • Ludwig-Maximilian-University of Munich
      • Department of Neurology
      München, Bavaria, Germany
    • Vanderbilt University
      • • Department of Molecular Physiology and Biophysics
      • • Center for Human Genetics Research (CHGR)
      Nashville, MI, United States
  • 2008–2013
    • University of Cambridge
      • Department of Psychology
      Cambridge, England, United Kingdom
    • Boston University
      • Department of Neurology
      Boston, MA, United States
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
    • CHRU de Strasbourg
      Strasburg, Alsace, France
  • 2012
    • University of Duisburg-Essen
      Essen, North Rhine-Westphalia, Germany
    • Cardiff University
      • Centre for Neuropsychiatric Genetics and Genomics
      Cardiff, WLS, United Kingdom
    • Broad Institute of MIT and Harvard
      Cambridge, Massachusetts, United States
    • Hacettepe University
      • Department of Pediatrics
      Ankara, Ankara, Turkey
    • University College London
      • Department of Clinical Neuroscience
      London, ENG, United Kingdom
    • Karolinska Institutet
      • Department of Laboratory Medicine
      Solna, Stockholm, Sweden
  • 2011
    • Norfolk and Norwich University Hospitals NHS Foundation Trust
      • Department of Neurology
      Norwich, England, United Kingdom
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2003–2008
    • Virginia Polytechnic Institute and State University
      Blacksburg, Virginia, United States
  • 2007
    • Hertie-Institute for Clinical Brain Research
      Tübingen, Baden-Württemberg, Germany
  • 1999–2007
    • Newcastle University Medicine Malaysia
      Bharu, Johor, Malaysia
  • 2006
    • National Institute of Environmental Health Sciences
      • Laboratory of Molecular Genetics (LMG)
      Durham, North Carolina, United States
    • National Institutes of Health
      • Molecular Targets Laboratory
      Bethesda, MD, United States
  • 2004
    • University of Bologna
      Bolonia, Emilia-Romagna, Italy
  • 2001
    • Royal Surrey County NHS Foundation Trust
      Guilford, England, United Kingdom
  • 2000
    • University of Texas Medical Branch at Galveston
      • Department of Radiation Oncology
      Galveston, TX, United States