Charles Shaw-Smith

University of Exeter, Exeter, England, United Kingdom

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Publications (58)673.71 Total impact

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    ABSTRACT: Neonatal diabetes is a highly genetically heterogeneous disorder. There are over 20 distinct syndromic and non-syndromic forms, including dominant, recessive and X-linked subtypes. Biallelic truncating or mis-sense mutations in the DNA-binding domain of the RFX6 transcription factor cause an autosomal recessive, syndromic form of neonatal diabetes previously described as Mitchell-Riley syndrome. In all, eight cases have been reported, with the age at onset of diabetes in the first 2 weeks of life. Here we report two individuals born to double first cousins in whom intestinal atresias consistent with a diagnosis of Mitchell-Riley syndrome were diagnosed at birth, but in whom diabetes did not present until the ages of 3 and 6 years. Novel compound heterozygous RFX6 nonsense mutations (p.Arg726X/p.Arg866X) were identified at the 3' end of the gene. The later onset of diabetes in these patients may be due to incomplete inactivation of RFX6. Genetic testing for RFX6 mutations should be considered in patients presenting with intestinal atresias in the absence of neonatal diabetes.European Journal of Human Genetics advance online publication, 12 August 2015; doi:10.1038/ejhg.2015.161.
    No preview · Article · Aug 2015 · European journal of human genetics: EJHG
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    Full-text · Dataset · Jul 2015
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    ABSTRACT: Neonatal diabetes is a rare form of diabetes, characterized by onset in the first 6 months of life. A number of cases are due to pancreas agenesis. Recently, PTF1A enhancer mutations have been shown to cause neonatal diabetes associated with pancreatic agenesis. Herein, we report the clinical features of two siblings with PTF1A enhancer mutations, one of whom had neonatal diabetes, whereas the elder sister had a milder form of the disease with onset of diabetes at 9 years of age. © 2015 S. Karger AG, Basel.
    No preview · Article · Jul 2015 · Hormone Research in Paediatrics
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    ABSTRACT: Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.
    Full-text · Article · Dec 2014 · Nature
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    ABSTRACT: The GATA family zinc finger transcription factors GATA4 and GATA6 are known to play important roles in the development of the pancreas. In mice both Gata4 and Gata6 are required for pancreatic development. In humans GATA6 haploinsufficiency can cause pancreatic agenesis and heart defects. Congenital heart defects are also common in patients with GATA4 mutations and deletions but the role of GATA4 in the developing human pancreas is unproven.We report 5 patients with deletions (n=4) or mutations of the GATA4 gene who have diabetes and a variable exocrine phenotype. In four cases diabetes presented in the neonatal period (age at diagnosis 1-7 days). A de novo GATA4 missense mutation (p.N273K) was identified in a patient with complete absence of the pancreas confirmed at post mortem. This mutation affects a highly conserved residue located in the second zinc finger domain of the GATA4 protein. In vitro studies showed reduced DNA binding and transactivational activity of the mutant protein.We show that GATA4 mutations/deletions are a cause of neonatal or childhood-onset diabetes with or without exocrine insufficiency. These results confirm a role for GATA4 in normal development of the human pancreas.
    Full-text · Article · Apr 2014 · Diabetes
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    ABSTRACT: The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ∼400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.
    Full-text · Article · Nov 2013 · Nature Genetics
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    ABSTRACT: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Non-pulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and ten deletions, we have identified an additional thirty eight novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, twenty missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic whereas four familial cases with three showing maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA binding domain, indicating its plausible role in gene regulation. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.
    Full-text · Article · Mar 2013 · Human Mutation
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    ABSTRACT: Aims Recessive PDX1 (IPF1) mutations are a rare cause of pancreatic agenesis, with three cases reported worldwide. A recent report described two cousins with a homozygous hypomorphic PDX1 mutation causing permanent neonatal diabetes with subclinical exocrine insufficiency. The aim of our study was to investigate the possibility of hypomorphic PDX1 mutations in a large cohort of patients with permanent neonatal diabetes and no reported pancreatic hypoplasia or exocrine insufficiency. Methods PDX1 was sequenced in 103 probands with isolated permanent neonatal diabetes in whom ABCC8, KCNJ11 and INS mutations had been excluded. Results Sequencing analysis identified biallelic PDX1 mutations in three of the 103 probands with permanent neonatal diabetes (2.9%). One proband and his affected brother were compound heterozygotes for a frameshift and a novel missense mutation (p.A34fsX191; c.98dupC and p.P87L; c.260C>T). The other two probands were homozygous for novel PDX1 missense mutations (p.A152G; c.455C>G and p.R176Q; c.527G>A). Both mutations affect highly conserved residues located within the homeobox domain. None of the four cases showed any evidence of exocrine pancreatic insufficiency, either clinically, or, where data were available, biochemically. In addition a heterozygous nonsense mutation (p.C18X; c.54C>A) was identified in a fourth case. Conclusions This study demonstrates that recessive PDX1 mutations are a rare but important cause of isolated permanent neonatal diabetes in patients without pancreatic hypoplasia/agenesis. Inclusion of the PDX1 gene in mutation screening for permanent neonatal diabetes is recommended as a genetic diagnosis reveals the mode of inheritance, allows accurate estimation of recurrence risks and confirms the requirement for insulin treatment.
    Full-text · Article · Jan 2013 · Diabetic Medicine
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    ABSTRACT: We recently reported de novo GATA6 mutations as the most common cause of pancreatic agenesis, accounting for 15 of 27 (56%) patients with insulin-treated neonatal diabetes and exocrine pancreatic insufficiency requiring enzyme replacement therapy. We investigated the role of GATA6 mutations in 171 subjects with neonatal diabetes of unknown genetic etiology from a cohort of 795 patients with neonatal diabetes. Mutations in known genes had been confirmed in 624 patients (including 15 GATA6 mutations). Sequencing of the remaining 171 patients identified nine new case subjects (24 of 795, 3%). Pancreatic agenesis was present in 21 case subjects (six new); two patients had permanent neonatal diabetes with no enzyme supplementation and one had transient neonatal diabetes. Four parents with heterozygous GATA6 mutations were diagnosed with diabetes outside the neonatal period (12-46 years). Subclinical exocrine insufficiency was demonstrated by low fecal elastase in three of four diabetic patients who did not receive enzyme supplementation. One parent with a mosaic mutation was not diabetic but had a heart malformation. Extrapancreatic features were observed in all 24 probands and three parents, with congenital heart defects most frequent (83%). Heterozygous GATA6 mutations cause a wide spectrum of diabetes manifestations, ranging from pancreatic agenesis to adult-onset diabetes with subclinical or no exocrine insufficiency.
    Full-text · Article · Dec 2012 · Diabetes
  • Francis H Sansbury · Sian Ellard · Charles Shaw-Smith · Peter Turnpenny

    No preview · Article · Dec 2012 · BMJ (online)
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    ABSTRACT: VACTERL association (sometimes termed "VATER association" depending on which component features are included) is typically defined by the presence of at least three of the following congenital malformations, which tend to statistically co-occur in affected individuals: Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities. Although the clinical criteria for VACTERL association may appear to be straightforward, there is wide variability in the way clinical geneticists define the disorder and the genetic testing strategy they use when confronted with an affected patient. In order to describe this variability and determine the most commonly used definitions and testing modalities, we present the results of survey responses by 121 clinical geneticists. We discuss the results of the survey responses, provide a literature review and commentary from a group of physicians who are currently involved in clinical and laboratory-based research on VACTERL association, and offer an algorithm for genetic testing in patients with this association. © 2012 Wiley Periodicals, Inc.
    No preview · Article · Dec 2012 · American Journal of Medical Genetics Part A
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    ABSTRACT: Permanent neonatal diabetes mellitus (PNDM) is diagnosed within the first 6 months of life, and is usually monogenic in origin. Heterozygous mutations in ABCC8, KCNJ11, and INS genes account for around half of cases of PNDM; mutations in 10 further genes account for a further 10%, and the remaining 40% of cases are currently without a molecular genetic diagnosis. Thiamine-responsive megaloblastic anaemia (TRMA), due to mutations in the thiamine transporter SLC19A2, is associated with the classical clinical triad of diabetes, deafness, and megaloblastic anaemia. Diabetes in this condition is well described in infancy but has only very rarely been reported in association with neonatal diabetes. We used a combination of homozygosity mapping and evaluation of clinical information to identify cases of TRMA from our cohort of patients with PNDM. Homozygous mutations in SLC19A2 were identified in three cases in which diabetes presented in the first 6 months of life, and a further two cases in which diabetes presented between 6 and 12 months of age. We noted the presence of a significant neurological disorder in four of the five cases in our series, prompting us to examine the incidence of these and other non-classical clinical features in TRMA. From 30 cases reported in the literature, we found significant neurological deficit (stroke, focal, or generalized epilepsy) in 27%, visual system disturbance in 43%, and cardiac abnormalities in 27% of cases. TRMA should be considered in the differential diagnosis of diabetes presenting in the neonatal period.
    No preview · Article · Feb 2012 · Pediatric Diabetes
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    ABSTRACT: Understanding the regulation of pancreatic development is key for efforts to develop new regenerative therapeutic approaches for diabetes. Rare mutations in PDX1 and PTF1A can cause pancreatic agenesis, however, most instances of this disorder are of unknown origin. We report de novo heterozygous inactivating mutations in GATA6 in 15/27 (56%) individuals with pancreatic agenesis. These findings define the most common cause of human pancreatic agenesis and establish a key role for the transcription factor GATA6 in human pancreatic development.
    No preview · Article · Dec 2011 · Nature Genetics
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    ABSTRACT: Primary microcephaly is an autosomal recessive disorder characterized by marked reduction in human brain size. Microcephalin (MCPH1), one of the genes mutated in primary microcephaly, plays an important role in DNA damage checkpoint control and mitotic entry. Additionally, MCPH1 ensures the proper temporal activation of chromosome condensation during mitosis, by acting as a negative regulator of the condensin II complex. We previously found that deletion of the of the MCPH1 N terminus leads to the premature chromosome condensation (PCC) phenotype. In the present study, we unexpectedly observed that a truncated form of MCPH1 appears to be expressed in MCPH1(S25X/S25X) patient cells. This likely results from utilization of an alternative translational start codon, which would produce a mutant MCPH1 protein with a small deletion of its N-terminal BRCT domain. Furthermore, missense mutations in the MCPH1 cluster at its N terminus, suggesting that intact function of this BRCT protein-interaction domain is required both for coordinating chromosome condensation and human brain development. Subsequently, we identified the SET nuclear oncogene as a direct binding partner of the MCPH1 N-terminal BRCT domain. Cells with SET knockdown exhibited abnormal condensed chromosomes similar to those observed in MCPH1-deficient mouse embryonic fibroblasts. Condensin II knockdown rescued the abnormal chromosome condensation phenotype in SET-depleted cells. In addition, MCPH1 V50G/I51V missense mutations, impair binding to SET and fail to fully rescue the abnormal chromosome condensation phenotype in Mcph1(-/-) mouse embryonic fibroblasts. Collectively, our findings suggest that SET is an important regulator of chromosome condensation/decondensation and that disruption of the MCPH1-SET interaction might be important for the pathogenesis of primary microcephaly.
    No preview · Article · Jun 2011 · Journal of Biological Chemistry
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    ABSTRACT: Primary microcephaly is an autosomal recessive disorder characterized by marked reduction in human brain size. Microcephalin (MCPH1), one of the genes mutated in primary microcephaly, plays an important role in DNA damage checkpoint control and mitotic entry. Additionally, MCPH1 ensures the proper temporal activation of chromosome condensation during mitosis, by acting as a negative regulator of the condensin II complex. We previously found that deletion of the of the MCPH1 N terminus leads to the premature chromosome condensation (PCC) phenotype. In the present study, we unexpectedly observed that a truncated form of MCPH1 appears to be expressed in MCPH1S25X/S25X patient cells. This likely results from utilization of an alternative translational start codon, which would produce a mutant MCPH1 protein with a small deletion of its N-terminal BRCT domain. Furthermore, missense mutations in the MCPH1 cluster at its N terminus, suggesting that intact function of this BRCT protein-interaction domain is required both for coordinating chromosome condensation and human brain development. Subsequently, we identified the SET nuclear oncogene as a direct binding partner of the MCPH1 N-terminal BRCT domain. Cells with SET knockdown exhibited abnormal condensed chromosomes similar to those observed in MCPH1-deficient mouse embryonic fibroblasts. Condensin II knockdown rescued the abnormal chromosome condensation phenotype in SET-depleted cells. In addition, MCPH1 V50G/I51V missense mutations, impair binding to SET and fail to fully rescue the abnormal chromosome condensation phenotype in Mcph1−/− mouse embryonic fibroblasts. Collectively, our findings suggest that SET is an important regulator of chromosome condensation/decondensation and that disruption of the MCPH1-SET interaction might be important for the pathogenesis of primary microcephaly.
    No preview · Article · Jun 2011 · Journal of Biological Chemistry
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    ABSTRACT: Report of a 16q24.1 deletion in a premature newborn, demonstrating the usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn and multiple congenital malformations. Descriptive case report. Genetic department and neonatal intensive care unit of a tertiary care children's hospital. None. We report the case of a preterm male infant, born at 26 wks of gestation. A cardiac malformation and bilateral hydronephrosis were diagnosed at 19 wks of gestation. Karyotype analysis was normal, and a 22q11.2 microdeletion was excluded by fluorescence in situ hybridization analysis. A cesarean section was performed due to fetal distress. The patient developed persistent pulmonary hypertension unresponsive to mechanical ventilation and nitric oxide treatment and expired at 16 hrs of life. An autopsy revealed partial atrioventricular canal malformation and showed bilateral dilation of the renal pelvocaliceal system with bilateral ureteral stenosis and annular pancreas. Array-based comparative genomic hybridization analysis (Agilent oligoNT 44K, Agilent Technologies, Santa Clara, CA) showed an interstitial microdeletion encompassing the forkhead box gene cluster in 16q24.1. Review of the pulmonary microscopic examination showed the characteristic features of alveolar capillary dysplasia with misalignment of pulmonary veins. Some features were less prominent due to the gestational age. Our review of the literature shows that alveolar capillary dysplasia with misalignment of pulmonary veins is rare but probably underreported. Prematurity is not a usual presentation, and histologic features are difficult to interpret. In our case, array-based comparative genomic hybridization revealed a 16q24.1 deletion, leading to the final diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins. It emphasizes the usefulness of array-based comparative genomic hybridization analysis as a diagnostic tool with implications for both prognosis and management decisions in newborns with refractory persistent pulmonary hypertension and multiple congenital malformations.
    Full-text · Article · May 2011 · Pediatric Critical Care Medicine
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    ABSTRACT: Primary microcephaly is an autosomal recessive disorder characterized by a reduction in brain size and abnormal chromosome condensation. Microcephalin (MCPH1), one of the genes mutated in primary microcephaly, plays an important role in DNA damage checkpoint control and mitotic entry in cell cycle regulation. MCPH1 also acts as a negative regulator of the condensin II complex, ensuring the proper temporal activation of chromosome condensation during mitosis. We previously found that the N-terminus of MCPH1 is responsible for the premature chromosome condensation (PCC) phenotype. In the present study, we unexpectedly observed that a truncated form of MCPH1 is expressed in cells derived from a patient with primary microcephaly (S25X), further confirming that N-terminus of MCPH1 is required for proper chromosome condensation. Moreover, we identified SET nuclear oncogene, which binds directly to the N-terminus of MCPH1. Cells with SET knockdown exhibited PCC morphology similar to that observed in MCPH1-deficient mouse embryonic fibroblasts (MEFs). Condensin II knockdown reversed the PCC phenotype in SET-depleted cells. In addition, we identified V50G/I51V mutations in a microcephaly patient. The mutant MCPH1 exhibited reduced binding to SET and failed to rescue the PCC phenotype in MCPH1-/- MEFs. Collectively, our findings suggest that SET is a regulator of chromosome condensation/ decondensation and disruption of MCPH1/SET interaction contributes to the development of primary microcephaly.
    No preview · Article · Apr 2011 · Journal of Biological Chemistry
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    ABSTRACT: Congenital malformations involving the Müllerian ducts are observed in around 5% of infertile women. Complete aplasia of the uterus, cervix, and upper vagina, also termed Müllerian aplasia or Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, occurs with an incidence of around 1 in 4500 female births, and occurs in both isolated and syndromic forms. Previous reports have suggested that a proportion of cases, especially syndromic cases, are caused by variation in copy number at different genomic loci. In order to obtain an overview of the contribution of copy number variation to both isolated and syndromic forms of Müllerian aplasia, copy number assays were performed in a series of 63 cases, of which 25 were syndromic and 38 isolated. A high incidence (9/63, 14%) of recurrent copy number variants in this cohort is reported here. These comprised four cases of microdeletion at 16p11.2, an autism susceptibility locus not previously associated with Müllerian aplasia, four cases of microdeletion at 17q12, and one case of a distal 22q11.2 microdeletion. Microdeletions at 16p11.2 and 17q12 were found in 4/38 (10.5%) cases with isolated Müllerian aplasia, and at 16p11.2, 17q12 and 22q11.2 (distal) in 5/25 cases (20%) with syndromic Müllerian aplasia. The finding of microdeletion at 16p11.2 in 2/38 (5%) of isolated and 2/25 (8%) of syndromic cases suggests a significant contribution of this copy number variant alone to the pathogenesis of Müllerian aplasia. Overall, the high incidence of recurrent copy number variants in all forms of Müllerian aplasia has implications for the understanding of the aetiopathogenesis of the condition, and for genetic counselling in families affected by it.
    Full-text · Article · Mar 2011 · Journal of Medical Genetics
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    Vicki Martin · Charles Shaw-Smith
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    ABSTRACT: Intestinal malrotation is well covered in the surgical literature from the point of view of operative management, but few reviews to date have attempted to provide a comprehensive examination of the topic from the point of view of aetiology, in particular genetic aetiology. Following a brief overview of molecular embryology of midgut rotation, we present in this article instances of and case reports and case series of intestinal malrotation in which a genetic aetiology is likely. Autosomal dominant, autosomal recessive, X-linked and chromosomal forms of the disorder are represented. Most occur in syndromic form, that is to say, in association with other malformations. In many instances, recognition of a specific syndrome is possible, one of several examples discussed being the recently described association of intestinal malrotation with alveolar capillary dysplasia, due to mutations in the forkhead box transcription factor FOXF1. New advances in sequencing technology mean that the identification of the genes mutated in these disorders is more accessible than ever, and paediatric surgeons are encouraged to refer to their colleagues in clinical genetics where a genetic aetiology seems likely.
    Preview · Article · Aug 2010 · Pediatric Surgery International
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    ABSTRACT: Aortic arch artery patterning defects account for approximately 20% of congenital cardiovascular malformations and are observed frequently in velocardiofacial syndrome (VCFS). In the current study, we screened for chromosome rearrangements in patients suspected of VCFS, but who lacked a 22q11 deletion or TBX1 mutation. One individual displayed hemizygous CHD7, which encodes a chromodomain protein. CHD7 haploinsufficiency is the major cause of coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, and ear anomalies/deafness (CHARGE) syndrome, but this patient lacked the major diagnostic features of coloboma and choanal atresia. Because a subset of CHARGE cases also display 22q11 deletions, we explored the embryological relationship between CHARGE and VCSF using mouse models. The hallmark of Tbx1 haploinsufficiency is hypo/aplasia of the fourth pharyngeal arch artery (PAA) at E10.5. Identical malformations were observed in Chd7 heterozygotes, with resulting aortic arch interruption at later stages. Other than Tbx1, Chd7 is the only gene reported to affect fourth PAA development by haploinsufficiency. Moreover, Tbx1+/-;Chd7+/- double heterozygotes demonstrated a synergistic interaction during fourth PAA, thymus, and ear morphogenesis. We could not rescue PAA morphogenesis by restoring neural crest Chd7 expression. Rather, biallelic expression of Chd7 and Tbx1 in the pharyngeal ectoderm was required for normal PAA development.
    Full-text · Article · Nov 2009 · The Journal of clinical investigation

Publication Stats

5k Citations
673.71 Total Impact Points

Institutions

  • 2011-2015
    • University of Exeter
      • Peninsula College of Medicine and Dentistry
      Exeter, England, United Kingdom
  • 2012-2014
    • Royal Devon and Exeter NHS Foundation Trust
      Exeter, England, United Kingdom
  • 2006-2011
    • Wellcome Trust Sanger Institute
      Cambridge, England, United Kingdom
    • University of California, San Francisco
      San Francisco, California, United States
  • 2005-2009
    • University of Cambridge
      • Department of Medical Genetics
      Cambridge, England, United Kingdom
  • 2008
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 2007
    • Cambridge University Hospitals NHS Foundation Trust
      • Department of Medical Genetics
      Cambridge, England, United Kingdom
  • 2004
    • Norwich University
      Northfield, Vermont, United States
  • 2003
    • Imperial College London
      • Section of Hepatology and Gastroenterology
      Londinium, England, United Kingdom
  • 1996-1997
    • Ealing, Hammersmith & West London College
      Londinium, England, United Kingdom