Martin McKibbin

Leeds Teaching Hospitals NHS Trust, Leeds, England, United Kingdom

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Publications (41)286.44 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Retinal dystrophies are an overlapping group of genetically heterogeneous conditions resulting from mutations in more than 250 genes. Here we describe five families affected by an adult-onset retinal dystrophy with early macular involvement and associated central visual loss in the third or fourth decade of life. Affected individuals were found to harbor disease-causing variants in DRAM2 (DNA-damage regulated autophagy modulator protein 2). Homozygosity mapping and exome sequencing in a large, consanguineous British family of Pakistani origin revealed a homozygous frameshift variant (c.140delG [p.Gly47Valfs(∗)3]) in nine affected family members. Sanger sequencing of DRAM2 in 322 unrelated probands with retinal dystrophy revealed one European subject with compound heterozygous DRAM2 changes (c.494G>A [p.Trp165(∗)] and c.131G>A [p.Ser44Asn]). Inspection of previously generated exome sequencing data in unsolved retinal dystrophy cases identified a homozygous variant in an individual of Indian origin (c.64_66del [p.Ala22del]). Independently, a gene-based case-control association study was conducted via an exome sequencing dataset of 18 phenotypically similar case subjects and 1,917 control subjects. Using a recessive model and a binomial test for rare, presumed biallelic, variants, we found DRAM2 to be the most statistically enriched gene; one subject was a homozygote (c.362A>T [p.His121Leu]) and another a compound heterozygote (c.79T>C [p.Tyr27His] and c.217_225del [p.Val73_Tyr75del]). DRAM2 encodes a transmembrane lysosomal protein thought to play a role in the initiation of autophagy. Immunohistochemical analysis showed DRAM2 localization to photoreceptor inner segments and to the apical surface of retinal pigment epithelial cells where it might be involved in the process of photoreceptor renewal and recycling to preserve visual function. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 05/2015; DOI:10.1016/j.ajhg.2015.04.006 · 10.99 Impact Factor
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    ABSTRACT: Purpose: To identify the genetic basis of macular dystrophy in three affected siblings of a non-consanguineous Caucasian family living in the UK. Methods: Whole-exome sequencing (WES) was performed using SureSelectXT Human V4 target enrichment reagent followed by paired-end sequencing on a HiSeq2500.The data files were processed on the Galaxy platform, aligned to the human reference genome (hg19/GRCh37) and the reported variants annotated using Annovar. Variants were excluded if they were outside the exon and flanking splice recognition sites, were synonymous or had a minor allele frequency >1% in the exome variant server database. Variants were confirmed by PCR and Sanger sequencing. Results: Genomic DNA from an affected family member was analysed by WES and the list filtered for prioritization of variants that are in the known RetNet genes. We identified 5 heterozygous and 1 homozygous variant though none segregated with the disease phenotype in the family. WES analysis of a second affected siblingand comparison of the full lists for common variantsidentified 15 homozygous and 4 genes with compound heterozygous variants. It was noted that mutations in one of these candidates MFSD8 (major facilitator superfamily domain-containing protein 8) had recently been reported in 2 families to cause nonsyndromic recessive macular dystrophy (Roosing et al., Ophthalmology, 2014). Sanger sequencing of the MFSD8 variants, c.1006G>C, p.E336Q and c.1394G>A, p.R465Q, in the UK family confirmed that all the affected members were indeed compound heterozygous for the mutations. These results are surprising since all publications to date on mutations in this gene except the one above showed that recessive MFSD8 mutations cause a severe multisystem lysosomal storage disorder, neuronal ceroidlipofuscinosis. Conclusions: This is the second study and only the third family describing biallelic MFSD8 mutations causing a nonsyndromic eye phenotype, and independently confirms the findings of the recent report.It is worth highlighting that one of these mutations, p.E336Q, exists in a heterozygous state in all three families and may act as a modifier of disease symptoms resulting in the less severe phenotype. Commercial Relationships: Mohammed E. Elasrag, None; Martin McKibbin, None; James Poulter, None; Chris Inglehearn, None; Carmel Toomes, None; Manir Ali, None Support: This research was supported by Egyptian government scholarship for Mr Mohammed Elasrag
    The Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Denver, Colorado, U.S.A; 05/2015
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    ABSTRACT: Age-related macular degeneration (AMD) and Alzheimer's disease (AD) are degenerative, multifactorial diseases involving age-related accumulation of extracellular deposits linked to dysregulation of protein homeostasis. Here, we strengthen the evidence that an nsSNP (p.Ala25Thr) in the cysteine proteinase inhibitor cystatin C gene CST3, previously confirmed by meta-analysis to be associated with AD, is associated with exudative AMD. To our knowledge, this is the first report highlighting a genetic variant that increases the risk of developing both AD and AMD. Furthermore, we demonstrate that the risk associated with the mutant allele follows a recessive model for both diseases. We perform an AMD-CST3 case-control study genotyping 350 exudative AMD Caucasian individuals. Bringing together our data with the previously reported AMD-CST3 association study, the evidence of a recessive effect on AMD risk is strengthened (OR = 1.89, P = 0.005). This effect closely resembles the AD-CST3 recessive effect (OR = 1.73, P = 0.005) previously established by meta-analysis. This resemblance is substantiated by the high correlation between CST3 genotype and effect size across the two diseases (R (2) = 0.978). A recessive effect is in line with the known function of cystatin C, a potent enzyme inhibitor. Its potency means that, in heterozygous individuals, a single functional allele is sufficient to maintain its inhibitory function; only homozygous individuals will lack this form of proteolytic regulation. Our findings support the hypothesis that recessively acting variants account for some of the missing heritability of multifactorial diseases. Replacement therapy represents a translational opportunity for individuals homozygous for the mutant allele.
    Human Genetics 04/2015; DOI:10.1007/s00439-015-1552-7 · 4.52 Impact Factor
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    ABSTRACT: Purpose: To investigate the molecular basis of retinitis pigmentosa in two consanguineous families of Pakistani origin with multiple affected members. Methods: Homozygosity mapping and Sanger sequencing of candidate genes were performed in one family while the other was analyzed with whole exome next-generation sequencing. A minigene splicing assay was used to confirm the splicing defects. Results: In family MA48, a novel homozygous nucleotide substitution in C8orf37, c.244–2A>C, that disrupted the consensus splice acceptor site of exon 3 was found. The minigene splicing assay revealed that this mutation activated a cryptic splice site within exon 3, causing a 22 bp deletion in the transcript that is predicted to lead to a frameshift followed by premature protein truncation. In family MA13, a novel homozygous null mutation in C8orf37, c.555G>A, p.W185*, was identified. Both mutations segregated with the disease phenotype as expected in a recessive manner and were absent in 8,244 unrelated individuals of South Asian origin. Conclusions: In this report, we describe C8orf37 mutations that cause retinal dystrophy in two families of Pakistani origin, contributing further data on the phenotype and the spectrum of mutations in this form of retinitis pigmentosa.
    Molecular vision 03/2015; 21:236-243. · 2.25 Impact Factor
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    ABSTRACT: To study the effectiveness and clinical relevance of eyes treated with good (better than 6/12 or >70 Early Treatment Diabetic Retinopathy Study letters) visual acuity (VA) when initiating treatment with ranibizumab for neovascular age-related macular degeneration (nAMD) in the UK National Health Service. Currently eyes with VA better than (>) 6/12 are not routinely funded for therapy. Multicentre national nAMD database study on patients treated 3-5 years prior to the analysis. Anonymised structured data were collected from 14 centres. The primary outcome was the mean VA at year 1, 2 and 3. Secondary measures included the number of clinic visits and injections. The study included 12 951 treatment-naive eyes of 11 135 patients receiving 92 976 ranibizumab treatment episodes. A total of 754 patients had baseline VA better than 6/12 and at least 1-year of follow up. Mean VA of first treated eyes with baseline VA>6/12 at year 1, 2, 3 were 6/10, 6/12, 6/15, respectively and those with baseline VA 6/12 to >6/24 were 6/15, 6/17, 6/20, respectively (p values <0.001 for comparing differences between 6/12 and 6/12-6/24 groups). For the second eyes with baseline VA>6/12, mean VA at year 1, 2, 3 were 6/9, 6/9, 6/10 and those with baseline VA 6/12 to >6/24 were 6/15, 6/15, 6/27, respectively (p values <0.001-0.005). There was no significant difference in the average number of clinic visits or injections between those with VA better and worse than 6/12. All eyes with baseline VA>6/12 maintained better mean VA than the eyes with baseline VA 6/12 to >6/24 at all time points for at least 2 years. The significantly better visual outcome in patients who were treated with good baseline VA has implications on future policy regarding the treatment criteria for nAMD patients' funding. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
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    ABSTRACT: A large number of genes can cause inherited retinal degenerations when mutated. It is important to identify the cause of disease for a better disease prognosis and a possible gene-specific therapeutic intervention. To identify the cause of disease in families with nonsyndromic retinitis pigmentosa. Patients and family members were recruited for the study and underwent clinical evaluation and genetic analyses. Identification of sequence variants in genes using next-generation sequencing. We performed exome sequencing for 4 families, which was followed by Sanger sequencing of the identified mutations in 120 ethnicity-matched patients. In total, we identified 4 BBS2 missense mutations that cause nonsyndromic retinitis pigmentosa. Three siblings of Moroccan Jewish ancestry were compound heterozygotes for p.A33D and p.P134R, and 6 patients belonging to 4 families of Ashkenazi Jewish ancestry were homozygous for either p.D104A or p.R632P, or compound heterozygous for these 2 mutations. The mutations cosegregated with retinitis pigmentosa in the studied families, and the affected amino acid residues are evolutionarily conserved. Our study shows that BBS2 mutations can cause nonsyndromic retinitis pigmentosa and highlights yet another candidate for this genetically heterogeneous condition.
    Jama Ophthalmology 12/2014; 133(3). DOI:10.1001/jamaophthalmol.2014.5251 · 3.83 Impact Factor
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    ABSTRACT: Purpose To study the characteristics of second treated eyes in patients with neovascular age-related macular degeneration (nAMD) treated with ranibizumab in the United Kingdom National Health Service. Design Multicenter national nAMD database study. Participants Twelve thousand nine hundred fifty-one treatment-naïve eyes of 11 135 patients receiving 92 976 ranibizumab injections. Methods Up to 5 years of routinely collected, anonymized data within electronic medical record systems were extracted remotely from 14 centers. Participating centers exclusively used ranibizumab to treat nAMD (loading phase of 3 monthly injections followed by monthly visits and pro re nata re-treatment). The minimum data set included: age, logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) at baseline and at all subsequent visits, and injection episodes. Main Outcome Measures Baseline, change and actual VA over 3 years, and number of treatments and clinic visits. Results During the study, 1816 (16.3%) of the 11 135 patients received treatment to the fellow eye. Mean baseline and final VA were 0.66 (standard deviation, 0.32) and 0.65 (0.40) for first treated eyes and 0.41 (0.34) and 0.56 (0.40) for second treated eyes. The rate of VA loss after the loading phase was similar in first and second treated eyes (0.03 and 0.05 logMAR units/year). When fellow eyes with baseline VA worse than 20/200 were excluded to restrict analyses to eyes at risk of nAMD, the rate of second-eye involvement was 14.0% per year (42%/3 years). Mean number of injections/visits in years 1, 2, and 3 were similar for first and second treated eyes (5.6/8.2, 3.9/8.0, 3.8/8.2 and 5.5/8.7, 3.6/9.4, and 3.8/9.1, respectively). Conclusions Second treated eyes with nAMD commence treatment with better baseline VA, do not show significant vision gain but maintain better VA than first treated eyes at all time points for at least 3 years, making them the more important eye functionally. These data highlight the high burden of second eye involvement, with almost half of all eyes at risk requiring bilateral treatment by 3 years, and the need for regular monitoring of fellow eyes for best visual outcomes which theoretically may reduce the benefits of extended monitoring regimens.
    Ophthalmology 10/2014; 121(10). DOI:10.1016/j.ophtha.2014.04.026 · 6.17 Impact Factor
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    ABSTRACT: Retinal dystrophies are genetically heterogeneous, resulting from mutations in over 200 genes. Prior to the development of massively parallel sequencing, comprehensive genetic screening was unobtainable for most patients. Identifying the causative genetic mutation facilitates genetic counselling, carrier testing and prenatal/pre-implantation diagnosis, and often leads to a clearer prognosis. In addition, in a proportion of cases, when the mutation is known treatment can be optimised and patients are eligible for enrolment into clinical trials for gene-specific therapies.
    PLoS ONE 08/2014; 9(8):e104281. DOI:10.1371/journal.pone.0104281 · 3.53 Impact Factor
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    ABSTRACT: This paper investigates the willingness of adults with inherited retinal disease to undergo and pay for diagnostic genetic testing in three hypothetical scenarios and to explore the factors that influence decision making. Fifty patients were presented with three scenarios whereby genetic testing provided increasing information: confirming the diagnosis and inheritance pattern alone, providing additional information on future visual function, and identifying in addition a new treatment which could stabilise their condition. Willingness to pay (WTP) was elicited using an iterative bidding game. Regression analysis was used to investigate the probability of agreeing to and paying for testing. Qualitative data were also reviewed to provide a comprehensive understanding of WTP and decision making. The majority of participants agreed to undergo genetic testing in each of the three scenarios. Scenario 2 was the least acceptable with 78% of participants agreeing to genetic testing. The probability of agreeing to genetic testing decreased with age. Between 72 and 96% of participants reported a WTP for genetic testing. Average WTP was £539, £1516, and £6895 for scenarios 1, 2, and 3 respectively. Older participants and participants with higher incomes were willing to pay more for testing. Qualitative data provided additional detail about the rationale behind participants' decisions. The study suggests that patients with inherited retinal disease were willing to undergo and to pay for diagnostic genetic testing, suggesting that they valued the information it may provide. However, several patients preferred not to receive prognostic information and were less willing to pay for genetic testing that yielded such detail.European Journal of Human Genetics advance online publication, 11 June 2014; doi:10.1038/ejhg.2014.111.
    European journal of human genetics: EJHG 06/2014; 23(3). DOI:10.1038/ejhg.2014.111 · 4.23 Impact Factor
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    ABSTRACT: Advances in sequencing technology and the movement of genetic testing into all areas of medicine will increase opportunities for molecular confirmation of a clinical diagnosis. For health-care professionals without formal genetics training, there is a need to know what patients understand about genetics and genetic testing and their information needs and preferences for the disclosure of genetic testing results. These topics were explored during face-to-face interviews with 50 adults with inherited retinal disease, selected in order to provide a diversity of opinions. Participants had variable understanding of genetics and genetic testing, including basic concepts such as inheritance patterns and the risk to dependents, and many did not understand the term 'genetic counselling'. Most were keen for extra information on the risk to others, the process for genetic testing and how to share the information with other family members. Participants were divided as to whether genetic testing should be offered at the time of the initial diagnosis or later. Many would prefer the results to be given by face-to-face consultation, supplemented by further information in a format accessible to those with visual impairment. Health-care professionals and either leaflets or websites of trusted agencies were the preferred sources of information. Permission should be sought for disclosure of genetic information to other family members. The information needs of many patients with inherited retinal disease appear to be unmet. An understanding of their information needs and preferences is required to help health-care professionals provide optimal services that meet patient expectations.European Journal of Human Genetics advance online publication, 8 January 2014; doi:10.1038/ejhg.2013.296.
    European journal of human genetics: EJHG 01/2014; DOI:10.1038/ejhg.2013.296 · 4.23 Impact Factor
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    ABSTRACT: Availability and accuracy of genetic testing in ophthalmology has increased yet the benefits are unclear especially for those conditions where cure or treatments are limited. To explore attitudes to and patients' understanding of possible advantages and disadvantages of genetic testing for inherited retinal disease, we undertook focus groups in three West Yorkshire towns in the UK. Most of our participants had retinitis pigmentosa and one of the focus groups consisted of participants from (British) Asian ethnic background. Here, we report only those attitudes which were common in all three focus groups. Some of the attitudes have already been reported in the literature. Novel findings include attitudes held towards informed choice and life planning, particularly among more severely affected participants. For example, participants appreciated that genetic testing increases informed choice and enables life planning, but these understandings tended to be in a specific sense: informed choice whether to have children and family planning in order to prevent illness recurrence. We conclude that even though these patients are not a homogeneous group, their attitudes tend to be underpinned by deep anxiety of passing their visual impairment onto their children. In this respect, they differ importantly from a small minority of the deaf who would prefer to have children with hearing loss, and from the more general population who do not believe that blindness is a "severe" enough disability to warrant avoiding having children.
    Journal of community genetics 12/2013; DOI:10.1007/s12687-013-0176-7
  • BMJ (online) 11/2013; 347:f6610. DOI:10.1136/bmj.f6610 · 16.38 Impact Factor
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    Ophthalmology 09/2013; 120(9):1944-1945.e1. DOI:10.1016/j.ophtha.2013.06.010 · 6.17 Impact Factor
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    ABSTRACT: OBJECTIVE: To investigate qualitative and quantitative differences in the structure of the posterior segment of the eye in 1-day post-hatch and 12-month-old retinal dysplasia and degeneration (rdd) and wild-type chickens. ANIMAL STUDIED: Retinal dysplasia and degeneration and wild-type chickens. PROCEDURE: Using a commercially available spectral domain optical coherence tomography (OCT) system, 15° horizontal line scans were performed in both eyes of 24 live birds. Qualitative differences in retinal lamination and choroidal structure were investigated, and retinal and choroidal thickness were measured. RESULTS: Progressive retinal thinning with loss of outer retinal lamination and changes in the appearance of the choroid were seen in the rdd birds. Mean total retinal thickness was 202 μm (SD 7.8) and 251 μm (SD 8.8) in the rdd and wild-type chicks and 154 μm (SD 18) and 280 μm (SD 10.8) in the adult birds. Much of the difference was the result of loss of outer retinal lamination and thickness in the rdd birds. Mean choroidal thickness was 76 μm (SD 19.6) and 112 μm (SD 36.9) in the rdd and wild-type chicks and 85 μm (SD 23.7) and 228 μm (SD 44.1) in the rdd and wild-type adult birds, respectively. CONCLUSIONS: Differences in retinal and choroidal structure and thickness between rdd and wild-type birds were evident on spectral domain OCT imaging at 1-day post-hatch and more marked at 1 year. Spectral domain OCT may provide a reliable end point for therapeutic intervention in this animal model of inherited retinal degeneration.
    Veterinary Ophthalmology 05/2013; 17(2). DOI:10.1111/vop.12051 · 1.09 Impact Factor
  • David S M Burton, Manir Ali, Martin McKibbin
    Investigative ophthalmology & visual science 01/2013; 54(1). DOI:10.1167/iovs.12-11472 · 3.66 Impact Factor
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    ABSTRACT: Whilst the majority of inherited diseases have been found to be caused by single base substitutions, small insertions or deletions (<1Kb), a significant proportion of genetic variability is due to copy number variation (CNV). The possible role of CNV in monogenic and complex diseases has recently attracted considerable interest. However, until the development of whole genome, oligonucleotide micro-arrays, designed specifically to detect the presence of copy number variation, it was not easy to screen an individual for the presence of unknown deletions or duplications with sizes below the level of sensitivity of optical microscopy (3-5 Mb). Now that currently available oligonucleotide micro-arrays have in excess of a million probes, the problem of copy number analysis has moved from one of data production to that of data analysis. We have developed CNViewer, to identify copy number variation that co-segregates with a disease phenotype in small nuclear families, from genome-wide oligonucleotide micro-array data. This freely available program should constitute a useful addition to the diagnostic armamentarium of clinical geneticists.
    PLoS ONE 08/2012; 7(8):e43466. DOI:10.1371/journal.pone.0043466 · 3.53 Impact Factor
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    ABSTRACT: Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder.
    Nature Genetics 07/2012; 44(9):1035-9. DOI:10.1038/ng.2356 · 29.65 Impact Factor
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    ABSTRACT: The atonal homolog 7 (ATOH7) gene encodes a transcription factor involved in determining the fate of retinal progenitor cells and is particularly required for optic nerve and ganglion cell development. Using a combination of autozygosity mapping and next generation sequencing, we have identified homozygous mutations in this gene, p.E49V and p.P18RfsX69, in two consanguineous families diagnosed with multiple ocular developmental defects, including severe vitreoretinal dysplasia, optic nerve hypoplasia, persistent fetal vasculature, microphthalmia, congenital cataracts, microcornea, corneal opacity and nystagmus. Most of these clinical features overlap with defects in the Norrin/β-catenin signalling pathway that is characterized by dysgenesis of the retinal and hyaloid vasculature. Our findings document Mendelian mutations within ATOH7 and imply a role for this molecule in the development of structures at the front as well as the back of the eye. This work also provides further insights into the function of ATOH7, especially its importance in retinal vascular development and hyaloid regression.
    Human Molecular Genetics 11/2011; 21(4):776-83. DOI:10.1093/hmg/ddr509 · 6.68 Impact Factor
  • Archives of ophthalmology 11/2011; 129(11):1506-7. DOI:10.1001/archophthalmol.2011.321 · 4.49 Impact Factor
  • Kamron N Kahn, Martin McKibbin, Rehna S Kahn
    Investigative ophthalmology & visual science 10/2011; 52(10):7221; author reply 7221. DOI:10.1167/iovs.11-8019 · 3.66 Impact Factor

Publication Stats

680 Citations
286.44 Total Impact Points


  • 2015
    • Leeds Teaching Hospitals NHS Trust
      Leeds, England, United Kingdom
  • 2000–2015
    • St. James University
      Сент-Джеймс, New York, United States
  • 2014
    • IBMS
      Londinium, England, United Kingdom
    • Moorfields Eye Hospital NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2006–2013
    • University of Leeds
      • • School of Medicine
      • • Section of Ophthalmology and Neurosciences
      • • Leeds Institute of Molecular Medicine (LIMM)
      Leeds, England, United Kingdom
  • 2011
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
  • 2009
    • Aga Khan University Hospital, Karachi
      • Department of Medicine
      Karachi, Sindh, Pakistan
  • 2008
    • Saint James School Of Medicine
      Παρκ Ριτζ, Illinois, United States
  • 2007
    • WWF United Kingdom
      Londinium, England, United Kingdom