Angus J Clarke

Cardiff University, Cardiff, Wales, United Kingdom

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Publications (14)51.26 Total impact

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    ABSTRACT: Ectodermal dysplasias (EDs) comprise a large clinically and etiologically heterogeneous group of genetic disorders characterized by abnormalities in tissues derived from the embryonic ectoderm. Controversy exists over which syndromes should be classified as EDs and which should be excluded from the classification. The challenge will be to balance comprehensiveness within the classification with usability and accessibility so that the benefits truly serve the needs of researchers, health-care providers, and ultimately the individuals and families directly affected by EDs. The overarching goal of the Second International Conference was to develop a consensus on EDs classifications, with the ultimate goal of creating a system that integrates clinical and molecular knowledge, using an interactive Internet-based database that clinicians, researchers, and laymen can use. The Conference, brought together a group of experts from around the world, including a diverse health-care providers, researchers, patient advocate representatives, and administrators. The Conference was modeled after the 2008 conference, with plenary sessions, scientific updates, and small group discussions. Based on the present clinical knowledge, new molecular advances and both coupled with new bioinformatics developments, the participants agree to develop a multi-axis system approach for the classification of EDs. The multi-axis approach will include a clinical/phenotype axis, a gene-based axis, and a functional/pathways axis. The significance of the conference outcomes includes, a new classification approach that will foster a better understanding of EDs, open new fields of research and develop a nosologic approach that may have broad implications for classifying other hereditary conditions. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 10/2014; 164A(10). DOI:10.1002/ajmg.a.36507 · 2.30 Impact Factor
  • Angus J Clarke
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    ABSTRACT: Introduction: Next-generation sequencing (NGS) is transforming the conduct of genetic research and diagnostic investigation. This creates new challenges as it generates additional information, including unsought and unwanted information. Nevertheless, this information must be deliberately managed-interpreted, disclosed and then either stored or destroyed. Areas of agreement: Handling the process of consent to exome or genome sequencing should include discussion about the possible detection of variants of uncertain significance (VUSs) or incidental findings (IFs) that the patient may prefer not to hear about. A plan should be drawn up that specifies whether and how the patient would be recontacted in the future with new interpretations. Areas of controversy: There is an active debate about which IFs or VUSs should be disclosed to the patient when an exome or genome sequence has been performed, or whether all findings of any possible relevance should always be disclosed. How this is managed has important implications for the initial explanation of the test to the patient and the process of consent. The assumption is often made that all sequence information should be stored, but this may not be sustainable or useful. Growing points: Efforts are being made to build a consensus on what 'incidental' information should be disclosed. These policy questions are being addressed in many centres and practices are evolving rapidly. Areas timely for developing research: Those interested in genetics, public health, bioethics and medical ethics may wish to debate these issues and influence future practice in both genetic research and genetic diagnostic services.
    British Medical Bulletin 08/2014; 111(1). DOI:10.1093/bmb/ldu017 · 4.36 Impact Factor
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    ABSTRACT: Ectodermal dysplasias (EDs) are a large and heterogeneous group of hereditary disorders characterized by abnormalities in structures of ectodermal origin. Incontinentia pigmenti (IP) is an ED characterized by skin lesions evolving over time, as well as dental, nail, and ocular abnormalities. Due to X-linked dominant inheritance IP symptoms can only be seen in female individuals while affected males die during development in utero. We observed a family of horses, in which several mares developed signs of a skin disorder reminiscent of human IP. Cutaneous manifestations in affected horses included the development of pruritic, exudative lesions soon after birth. These developed into wart-like lesions and areas of alopecia with occasional wooly hair re-growth. Affected horses also had streaks of darker and lighter coat coloration from birth. The observation that only females were affected together with a high number of spontaneous abortions suggested an X-linked dominant mechanism of transmission. Using next generation sequencing we sequenced the whole genome of one affected mare. We analyzed the sequence data for non-synonymous variants in candidate genes and found a heterozygous nonsense variant in the X-chromosomal IKBKG gene (c.184C>T; p.Arg62*). Mutations in IKBKG were previously reported to cause IP in humans and the homologous p.Arg62* variant has already been observed in a human IP patient. The comparative data thus strongly suggest that this is also the causative variant for the observed IP in horses. To our knowledge this is the first large animal model for IP.
    PLoS ONE 12/2013; 8(12):e81625. DOI:10.1371/journal.pone.0081625 · 3.53 Impact Factor
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    ABSTRACT: This report is of a round-table discussion held in Cardiff in September 2009 for Cesagen, a research centre within the Genomics Network of the UK's Economic and Social Research Council (ESRC). The meeting was arranged to explore ideas as to the likely future course of human genomics.
    Human genomics 08/2012; 6(1):11. DOI:10.1186/1479-7364-6-11
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    ABSTRACT: The paper by Mand et al raises important questions about the predictive genetic testing of children. They focus on those claims made by professionals that are open to empirical enquiry and give too little weight to those claims that do not require empirical support. The authors remind us that some commentators oppose empirical enquiry because of the concern that gathering evidence of the consequences of such testing may itself be harmful or unethical. They respond by asserting that the relevant research questions are 'eminently testable' but fail to discuss the challenges of such research, including the questions of timescale, consent or the nature of the data whose collection (they assert) would resolve the perceived difficulties with the genetic testing of children. They conclude that empirical research is required without resolving the weighty arguments against predictive testing of young children or explaining how the evidence they wish to collect could overcome the force of the arguments that favour caution.
    Journal of medical ethics 05/2012; 38(9):527-8; discussion 533-4. DOI:10.1136/medethics-2012-100598 · 1.69 Impact Factor
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    ABSTRACT: Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was to revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials. RettSearch members, representing the majority of the international clinical RTT specialists, participated in an iterative process to come to a consensus on a revised and simplified clinical diagnostic criteria for RTT. The clinical criteria required for the diagnosis of classic and atypical RTT were clarified and simplified. Guidelines for the diagnosis and molecular evaluation of specific variant forms of RTT were developed. These revised criteria provide clarity regarding the key features required for the diagnosis of RTT and reinforce the concept that RTT is a clinical diagnosis based on distinct clinical criteria, independent of molecular findings. We recommend that these criteria and guidelines be utilized in any proposed clinical research.
    Annals of Neurology 12/2010; 68(6):944-50. DOI:10.1002/ana.22124 · 11.91 Impact Factor
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    Angus J Clarke, David N Cooper
    European journal of human genetics: EJHG 03/2010; 18(8):859-61. DOI:10.1038/ejhg.2010.35 · 3.56 Impact Factor
  • Angus J. Clarke
    Human Genetics 09/2009; 126(3):473-474. DOI:10.1007/s00439-009-0710-1 · 4.52 Impact Factor
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    Angus J Clarke, Clara Gaff
    Archives of Disease in Childhood 12/2008; 93(11):911-4. DOI:10.1136/adc.2006.113381 · 2.91 Impact Factor
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    ABSTRACT: As an individual's understanding of their genetic risk may influence risk management decisions, it is important to understand the ways in which risk is constructed and interpreted. We systematically reviewed the literature, undertaking a narrative synthesis of 59 studies presenting data on the ways in which individuals perceive, construct and interpret their risk, and the subsequent effects. While most studies assessed perceived risk quantitatively, the combined evidence suggests individuals find risk difficult to accurately quantify, with a tendency to overestimate. Rather than being a stand-alone concept, risk is something lived and experienced and the process of constructing risk is complex and influenced by many factors. While evidence of the effects of perceived risk is limited and inconsistent, there is some evidence to suggest high risk estimations may adversely affect health and lead to inappropriate uptake of medical surveillance and preventative measures by some individuals. A more focused approach to research is needed with greater exploration of the ways in which risk is constructed, along with the development of stronger theoretical models, to facilitate effective and patient-centered counseling strategies.
    Journal of Genetic Counseling 03/2008; 17(1):30-63. DOI:10.1007/s10897-007-9132-1 · 1.75 Impact Factor
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    Clara L Gaff, Angus J Clarke, Paul Atkinson
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    ABSTRACT: The communication of risk is a central activity in clinical genetics, with genetic health professionals encouraging the dissemination of relevant information by individuals to their at-risk family members. To understand the process by which communication occurs as well as its outcomes, a systematic review of actual communication in families about genetic risk was conducted. Findings from 29 papers meeting the inclusion criteria were summarised and are presented narratively. Family communication about genetic risk is described as a deliberative process, in which: sense is made of personal risk; the vulnerability and receptivity of the family member is assessed; decisions are made about what will be conveyed; and the right time to disclose is selected. The communication strategy adopted will depend on these factors and varies within families as well as between families. Inherent in these processes are conflicting senses of responsibility: to provide potentially valuable information and to prevent harm that may arise from this knowledge. However, the research ‘outcomes’ of communication have been professionally determined (number of relatives reported as informed, uptake of testing, knowledge of the recipient) and are typically unrelated to the concerns of the family member. The impact of communication on the individual, family members, and family relationships is of concern to the individual conveying the information, but this is largely self-reported. Currently, there is insufficient information to inform the development of theoretically and empirically based practice to foster ‘good’ communication. The implications for future research are discussed.
    European Journal of HumanGenetics 02/2008; 16(3):402-402. DOI:10.1038/sj.ejhg.5201971 · 4.23 Impact Factor
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    ABSTRACT: The communication of risk is a central activity in clinical genetics, with genetic health professionals encouraging the dissemination of relevant information by individuals to their at-risk family members. To understand the process by which communication occurs as well as its outcomes, a systematic review of actual communication in families about genetic risk was conducted. Findings from 29 papers meeting the inclusion criteria were summarised and are presented narratively. Family communication about genetic risk is described as a deliberative process, in which: sense is made of personal risk; the vulnerability and receptivity of the family member is assessed; decisions are made about what will be conveyed; and the right time to disclose is selected. The communication strategy adopted will depend on these factors and varies within families as well as between families. Inherent in these processes are conflicting senses of responsibility: to provide potentially valuable information and to prevent harm that may arise from this knowledge. However, the research 'outcomes' of communication have been professionally determined (number of relatives reported as informed, uptake of testing, knowledge of the recipient) and are typically unrelated to the concerns of the family member. The impact of communication on the individual, family members, and family relationships is of concern to the individual conveying the information, but this is largely self-reported. Currently, there is insufficient information to inform the development of theoretically and empirically based practice to foster 'good' communication. The implications for future research are discussed.
    European Journal of HumanGenetics 11/2007; 15(10):999-1011. DOI:10.1038/sj.ejhg.5201883 · 4.23 Impact Factor
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    ABSTRACT: A translocation that disrupted the netrin G1 gene (NTNG1) was recently reported in a patient with the early seizure variant of Rett syndrome (RTT). The netrin G1 protein (NTNG1) has an important role in the developing central nervous system, particularly in axonal guidance, signalling and NMDA receptor function and was a good candidate gene for RTT. We recruited 115 patients with RTT (females: 25 classic and 84 atypical; 6 males) but no mutation in the MECP2 gene. For those 52 patients with epileptic seizure onset in the first 6 months of life, CDKL5 mutations were also excluded. We aimed to determine whether mutations in NTNG1 accounted for a significant subset of patients with RTT, particularly those with the early onset seizure variant and other atypical presentations. We sequenced the nine coding exons of NTNG1 and identified four sequence variants, none of which were likely to be pathogenic. Mutations in the NTNG1 gene appear to be a rare cause of RTT but NTNG1 function demands further investigation in relation to the central nervous system pathophysiology of the disorder.
    American Journal of Medical Genetics Part A 04/2006; 140(7):691-4. DOI:10.1002/ajmg.a.31133 · 2.05 Impact Factor
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    ABSTRACT: Mutations in the CDKL5 gene (also known as STK9) have recently been shown to cause early onset epilepsy and severe mental retardation (ISSX or West syndrome). Patients with CDKL5 mutations sometimes also show features similar to those seen in Rett Syndrome (RTT). We have screened the CDKL5 gene in 94 patients with RTT or a RTT-like phenotype who had tested negative for MECP2 mutations (13 classical RTT female subjects, 25 atypical RTT female subjects, 40 RTT-like female and 16 RTT-like male subjects; 33 of the patients had early onset seizures). Novel pathogenic CDKL5 mutations were identified in three girls, two of whom had initially been diagnosed with the early onset seizure variant of RTT and the other with early onset seizures and some features of RTT. In addition, the 33 patients with early seizures were screened for the most common mutations in the ARX gene but none were found. Combining our three new cases with the previously published cases, 13/14 patients with CDKL5 mutations presented with seizures before the age of 3 months.
    European Journal of HumanGenetics 11/2005; 13(10):1113-20. DOI:10.1038/sj.ejhg.5201451 · 4.23 Impact Factor