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Angus Clarke

Publications and source records attributed to Angus Clarke.

16 recordsLinked to original sources
PubMed2026

RNU4ATAC-opathy: Clinical, molecular, and transcriptomic insights from a large cohort.

PURPOSE: We aim to better define the genotype and phenotype spectrum of RNU4ATAC-opathy, demonstrate the utility of RNA sequencing (RNA-seq) for variant classification, and highlight the challenges in detecting variants in this noncoding gene. METHODS: Sixty individuals with molecularly confirmed RNU4ATAC-opathy were recruited from multiple clinical and research centers internationally. RNA-seq was available for 7 affected individuals. RESULTS: We report the clinical and molecular findings of 60 individuals, including 42 not previously described, and 33 distinct RNU4ATAC variants, 13 of which are novel. Core features in this cohort-present in most individuals assessed and varying in severity-include microcephaly, short stature, skeletal anomalies, developmental delay, cerebral anomalies, skin conditions, and immune deficiency. Additional findings, such as diabetes, holoprosencephaly, and the absence of various core features in some individuals, highlight the broad phenotypic spectrum. All individuals who underwent RNA-seq showed a consistent pattern of minor intron retention. In 6 individuals, RNA-seq enabled the reclassification of variants of uncertain significance as likely pathogenic. Although RNU4ATAC variants are generally covered by clinical exomes, they are often overlooked in analysis because of their noncoding nature. CONCLUSION: This study highlights the variability of phenotypes and genotypes associated with RNU4ATAC-opathy. Laboratories should ensure RNU4ATAC and other noncoding genes are appropriately assessed by their analysis pipelines.

Lowry-Wood syndrome↗
PubMed2006

Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation.

INTRODUCTION: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that is usually associated with mutations in the MECP2 gene. The most common mutations in the gene are p.R168X and p.T158M. The influence of X-chromosome inactivation (XCI) on clinical severity in patients with RTT with these mutations was investigated, taking into account the extent and direction of skewing. METHODS: Female patients and their parents were recruited from the UK and Australia. Clinical severity was measured by the Pineda Severity and Kerr profile scores. The degree of XCI and its direction relative to the X chromosome parent of origin were measured in DNA prepared from peripheral blood leucocytes, and allele-specific polymerase chain reaction was used to determine the parental origin of mutation. Combining these, the percentage of cells expected to express the mutant allele was calculated. RESULTS: Linear regression analysis was undertaken for fully informative cases with p.R168X (n = 23) and p.T158M (n = 20) mutations. A statistically significant increase in clinical severity with increase in the proportion of active mutated allele was shown for both the p.R168X and p.T158M mutations. CONCLUSIONS: XCI may vary in neurological and haematological tissues. However, these data are the first to show a relationship between the degree and direction of XCI in leucocytes and clinical severity in RTT, although the clinical utility of this in giving a prognosis for individual patients is unclear.

Amino Acid Substitution↗
PubMed2006

The causation of disease - the practical and ethical consequences of competing explanations.

The prevention, treatment and management of disease are closely linked to how the causes of a particular disease are explained. For multi-factorial conditions, the causal explanations are inevitably complex and competing models may exist to explain the same condition. Selecting one particular causal explanation over another will carry practical and ethical consequences that are acutely relevant for health policy. In this paper our focus is two-fold; (i) the different models of causal explanation that are put forward within current scientific literature for the high and rising prevalence of the common complex conditions of coronary artery disease (CAD) and type 2 diabetes mellitus (T2D); and (ii) how these explanations are taken up (or not) within national health policy guidelines. We examine the causal explanations for these two conditions through a systematic database search of current scientific literature. By identifying different causal explanations we propose a three-tier taxonomy of the most prominent models of explanations: (i) evolutionary, (ii) lifecourse, and (iii) lifestyle and environment. We elaborate this taxonomy with a micro-level thematic analysis to illustrate how some explanations are semantically and rhetorically foregrounded over others. We then investigate the uptake of the scientific causal explanations in health policy documents with regard to the prevention and management recommendations of current National Service Frameworks for CAD and T2D. Our findings indicate a lack of congruence between the complexity and frequent overlap of causal explanations evident in the scientific literature and the predominant focus on lifestyle recommendations found in the mainstream health policy documents.

Bioethics↗
PubMed2005

(Mis)alignments in counseling for Huntington's Disease predictive testing: clients' responses to reflective frames.

As a sequel to an earlier paper (Sarangi et al., 2004. J Genet Couns, 13(2), 135-155) examining genetic counselors' initiation of reflective frames, in this paper we analyze the variable ways in which clients respond to such reflective frames in the clinical setting. Of the six types of reflective questions identified, we focus on two types, which recur throughout the counseling protocol: (i) questions about clients' decisions to have genetic testing and (ii) questions exploring the potential impact of a positive or negative test result. The analytic focus here is on the mismatches surrounding clients' apparent readiness to discuss coping with the onset of disease (risk of disease) when they have been asked to discuss coping with genetic test results (risk of knowing). Our theoretical discussion is centered around the notion of alignment as a framework for locating the convergence and divergence of counselors' and clients' agendas in interaction. Drawing on detailed transcripts of 24 Huntington's Disease counseling consultations in South Wales, we analyze 119 counselor-client question-response sequences using the methodology of discourse analysis. Preliminary coding of clients' responses led us to identify three recurrent themes: (a) gaining knowledge as a basis for future action; (b) needing to know as a subjective necessity; and (c) downplaying what can be known. In a further analysis of extended data extracts, we draw attention to how clients display varying degrees of engagement with regard to the testing process and outcomes along the temporal and social axes. At one extreme, clients may take up the opportunity to engage in self-reflection, and thus endorse the legitimacy of the reflective frame. At the other extreme, clients may implicitly or explicitly challenge the relevance of self-reflection, and hence the usefulness of this counselor-initiated routine. We suggest that clients' varied response behaviors result from the perceived need of some clients to display their 'readiness' for predictive testing-an overarching 'meta-question' posed by the very existence of the counseling protocol.

Attitude to Health↗
PubMed2005

Variation in exon 1 coding region and promoter of MECP2 in Rett syndrome and controls.

Mutations in MECP2 are a cause of Rett syndrome. Recently, a new isoform of MeCP2 was described, which has an alternative N-terminus, transcribed from exon 1. We screened exon 1 and the promoter region of MECP2 in 97 mutation-negative Rett syndrome cases. We found two sequence variants, but there was no evidence that they are pathogenic. Mutations in exon 1 and the promoter of MECP2 are not a common cause of Rett syndrome.

Case-Control Studies↗
PubMed2005

Genetic professionals' reports of nondisclosure of genetic risk information within families.

Patients attending genetic clinics are often the main gatekeepers of information for other family members. There has been much debate about the circumstances under which professionals may have an obligation, or may be permitted, to pass on personal genetic information about their clients but without their consent to other family members. We report findings from the first prospective study investigating the frequency with which genetics professionals become concerned about the failure of clients to pass on such information to their relatives. In all, 12 UK and two Australian regional genetic services reported such cases over 12 months, including details of actions taken by professionals in response to the clients' failure to disclose information. A total of 65 cases of non-disclosure were reported, representing <1% of the genetic clinic consultations in the collaborating centres during the study period. These included 39 cases of the failure of parents not passing full information to their adult offspring, 22 cases where siblings or other relatives were not given information and four cases where information was withheld from partners -- including former and prospective partners. Professionals reported clients' reasons for withholding information as complex, more often citing concern and the desire to shield relatives from distress rather than poor family relationships. In most cases, the professionals took further steps to persuade their clients to make a disclosure but in no instance did the professional force a disclosure without the client's consent.

Attitude of Health Personnel↗
PubMed2005

Dimensional phenotypic analysis and functional categorisation of mutations reveal novel genotype-phenotype associations in Rett syndrome.

We aimed to improve the understanding of genotype-phenotype correlations in Rett syndrome (RS) by adopting a novel approach to categorising phenotypic dimensions - separating typicality of presentation, outcome severity and age of onset - and by classifying MECP2 mutations strictly by predicted functional attributes. MECP2 mutation screening results were available on 190 patients with a clinical diagnosis of RS (140 cases with classic RS, 50 with atypical RS). 135 cases had identified mutations. Of the 140 patients, 116 with classic RS (82.9%) had an identified mutation compared with 19 of 50 patients (38%) with an atypical presentation. Cases with early onset of regression and seizures, and those with clinical features that might indicate alternative aetiologies, were less likely to have mutations. Individuals with late truncating mutations had a less typical presentation than cases with missense and early truncating mutations, presumably reflecting greater residual function of MECP2 protein. Individuals with early truncating mutations had a more severe outcome than cases with missense and late truncating mutations. These findings held when restricting the analysis to cases over 15 years of age and classic cases only. Previous findings of variation in severity among the common mutations were confirmed. The approach to phenotypic and genotypic classification adopted here allowed us to identify genotype-phenotype associations in RS that may aid our understanding of pathogenesis and also contribute to clinical knowledge on the impact of different types of mutations.

Adolescent↗
PubMed2005

Dysmorphology and the spectacle of the clinic.

Dysmorphology is the medical study of abnormal forms in the human and is concerned with the identification and classification of a variety of congenital malformations. Such diagnostic work rests on the inspection of images of affected individuals. Based on physical appearance individuals are classified in terms of a wide range of conditions, often with 'exotic' nomenclatures. This paper will describe the features of clinical dysmorphology and the process of classification. It derives from an ethnographic study of clinical consultations and meetings among medical geneticists in UK hospitals. We suggest that contemporary dysmorphology can be understood in terms of long-standing forms of medical knowledge, medical representations and medical discourse. Notwithstanding the new forms of technology provided by genetic science, 'the clinic' still asserts its symbolic and functional power: the 'gaze' of the clinician and the clinician's warrant of personal knowledge exert their influence. The adjudication of dysmorphology is a contemporary exemplar of the spectacular.

Adult↗
PubMed2004

Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G-->A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps--but is not identical to--that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.

Amino Acid Sequence↗
PubMed2004

Initiation of reflective frames in counseling for Huntingtons Disease predictive testing.

Genetic professionals and clients are likely to assign different meanings to the extended format of the counseling protocols for predictive testing. In order to facilitate informed, client-centered decisions about the possibility of predictive testing, counselors routinely use the question format to initiate what we call "reflective frames" that invite clients to discuss their feelings and encourage them to adopt introspective and self-reflective stances toward their own experience--spanning the past, the present, and the hypothetical future. We suggest that such initiations of reflective frames constitute a key element of counselors' nondirective stance, although the exact nature of their formulations can be complex and varied. Examining 24 Huntington's Disease (HD) clinic sessions involving 12 families in South Wales with the tools of discourse analysis, our focus in this paper is twofold: (i) to propose a classification of six types of reflective questions (e.g. nonspecific invites, awareness and anxiety, decision about testing, impact of result, dissemination, and other) and to examine their distribution across the various clinic appointments, and (ii) to investigate the scope of these questions in terms of temporal and social axes. We link our analysis to the current debate within the genetic counseling profession about the merits of reflection- versus information-focused counseling styles and the need to abide by professionally warranted and institutionally embedded counseling protocols.

Adaptation, Psychological↗
PubMed2002

Constructing an account by contrast in counselling for childhood genetic testing.

Genetic counselling sessions are rich and complex sites of accounting practices for decision-making in which clinicians are meant to facilitate rather than control the decisions made by their clients. This often means the adoption of a non-directive stance as counsellors lay out various possible courses of action from which the client can choose, while both client and counsellor may need to bear in mind a wide range of practical and ethical issues. With regard to childhood predictive testing, the complexity of decision-making is manifest not only in relation to the severity of the genetic condition being discussed, but also in terms of who controls the information, who might be affected by it and who makes decisions on whose behalf. In this paper we use discourse analytic methods to examine a single case where the clinician and the parent negotiate decisions about childhood testing and the extent to which the parent can influence this process. In discursive terms, we show how the child's future autonomy is juxtaposed against the parent's current rights. In order fully to understand the various characters and events deployed in the accounting practices of the parent and the genetic counsellor, we focus on one rhetorical device, i.e., contrast, as it is manifest at different levels of representation. We conclude that the interplay between a selected set of the contrast pairs contributes towards recursive interactional patterns as far as non-directive counselling is concerned, and consequently has implications for procedural outcomes.

Adolescent↗
PubMed2002

Genotype-phenotype correlations in X-linked myotubular myopathy.

X-linked myotubular myopathy is a severe congenital myopathy that presents in the neonatal period with profound hypotonia and an inability to establish spontaneous respiration. Usually death occurs in infancy from respiratory failure. However, there is phenotypic variability; a number of affected boys have achieved respiratory independence and become ambulatory. Disease-causing mutations have been identified throughout the MTM1 gene on Xq28. MTM1 encodes the protein myotubularin, which is expressed ubiquitously. The main objectives of this study were to establish whether the nature or site of the mutation in the MTM1 gene could predict severity of the disease and to investigate whether early intensive clinical intervention facilitated survival until spontaneous improvement occurred. An association was demonstrated between the presence of a non-truncating mutation of the MTM1 gene and the mild phenotype. However, many non-truncating mutations were also seen in association with the severe phenotype and these were not confined to recognized functional domains of the protein. This suggests that the use of mutation analysis to predict prognosis in the early period following diagnosis is limited. Unexpectedly, over 50 patients surviving for more than 1 year were identified in this study. Further information obtained on 40 of these cases revealed that 50% were receiving 24-h ventilatory support, while 27% were ventilated at night only. The high survival rate for this disorder therefore reflects intensive medical intervention without which the majority of these boys would not survive.

Chi-Square Distribution↗
PubMed1993

Response to: What counts as success in genetic counselling?

Clinical genetics encompasses a wider range of activities than discussion of reproductive risks and options. Hence, it is possible for a clinical geneticist to reduce suffering associated with genetic disease without aiming to reduce the birth incidence of such diseases. Simple cost-benefit analyses of genetic-screening programmes are unacceptable; more sophisticated analyses of this type have been devised but entail internal inconsistencies and do not seem to result in changed clinical practice. The secondary effects of screening programmes must be assessed before they can be properly evaluated, including the inadvertent diagnosis of unsought conditions, and the wider social effects of the programmes on those with mental handicap. This has implications for the range of prenatal tests that should be made available. While autonomy must be fully respected, it cannot itself constitute a goal of clinical genetics. The evaluation of these services requires interdepartmental comparisons of workload, and quality judgements of clients and peers.

Abortion, Eugenic↗