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4.
Nat Genet ; 49(2): 223-237, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27992417

RESUMO

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.


Assuntos
Distonia/genética , Histona-Lisina N-Metiltransferase/genética , Mutação/genética , Adolescente , Proteínas de Ligação a DNA/genética , Feminino , Histona Metiltransferases , Histonas/genética , Humanos , Lisina/genética , Masculino , Metilação , Proteínas Nucleares/genética
5.
Am J Med Genet A ; 170(11): 2835-2846, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27667800

RESUMO

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. We describe 32 KBG patients aged 2-47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half the patients. We identified 20 ANKRD11 mutations (18 novel: all truncating) confirmed by Sanger sequencing in 32 patients. Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. There were no conclusive phenotype-genotype correlations. Our findings suggest that mutation of ANKRD11 is a common Mendelian cause of developmental delay. Affected patients may not show the characteristic KBG phenotype and the diagnosis is therefore easily missed. We propose updated diagnostic criteria/clinical recommendations for KBG syndrome and suggest that inclusion of ANKRD11 will increase the utility of gene panels designed to investigate developmental delay. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Deleção Cromossômica , Cromossomos Humanos Par 16 , Hibridização Genômica Comparativa , Facies , Feminino , Humanos , Masculino , Fenótipo , Proteínas Repressoras/genética
6.
Front Plant Sci ; 6: 1078, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26697036

RESUMO

The assembly of photosynthetically competent chloroplasts occurs in angiosperm seedlings when first exposed to light, and is due to the control by light of photosynthesis-associated nuclear genes (PhANGs), also dependent upon plastid-to-nucleus "biogenic" communication signals. The relationship between light- and plastid signal-regulation of PhANGs is close but poorly understood. In contrast, many conifers green in the dark and the promoter of a pine PhANG, Lhcb, is active in the dark in tobacco. Here, we show that the activity of this promoter in tobacco is sensitive to plastid photobleaching, or to the inhibition of plastid translation in the light or the dark, and the same interventions reduce expression of the native gene in pine seedlings, demonstrating classic plastid biogenic signaling in gymnosperms. Furthermore, Arabidopsis mutations causing defective plastid biogenesis suppress the effect in darkness of mutations in COP1 and DET1, repressors of photomorphogenesis, for the expression of several PhANGs but not a photosynthesis-unrelated, light-regulated gene. GLK transcriptional regulators mediate the response of LHCB but not of other tested PhANGs. We propose the ability to suppress PhANG response to positive plastid biogenic signals in the dark may have contributed to the evolution of light-controlled chloroplast biogenesis.

8.
Prenat Diagn ; 32(12): 1197-204, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23097180

RESUMO

OBJECTIVE: To present the results of 10 years of quantitative fluorescence PCR (QF-PCR) analysis of prenatal samples for the rapid diagnosis of the common aneuploidies. This represents the largest QF-PCR data set from a single testing centre. METHODS: QF-PCR analysis using a single assay containing 17 microsatellite markers was applied to all prenatal samples for the identification of trisomies 13, 18 and 21 and triploidy. A separate assay containing 14 sex chromosome markers was targeted to prenatal samples at increased risk of monosomy X. RESULTS: Results from 40,624 prenatal samples comprising 14,144 chorionic villus and 26,480 amniotic fluid samples are summarised. A QF-PCR result was not possible for 2.24% amniotic fluid and 0.25% chorionic villus samples because of the presence of an additional genotype consistent with maternal cell contamination. Just 0.08% samples were uninformative for one or more chromosomes and 0.05% of samples failed to produce a genotype. Ninety-eight percent of samples were reported the following working day from sample receipt. Consumable costs were £ 5/sample. CONCLUSION: QF-PCR analysis is proven to be an accurate, robust and efficient method for the rapid diagnosis of common aneuploidies in prenatal samples. It has the advantage of detecting triploidy and mosaicism and benefits from considerable economy of scale.


Assuntos
Monossomia/diagnóstico , Reação em Cadeia da Polimerase/métodos , Diagnóstico Pré-Natal/métodos , Trissomia/diagnóstico , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 21 , Cromossomos Humanos X , Feminino , Fluorescência , Humanos , Monossomia/genética , Gravidez , Estudos Retrospectivos , Aberrações dos Cromossomos Sexuais , Fatores de Tempo , Trissomia/genética
10.
Methods Mol Biol ; 774: 3-18, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21822829

RESUMO

The power of Arabidopsis as a model organism lies in the depth and breadth of genetic tools available for its study. This also applies to the study of chloroplast biology. Although vast numbers of mutants have been identified in Arabidopsis, the continued use of forward-genetic screening approaches remains valuable for the isolation and study of previously overlooked mutants and novel mutations in sensitised backgrounds (i.e., suppressors or enhancers of previously known mutants). In addition, reverse-genetic collections of insertional mutants are now extensive and provide unique opportunities for gene function discovery. Here, we describe methods for the chemical mutagenesis of Arabidopsis, the screening of mutants visually, on the basis of gene-expression phenotypes (scored as reduced or enhanced activity of reporter genes), and the use of databases to select for existing mutations from historic collections or insertional mutagenesis programmes.


Assuntos
Arabidopsis/genética , Cloroplastos/genética , Metanossulfonato de Etila/metabolismo , Testes Genéticos/métodos , Mutagênese Insercional/métodos , Mutação/genética , Genes Reporter/genética , Genótipo , Genética Reversa
11.
Mol Cytogenet ; 3: 19, 2010 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-20942916

RESUMO

BACKGROUND: Array CGH has recently been introduced into our laboratory in place of karyotype analysis for patients with suspected genomic imbalance. Results require confirmation to check sample identity, and analysis of parental samples to determine inheritance and thus assess the clinical significance of the abnormality. Here we describe an MLPA-based strategy for the follow-up of abnormal aCGH results. RESULTS: In the first 17 months of our MLPA-based aCGH follow-up service, 317 different custom MLPA probes for novel aCGH-detected abnormalities were developed for inheritance studies in 164 families. In addition, 110 samples were tested for confirmation of aCGH-detected abnormalities in common syndromic or subtelomeric regions using commercial MLPA kits. Overall, a total of 1215 samples have been tested by MLPA. A total of 72 de novo abnormalities were confirmed. CONCLUSIONS: Confirmation of aCGH-detected abnormalities and inheritance of these abnormalities are essential for accurate diagnosis and interpretation of aCGH results. The development of a new service utilising custom made MLPA probes and commercial MLPA kits for follow-up studies of array CGH results has been found to be efficient and flexible in our laboratory.

12.
Prenat Diagn ; 30(6): 509-17, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20509149

RESUMO

OBJECTIVE: To analyse the results of the first 2 years of a QF-PCR stand-alone testing strategy for the prenatal diagnosis of aneuploidy in the London region and to determine the advantages and disadvantages of this policy. METHODS: A review of the results of 9737 prenatal samples received for exclusion of chromosome abnormalities. All samples were subjected to QF-PCR testing for common aneuploidies but only samples fulfilling specific criteria subsequently had a full karyotype analysis. RESULTS: Of the 9737 samples received, 10.3% had a chromosome abnormality detected by QF-PCR testing. Of the 7284 samples received with no indication for karyotype analysis, 25 (0.3%) received a normal QF-PCR result but subsequently had an abnormal karyotype detected either prenatally as a privately funded test or postnatally. Of these samples, without subsequent abnormal ultrasound findings, five had a chromosome abnormality associated with a poor prognosis, representing 0.069% of samples referred for Down syndrome testing. CONCLUSION: While back-up karyotyping is required for some samples, using QF-PCR as a stand-alone prenatal test for pregnancies without ultrasound abnormalities reduces costs, provides rapid delivery of results, and avoids ambiguous and uncertain karyotype results, reducing parental anxiety.


Assuntos
Transtornos Cromossômicos/diagnóstico , Reação em Cadeia da Polimerase/métodos , Diagnóstico Pré-Natal/métodos , Algoritmos , Aneuploidia , Coleta de Amostras Sanguíneas/normas , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/genética , Reações Falso-Negativas , Feminino , Humanos , Cariotipagem/métodos , Londres/epidemiologia , Reação em Cadeia da Polimerase/normas , Reação em Cadeia da Polimerase/estatística & dados numéricos , Gravidez , Diagnóstico Pré-Natal/estatística & dados numéricos , Projetos de Pesquisa , Estudos Retrospectivos
13.
BMC Med Genet ; 8: 9, 2007 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-17338807

RESUMO

BACKGROUND: Commercial MLPA kits (MRC-Holland) are available for detecting imbalance at the subtelomere regions of chromosomes; each kit consists of one probe for each subtelomere. METHODS: For validation of the kits, 208 patients were tested, of which 128 were known to be abnormal, corresponding to 8528 genomic regions overall. Validation samples included those with trisomy 13, 18 and 21, microscopically visible terminal deletions and duplications, sex chromosome abnormalities and submicroscopic abnormalities identified by multiprobe FISH. A robust and sensitive analysis system was developed to allow accurate interpretation of single probe results, which is essential as breakpoints may occur between MLPA probes. RESULTS: The validation results showed that MLPA is a highly efficient technique for medium-throughput screening for subtelomere imbalance, with 95% confidence intervals for positive and negative predictive accuracies of 0.951-0.996 and 0.9996-1 respectively. A diagnostic testing strategy was established for subtelomere MLPA and any subsequent follow-up tests that may be required. The efficacy of this approach was demonstrated during 15 months of diagnostic testing when 455 patients were tested and 27 (5.9%) abnormal cases were detected. CONCLUSION: The development of a robust, medium-throughput analysis system for the interpretation of results from subtelomere assays will be of benefit to other Centres wishing to implement such an MLPA-based service.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Técnicas de Amplificação de Ácido Nucleico , Telômero/genética , Criança , Deficiências do Desenvolvimento/diagnóstico , Testes Genéticos , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/diagnóstico , Trissomia/diagnóstico , Trissomia/genética
14.
Prenat Diagn ; 27(4): 332-9, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17286305

RESUMO

OBJECTIVE: To investigate complete discrepancies in the prenatal diagnosis of trisomy 21 between QF-PCR analysis of uncultured villi and karyotyping of cultured cells in three chorion villus samples. METHODS: Clinical details were obtained from all three patients. Follow-up studies were undertaken where possible by evaluation of chromosome 21 copy number with QF-PCR, interphase FISH, MLPA and karyotyping, and by post-mortem examination. RESULTS: Case 1: severe oligohydramnios and microcephaly on scan. QF-PCR: trisomy 21; MLPA: trisomy 21; cultured karyotype: 46,XY[48]. Placental and fetal tissue results and post-mortem examination indicated a euploid fetus with trisomy 21 mosaicism confined to the placenta. Case 2: Down screen risk 1:16; NT = 4.4 mm; absent nasal bone (Caucasian mother). QF-PCR: disomy 21; cultured karyotype: 47,XY,+ 21[23]. Neck thickening noted at delivery-post-mortem refused, no fetal tissue available. Placental tissue indicated mosaicism for trisomy 21. Case 3: Down screen risk 1:91; NT = 6.7 mm. QF-PCR: disomy 21; cultured karyotype: 46,XX,der(21;21)(q10;q10)[60]. No follow-up possible. PCR genotyping of cultured cells confirmed sample identity in all three cases. Chromosome 21 markers observed by PCR were biallelic in all three cases, indicating that a mitotic error could account for the presence of the abnormal cell lines in each case. CONCLUSION: QF-PCR analysis of uncultured villi and cultured karyotyping may rarely show complete discrepancy in the prediction of fetal trisomy 21 in CVS. Within-biopsy sample mosaicism, together with the testing of different cell populations, provide an explanation for these results. Practical ways to minimise the risk of such discrepancy are proposed.


Assuntos
Amostra da Vilosidade Coriônica , Síndrome de Down/diagnóstico , Cariotipagem , Reação em Cadeia da Polimerase/métodos , Adulto , Células Cultivadas , Síndrome de Down/genética , Feminino , Seguimentos , Marcadores Genéticos , Humanos , Gravidez
17.
Nurs Stand ; 16(27): 40-4, 2002 Mar 20-26.
Artigo em Inglês | MEDLINE | ID: mdl-11949568

RESUMO

This article outlines the findings from three RCN discussion groups, which aimed to gain an understanding of how nurses were responding to clinical governance and to what extent they were involved in its implementation. The article focuses mainly on the third round with clinical nursing staff, senior managers and clinical governance facilitators. Three key issues were reported by nurses taking part in all three rounds of discussion groups. First, there is the need to raise awareness among frontline clinical staff to ensure that clinical governance becomes recognised as an integral part of their clinical workload rather than being seen as an optional extra. The second issue is the need to change organisational culture to make it more receptive to clinical governance. Third is the requirement to establish greater levels of partnerships between clinicians and managers, patients and professionals, and professional groups. However, the authors caution that the organisational cultural change necessary for the successful implementation of clinical governance is not as straightforward as the literature appears to suggest, and argue that this remains a key challenge for organisational leaders, managers and clinical staff.


Assuntos
Atitude do Pessoal de Saúde , Competência Clínica/normas , Tomada de Decisões Gerenciais , Recursos Humanos de Enfermagem/psicologia , Supervisão de Enfermagem/organização & administração , Grupos Focais , Humanos , Determinação de Necessidades de Cuidados de Saúde , Pesquisa Metodológica em Enfermagem , Recursos Humanos de Enfermagem/organização & administração , Cultura Organizacional , Inovação Organizacional , Medicina Estatal/organização & administração , Reino Unido
18.
J Adv Nurs ; 37(6): 577-88, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11879422

RESUMO

AIM OF PAPER: This paper presents the findings of a concept analysis of facilitation in relation to successful implementation of evidence into practice. BACKGROUND: In 1998, we presented a conceptual framework that represented the interplay and interdependence of the many factors influencing the uptake of evidence into practice. One of the three elements of the framework was facilitation, alongside the nature of evidence and context. It was proposed that facilitators had a key role in helping individuals and teams understand what they needed to change and how they needed to change it. As part of the on-going development and refinement of the framework, the elements within it have undergone a concept analysis in order to provide theoretical and conceptual clarity. METHODS: The concept analysis approach was used as a framework to review critically the research literature and seminal texts in order to establish the conceptual clarity and maturity of facilitation in relation to its role in the implementation of evidence-based practice. FINDINGS: The concept of facilitation is partially developed and in need of delineation and comparison. Here, the purpose, role and skills and attributes of facilitators are explored in order to try and make distinctions between this role and other change agent roles such as educational outreach workers, academic detailers and opinion leaders. CONCLUSIONS: We propose that facilitation can be represented as a set of continua, with the purpose of facilitation ranging from a discrete task-focused activity to a more holistic process of enabling individuals, teams and organizations to change. A number of defining characteristics of facilitation are proposed. However, further research to clarify and evaluate different models of facilitation is required.


Assuntos
Medicina Baseada em Evidências/organização & administração , Prática Profissional/normas , Difusão de Inovações , Educação Médica Continuada , Educação Continuada em Enfermagem , Medicina Baseada em Evidências/educação , Fidelidade a Diretrizes , Humanos , Negociação , Equipe de Assistência ao Paciente , Facilitação Social
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