RESUMO
Change history: In this Letter, the received date should be 20 December 2017, instead of 27 April 2018. This has been corrected online.
RESUMO
Large-scale quantum networks promise to enable secure communication, distributed quantum computing, enhanced sensing and fundamental tests of quantum mechanics through the distribution of entanglement across nodes1-7. Moving beyond current two-node networks8-13 requires the rate of entanglement generation between nodes to exceed the decoherence (loss) rate of the entanglement. If this criterion is met, intrinsically probabilistic entangling protocols can be used to provide deterministic remote entanglement at pre-specified times. Here we demonstrate this using diamond spin qubit nodes separated by two metres. We realize a fully heralded single-photon entanglement protocol that achieves entangling rates of up to 39 hertz, three orders of magnitude higher than previously demonstrated two-photon protocols on this platform 14 . At the same time, we suppress the decoherence rate of remote-entangled states to five hertz through dynamical decoupling. By combining these results with efficient charge-state control and mitigation of spectral diffusion, we deterministically deliver a fresh remote state with an average entanglement fidelity of more than 0.5 at every clock cycle of about 100 milliseconds without any pre- or post-selection. These results demonstrate a key building block for extended quantum networks and open the door to entanglement distribution across multiple remote nodes.
RESUMO
This Article was originally published under a CC BY-NC-SA 4.0 license, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.
RESUMO
BACKGROUND: The phenotype of children with XXYY has predominantly been defined by comparison to other sex chromosome aneuploidies trisomies affecting male children; however, the intellectual ability of children with XXYY is lower than children with other sex chromosome aneuploidies trisomies. It is not known to what extent the phenotype identified to date is specific to XXYY, rather than a reflection of lower IQ. This study evaluates the mental health and behaviour of children with XXYY, in comparison to children with intellectual disabilities of heterogeneous genetic origin. METHODS: Fifteen children with XXYY and 30 controls matched for age (4-14 years), sex and intellectual ability were ascertained from the IMAGINE ID study. IMAGINE ID participants have intellectual disabilities due to genetic anomalies confirmed by National Health Service Regional Genetic Centre laboratories. The mental health and behaviour of participants was examined with the Development and Well-being Assessment and the Strengths and Difficulties Questionnaire. RESULTS: Children with XXYY experienced significantly more frequent and intense temper outbursts than the control group. CONCLUSION: Our results suggest that temper outbursts may be specifically associated with the XXYY phenotype. These problems have a significant impact on the daily lives of boys with XXYY and their families. It is crucial to ensure that families are well supported to manage these difficulties.
Assuntos
Ira/fisiologia , Deficiências do Desenvolvimento/fisiopatologia , Deficiência Intelectual/fisiopatologia , Humor Irritável/fisiologia , Síndrome de Klinefelter/fisiopatologia , Comportamento Problema , Comportamento Autodestrutivo/fisiopatologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/complicações , Humanos , Deficiência Intelectual/complicações , Síndrome de Klinefelter/complicações , Masculino , Comportamento Autodestrutivo/etiologiaRESUMO
Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.
Assuntos
Deficiência Intelectual/genética , Alelos , Consanguinidade , Exoma/genética , Família , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Humanos , Mutação , Paquistão , Linhagem , Sequenciamento do Exoma/métodosRESUMO
Genetic testing and management of the at-risk individual for neurofibromatosis type 2 (NF2) is complicated by the well-documented risk of mosaicism that causes a milder later onset more asymmetrical disease course. Risks of NF2 were derived from genetic testing of over 1000 individuals through the Manchester NF2-testing service. Individuals are at risk of NF2 or have 'potential' NF2 if they have features of the disease that fall short of diagnostic criteria or are the first-degree relative of someone with NF2 or suspected NF2. The present protocol devised for the Nationally Commissioned Group (NCG) NF2 service in England addresses the risks, genetic testing and screening protocol for individuals at risk of NF2. Screening with cranial magnetic resonance imaging is advised until the risk of NF2 falls below a pragmatic threshold of 1%. Multiple case scenarios are shown to illustrate how to use the protocol.
Assuntos
Testes Genéticos/métodos , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Adulto , Cromossomos Humanos Par 22/genética , Inglaterra , Genes da Neurofibromatose 2 , Humanos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Mosaicismo , Mutação , Guias de Prática Clínica como Assunto , Adulto JovemRESUMO
OBJECTIVE: To obtain penetrance data for Huntington's disease when DNA results are in the range of 36-39 CAG repeats and assess the consistency of reporting the upper allele from two reference centres. METHOD: Data were collected anonymously on age of onset or age last known to be unaffected from a cohort of individuals with results in this range. DNA samples were re-analysed in two reference centres. Kaplan-Meier analysis was used to construct an age of onset curve and penetrance figures. RESULTS: Clinical data and concordant DNA results from both reference centres were available for 176 samples; penetrance figures (and 95% confidence intervals) for this cohort, at age 65 and 75 years, were 63.9% (55.5% to 73.2%) and 74.2% (64.2% to 84.2%), respectively. Inclusion of 28 additional subjects for whom repeat DNA results were unavailable, obtained from only one reference centre, or discrepant by one repeat within this range, gave penetrance data (including 95% confidence intervals) at ages 65 and 75 years of 62.4% (54.4% to 70.4%) and 72.7.% (63.3% to 82.1%), respectively. 238 duplicate results were available from the reference centres; 10 (4.2%) differed by one CAG repeat in the reporting of the upper allele and in two (0.84%) of these cases the discrepancy was between 39 and 40 repeats. CONCLUSION: When DNA results are in this range, a conservative approach is to say that there is at least a 40% chance the person will be asymptomatic at age 65 years and at least a 30% chance the person will be asymptomatic at age 75 years.
Assuntos
Doença de Huntington/genética , Expansão das Repetições de Trinucleotídeos , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Coortes , Feminino , Humanos , Doença de Huntington/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Penetrância , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: To study the consent process experienced by participants who are enrolled in a molecular genetic research study that aims to find new genetic mutations responsible for an apparently inherited disorder. DESIGN: Semi-structured interviews and analysis/description of main themes. PARTICIPANTS: 78 members of 52 families who had been recruited to a molecular genetic study. RESULTS: People were well informed about the goals, risks and benefits of the genetic research study but could not remember the consent process. They had mostly been recruited to take part by trusted clinicians or their relatives but had little memory of, or concern about signing consent forms. Families appeared to regard the research as a continuation of their, or their relatives', clinical care. CONCLUSIONS: Ethical review should be more flexible in its attitude to consent forms and written information sheets for some sorts of research. For rare genetic disease studies where research has been discussed fully within the clinical setting then the consent obtained at that time could suffice rather than needing extra consent at a later stage. However, clinician-researchers will need to ensure that their duty of care extends for the duration of the research and beyond.
Assuntos
Ensaios Clínicos como Assunto/ética , Pesquisa em Genética/ética , Consentimento Livre e Esclarecido/ética , Seleção de Pacientes/ética , Doenças Raras/genética , Família , Feminino , Predisposição Genética para Doença/genética , Predisposição Genética para Doença/prevenção & controle , Humanos , Consentimento Livre e Esclarecido/psicologia , Consentimento Livre e Esclarecido/normas , Masculino , Sujeitos da Pesquisa/psicologia , Reino UnidoRESUMO
Mutations in CHD7 have been shown to be a major cause of CHARGE syndrome, which presents many symptoms and features common to other syndromes making its diagnosis difficult. Next generation sequencing (NGS) of a panel of intellectual disability related genes was performed in an adult patient without molecular diagnosis. A splice donor variant in CHD7 (c.5665 + 1G > T) was identified. To study its potential pathogenicity, exons and flanking intronic sequences were amplified from patient DNA and cloned into the pSAD® splicing vector. HeLa cells were transfected with this construct and a wild-type minigene and functional analysis were performed. The construct with the c.5665 + 1G > T variant produced an aberrant transcript with an insert of 63 nucleotides of intron 28 creating a premature termination codon (TAG) 25 nucleotides downstream. This would lead to the insertion of 8 new amino acids and therefore a truncated 1896 amino acid protein. As a result of this, the patient was diagnosed with CHARGE syndrome. Functional analyses underline their usefulness for studying the pathogenicity of variants found by NGS and therefore its application to accurately diagnose patients.
RESUMO
Mental retardation is more common in males than females in the population, assumed to be due to mutations on the X chromosome. The prevalence of the 24 genes identified to date is low and less common than expansions in FMR1, which cause Fragile X syndrome. Systematic screening of all other X linked genes in X linked families with mental retardation is currently not feasible in a clinical setting. The phenotypes of genes causing syndromic and non-syndromic mental retardation (NLGN3, NLGN4, RPS6KA3(RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, SMCX, and SLC16A2) are first discussed, as these may be the focus of more targeted mutation analysis. Secondly, the relative prevalence of genes causing only non-syndromic mental retardation (IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, and GDI) is summarised. Thirdly, the problem of recurrence risk where a molecular genetics diagnosis has not been made and what proportion of the male excess of mental retardation is due to monogenic disorders of the X chromosome are discussed.
Assuntos
Cromossomos Humanos X , Deficiência Intelectual/genética , Ataxia Cerebelar/genética , Mapeamento Cromossômico , Diagnóstico Diferencial , Marcadores Genéticos , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/psicologia , InteligênciaRESUMO
BACKGROUND: Most cases of Sotos syndrome are caused by intragenic NSD1 mutations or 5q35 microdeletions. It is uncertain whether allelic or genetic heterogeneity underlies the residual cases and it has been proposed that other mechanisms, such as 11p15 defects, might be responsible for Sotos cases without NSD1 mutations or 5q35 microdeletions. OBJECTIVE: To develop a multiplex ligation dependent probe amplification (MLPA) assay to screen NSD1 for exonic deletions/duplications. METHODS: Analysis was undertaken of 18 classic Sotos syndrome cases in which NSD1 mutations and 5q35 microdeletions were excluded. Long range polymerase chain reaction (PCR) was used to characterise the mechanism of generation of the partial NSD1 deletions. RESULTS: Eight unique partial NSD1 deletions were identified: exons 1-2 (n = 4), exons 3-5, exons 9-13, exons 19-21, and exon 22. Using long range PCR six of the deletions were confirmed and the precise breakpoints in five cases characterised. This showed that three had arisen through Alu-Alu recombination and two from non-homologous end joining. CONCLUSIONS: MLPA is a robust, inexpensive, simple technique that reliably detects both 5q35 microdeletions and partial NSD1 deletions that together account for approximately 15% of Sotos syndrome.
Assuntos
Deleção de Genes , Transtornos do Crescimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Deficiências da Aprendizagem/genética , Proteínas Nucleares/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Sequência de Bases , Estudos de Casos e Controles , Histona Metiltransferases , Histona-Lisina N-Metiltransferase , Humanos , Dados de Sequência Molecular , SíndromeRESUMO
A female patient with non-syndromic mental retardation was shown by high resolution GTL banding to have inherited an apparently balanced translocation, 46,X,t(X;8)(q28;q12)mat. Replication studies in the mother and daughter showed a skewed X inactivation pattern in lymphocytes, with the normal X chromosome preferentially inactivated. The mother also had significant intellectual disability. To investigate the possibility that a novel candidate gene for XLMR was disrupted at the X chromosome translocation breakpoint, we mapped the breakpoint using fluorescence in situ hybridisation (FISH). This showed that the four known genes involved in non-syndromic mental retardation in Xq28, FMR2, SLC6A8, MECP2, and GDI1, were not involved in the translocation. Intriguingly, we found that the X chromosome breakpoint in the daughter could not be defined by a single breakpoint spanning genomic clone and further analysis showed a 650 kb submicroscopic duplication between DXS7067 and DXS7060 on either side of the X chromosome translocation breakpoint. This duplicated region contains 11 characterised genes, of which nine are expressed in brain. Duplication of one or several of the genes within the 650 kb interval is likely to be responsible for the mental retardation phenotype seen in our patient. Xq28 appears to be an unstable region of the human genome and genomic rearrangements are recognised as major causes of two single gene defects, haemophilia A and incontinentia pigmenti, which map within Xq28. This patient therefore provides further evidence for the instability of this genomic region.
Assuntos
Cromossomos Humanos Par 8/genética , Cromossomos Humanos X/genética , Deficiência Intelectual/genética , Aberrações dos Cromossomos Sexuais , Translocação Genética , Criança , Pré-Escolar , Quebra Cromossômica , Feminino , Duplicação Gênica , Ligação Genética , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/patologia , Cariotipagem , Repetições de Microssatélites , SíndromeRESUMO
There is a strong association between prenatally diagnosed structural heart disease and fetal chromosomal abnormalities. Isomerism of the atrial appendages is an exception to this because the fetal karyotype is usually normal in this condition. A case of atrial isomerism diagnosed antenatally with a normal female karyotype but with a microdeletion of chromosome 22q11 is reported.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22 , Cardiopatias Congênitas/genética , Ultrassonografia Pré-Natal , Adulto , Feminino , Doenças Fetais/diagnóstico , Átrios do Coração/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico , Humanos , GravidezRESUMO
Amelia is an extremely rare abnormality with a highest reported incidence of 1 in 67,500 liveborn infants. We now report four cases in each of which amelia involving one upper limb occurred in association with anal atresia. The pattern of other abnormalities present in these cases suggests that this combination of amelia and anal atresia falls within the spectrum of the VACTERL association.
Assuntos
Anormalidades Múltiplas/patologia , Anus Imperfurado/complicações , Braço/anormalidades , Ectromelia/complicações , Anoftalmia/complicações , Criança , Fenda Labial/complicações , Fissura Palatina/complicações , Feminino , Cardiopatias Congênitas/complicações , Humanos , Recém-Nascido , Rim/anormalidades , Laringe/anormalidades , Masculino , Artérias Umbilicais/anormalidadesRESUMO
We describe three families with X-linked mental retardation, two with a deletion of a single amino acid and one with a missense mutation in the proximal domain of the RSK2(RPS6KA3) (ribosomal protein S6 kinase, 90 kDa, polypeptide 3) protein similar to mutations found in Coffin-Lowry syndrome (CLS). In two families, the clinical diagnosis had been nonsyndromic X-linked mental retardation. In the third family, although CLS had been suspected, the clinical features were atypical and the degree of intellectual disability much less than expected. These families show that strict reliance on classical clinical criteria for mutation testing may result in a missed diagnosis. A less targeted screening approach to mutation testing is advocated.
Assuntos
Síndrome de Coffin-Lowry/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação/genética , Fenótipo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Sequência de Aminoácidos , Sequência de Bases , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNARESUMO
This paper reviews the advances in molecular genetics over the recent years and discusses the impact it may have on those with intellectual disability and their families. The aim is not to present a comprehensive scientific treatise but rather to use illustrations from genetics to highlight our current thinking and draw attention to areas of uncertainty and misinformation. As our knowledge and understanding of the genetic basis of disease increases over the years, there may be significant benefits to some families, but the potential for discrimination against individuals on genetic grounds will also increase.
Assuntos
Efeitos Psicossociais da Doença , Ética Clínica , Saúde da Família , Serviços em Genética/ética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Biologia Molecular/ética , Biologia Molecular/métodos , Feminino , Projeto Genoma Humano , Humanos , Gravidez , Diagnóstico Pré-Natal , Estados UnidosRESUMO
We report a series of five patients with congenital heart defects in whom a prenatal diagnosis of 22q11 deletion has been made. The accurate cardiac and cytogenetic diagnoses were made between 20 and 23 weeks' gestation in all cases and the cardiac findings were all confirmed postnatally. The cardiac abnormalities included tetralogy of Fallot with absent pulmonary valve, pulmonary atresia with VSD, common arterial trunk, and left atrial isomerism with double outlet right ventricle. The problems of genetic counselling in these cases are discussed. A recommendation is made to test all fetuses with conotruncal heart abnormalities detected prenatally for a 22q11 deletion, whereas guidelines for other congenital heart disease types are less clear.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 11 , Cardiopatias Congênitas/genética , Diagnóstico Pré-Natal , Ecocardiografia , Feminino , Cardiopatias Congênitas/diagnóstico , Humanos , Miocárdio/patologia , Gravidez , Tetralogia de Fallot/patologia , Ultrassonografia Pré-NatalRESUMO
A patient with a complex chromosome rearrangement and unilateral Rieger syndrome is presented. This rearrangement involves four chromosomes and six breakpoints, one of which is at 4q25, the candidate region for Rieger syndrome. We discuss a novel approach to the elucidation of this case using a multiprobe fluorescence in situ hybridisation method to show rearrangements unpredictable from G banded analysis, and the clear and unambiguous presentation of the karyotype using computer generated colour ideograms.