Browsing by Author "Shirley Henderson"

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    Adventitious changes in long-range gene expression caused by polymorphic structural variation and promoter competition
    (2009-12-22) Karen M. Lower; Jim R. Hughes; Marco De Gobbi; Shirley Henderson; Vip Viprakasit; Chris Fisher; Anne Goriely; Helena Ayyub; Jackie Sloane-Stanley; Douglas Vernimmen; Cordelia Langford; David Garrick; Richard J. Gibbons; Douglas R. Higgs; John Radcliffe Hospital; Oxford Radcliffe Hospitals NHS Trust; Mahidol University; Wellcome Trust Sanger Institute
    It is well established that all of the cis-acting sequences required for fully regulated human α-globin expression are contained within a region of ≈120 kb of conserved synteny. Here, we show that activation of this cluster in erythroid cells dramatically affects expression of apparently unrelated and noncontiguous genes in the 500 kb surrounding this domain, including a gene (NME4) located 300 kb from the α-globin cluster. Changes in NME4 expression are mediated by physical cis-interactions between this gene and the α-globin regulatory elements. Polymorphic structural variation within the globin cluster, altering the number of α-globin genes, affects the pattern of NME4 expression by altering the competition for the shared α-globin regulatory elements. These findings challenge the concept that the genome is organized into discrete, insulated regulatory domains. In addition, this work has important implications for our understanding of genome evolution, the interpretation of genome-wide expression, expression-quantitative trait loci, and copy number variant analyses.
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    A novel 33-Gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemias
    (2016-10-01) Noémi B.A. Roy; Edward A. Wilson; Shirley Henderson; Katherine Wray; Christian Babbs; Steven Okoli; Wale Atoyebi; Avery Mixon; Mary R. Cahill; Peter Carey; Jonathan Cullis; Julie Curtin; Helene Dreau; David J.P. Ferguson; Brenda Gibson; Georgina Hall; Joanne Mason; Mary Morgan; Melanie Proven; Amrana Qureshi; Joaquin Sanchez Garcia; Nongnuch Sirachainan; Juliana Teo; Ulf Tedgård; Doug Higgs; David Roberts; Irene Roberts; Anna Schuh; John Radcliffe Hospital; Churchill Hospital; Erlanger Hospital; Cork University Hospital; Royal Victoria Infirmary; Salisbury NHS Foundation Trust; Sydney Children's Hospitals Network; Nuffield Department of Clinical Medicine; Royal Hospital for Sick Children Glasgow; Southampton University Hospitals NHS Trust; Hospital Universitario Reina Sofia; Mahidol University; Skånes universitetssjukhus
    © 2016 John Wiley & Sons Ltd Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next-generation-sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical-grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically-reliable diagnostic test and minimize false-negative results we developed an open-source tool (CoverMi) to accurately determine base-coverage and the ‘discoverability’ of known mutations for every sample. We validated our 33-gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS-based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family.