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Hill M.,Institute of Child Health | Lewis C.,Genetic Alliance UK | Jenkins L.,North East Thames Regional Molecular Genetics Laboratory | Allen S.,West Midlands Regional Genetics Laboratory | And 2 more authors.
Expert Opinion on Biological Therapy | Year: 2012

Introduction : Fetal sex determination has traditionally been performed in pregnancies at risk of sex-linked genetic conditions by analysis of chorionic villi or amniocytes following invasive tests. The development of noninvasive prenatal diagnosis (NIPD) using cell-free fetal DNA in maternal plasma has allowed women to have accurate information about fetal sex early in pregnancy without the risk of miscarriage. Areas covered : In the UK, NIPD for fetal sex determination has been offered on a research basis since 2003. Formal approval and regulation through national bodies is essential to ensure standardized laboratory services, appropriate funding and equity of access for service users. Here we describe the process of formal commissioning that has been supported by a multifaceted approach to service evaluation, including appraisal of analytical and clinical validity, clinical utility and economic costs together with an exploration of service users' and providers' attitudes, preferences and information needs. Expert opinion : Implementation strategies that reach beyond the assessment of laboratory test parameters to consider psychosocial and economic issues have been crucial in bringing NIPD for fetal sex determination into routine practice. Ongoing audit and monitoring of service delivery will ensure a high standard of care is maintained. © 2012 Informa UK, Ltd. Source


Jeffries S.J.,West Midlands Regional Genetics Laboratory | Jones L.,Northumbria University | Harrison C.J.,Northumbria University | Russell L.J.,Northumbria University
Haematologica | Year: 2014

Primary established genetic abnormalities in B-cell precursor acute lymphoblastic leukemia include high hyperdiploidy (51-65 chromosomes), the translocations t(12;21)(p13;q22)/ETV6-RUNX1 fusion and t(9;22)(q34;q11)/BCR-ABL1 fusion, MLL rearrangements and intrachromosomal amplification of chromosome 21. These rearrangements are of prognostic and therapeutic relevance and are usually mutually exclusive. We identified 28 patients at diagnosis with both a primary genetic rearrangement and an immunoglobulin heavy chain locus translocation using chromosomal analysis and fluorescence in situ hybridization. Among these patients, the immunoglobulin heavy chain locus translocation partner gene was identified in six (CRLF2, CEBPA, CEBPB, TRA/D@, IGF2BP1 and IGK@). Clonal architecture was investigated in 17 patients using multiple color interphase fluorescence in situ hybridization analysis, which showed that the translocation was acquired as a secondary abnormality in ten patients, in four patients the etiology was undetermined and in three patients it was observed in a separate clone from the primary chromosomal rearrangement. These findings demonstrate the co-existence of immunoglobulin heavy chain locus translocations with other primary chromosomal rearrangements either in the same or separate clones, which may have prognostic significance in B-cell precursor acute lymphoblastic leukemia. Clinical trials: UKALLXII: Study ID n. ISRCTN77346223 and ALL2003: Study ID n. ISRCTN07355119. © 2014 Ferrata Storti Foundation. Source


Bradshaw E.H.,West Midlands Regional Genetics Laboratory
Pharmacogenomics | Year: 2015

Third Annual Open Meeting of the UK Pharmacogenetics and Stratified Medicine Network 14 January 2015, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK The third Annual Open Meeting of the UK Pharmacogenetics and Stratified Medicine Network was held on 14 January 2015 in association with the Wellcome Trust on the Wellcome Trust Genome Campus at Hinxton, Cambridge, UK. In the morning, speakers from Cancer Research UK, the Medical Research Council, Genomics England, Innovate UK (formerly TSB) and the Department of Health described the current major projects they are funding. In the afternoon, speakers from various universities around the United Kingdom presented data on pharmacogenetics and stratified medicine research covering diverse disease areas including cancers, warfarin dosing, Gaucher disease and rheumatoid arthritis. © 2015 Future Medicine Ltd. Source


Tonks A.M.,West Midlands Perinatal Institute | Gornall A.S.,West Midlands Perinatal Institute | Larkins S.A.,West Midlands Regional Genetics Laboratory | Gardosi J.O.,West Midlands Perinatal Institute
Prenatal Diagnosis | Year: 2013

Objective: The objective of this study was to determine trends in prenatal detection and current estimates of prevalence for trisomies 18 (T18) and 13 (T13) and their implications for screening policy. Methods: We conducted a cohort study from a population-based regional anomaly register covering 995003 births (1995-2009). Results: There were 786 affected cases. Total prevalence of T18 increased from 3.95 in 1995-1999 to 6.94 per 10000 births in 2005-2009 (annual trend χ2=25.99, p<0.001) and live birth prevalence, when adjusted for in utero attrition, increased from 1.47 to 2.30 per 10000 births over the same time (annual trend χ2=6.36, p=0.01). For T18 and T13 combined, the proportion of cases diagnosed by prenatal karyotype or suspected by ultrasound increased from 85.1% (165/194) in 1995-1999 to 95.2% (299/314) in 2005-2009 (p<0.001). In 2005-2009, 50.3% of prenatal cytogenetic diagnoses for T18 and 38.5% of T13 were made after the discovery of first trimester ultrasound anomalies, and the majority, 56.4% (185/328), of affected pregnancies were karyotyped or had ended before 18weeks. Conclusion: T18 is increasing in prevalence because of maternal age and earlier surveillance. Prenatal diagnosis occurs mostly in the first trimester, without the intrinsic structures of a formal screening programme. These findings support the extension of first trimester combined screening to include T18 and T13. © 2013 Crown copyright. What's already known about this topic? Trisomies 18 and 13 (T18 and T13) are lethal chromosomal anomalies that are more commonly seen in older mothers. The changing pattern of maternal age suggests that the prevalence of both anomalies should be increasing, but reliable long-term evidence is lacking. In the UK, screening for T18 and T13 is undertaken routinely using second trimester ultrasound, whereas other European countries have elected to include T18 and T13 risk calculation within first trimester combined screening. What does this study add? Trisomy 18 is increasing in prevalence. Our study highlights the opportunistic nature of prenatal detection, which is increasing for both anomalies and taking place earlier in pregnancy. These findings may influence the National Screening Committee, as part of its current consultation, to provide a first trimester screening test for T18 and T13. © 2013 Crown copyright.. Source


Terrenoire E.,University of Birmingham | Terrenoire E.,West Midlands Regional Genetics Laboratory | Halsall J.A.,University of Birmingham | Turner B.M.,University of Birmingham
BMC Genetics | Year: 2015

Background: Using metaphase spreads from human lymphoblastoid cell lines, we previously showed how immunofluorescence microscopy could define the distribution of histone modifications across metaphase chromosomes. We showed that different histone modifications gave consistent and clearly defined immunofluorescent banding patterns. However, it was not clear to what extent these higher level distributions were influenced by long-term growth in culture, or by the specific functional associations of individual histone modifications. Results: Metaphase chromosome spreads from human lymphocytes stimulated to grow in short-term culture, were immunostained with antibodies to histone H3 mono- or tri-methylated at lysine 4 (H3K4me1, H3K4me3). Chromosomes were identified on the basis of morphology and reverse DAPI (rDAPI) banding. Both antisera gave the same distinctive immunofluorescent staining pattern, with unstained heterochromatic regions and a banded distribution along the chromosome arms. Karyotypes were prepared, showing the reproducibility of banding between sister chromatids, homologue pairs and from one metaphase spread to another. At the light microscope level, we detect no difference between the banding patterns along chromosomes from primary lymphocytes and lymphoblastoid cell lines adapted to long-term growth in culture. Conclusions: The distribution of H3K4me3 is the same across metaphase chromosomes from human primary lymphocytes and LCL, showing that higher level distribution is not altered by immortalization or long-term culture. The two modifications H3K4me1 (enriched in gene enhancer regions) and H3K4me3 (enriched in gene promoter regions) show the same distributions across human metaphase chromosomes, showing that functional differences do not necessarily cause modifications to differ in their higher-level distributions. © Terrenoire et al.; licensee BioMed Central. Source

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