المؤلفون: Gill Wilson, Anna de Burca, Marta Bleda, Lucy R. Wedderburn, Matthew Welland, Kathleen Stirrups, Valentina Cipriani, Kerrie Woods, Vijeya Ganesan, Susan Hill, Rosaline Quinlivan, Georgia Chan, Mehul T. Dattani, Robert McFarland, Graeme C.M. Black, Rutendo Mapeta, Augusto Rendon, Francesco Muntoni, James O.J. Davies, Mina Ryten, Rebecca E. Foulger, Arianna Tucci, Dina Halai, Tom Fowler, Noemi B.A. Roy, Sarah Leigh, Dragana Josifova, Philip Twiss, Ana L.T. Tavares, Zerin Hyder, Detlef Bockenhauer, Patrick Yu-Wai-Man, Lara Abulhoul, Nikolas Pontikos, Anthony T. Moore, Huw R. Morris, Patrick F. Chinnery, Nicholas W. Wood, Ellen A. Thomas, Shehla Mohammed, Sofia Douzgou, Tanya Lam, Kate Gibson, Robert Sarkany, Teofila Bueser, Wei Wei, Siddharth Banka, Alexander Broomfield, Hiva Fassihi, Nils Koelling, Carolyn Campbell, James Buchanan, Melita Irving, Sandrine Compeyrot-Lacassagne, Karola Rehmström, Austen Worth, Nikhil Thapar, Andrew R. Webster, Paul Brennan, Rita Horvath, Gavin Arno, Richard H Scott, Sam Malka, Andrew O.M. Wilkie, Sofie Ashford, Maria Bitner-Glindzicz, Jana Vandrovcova, William G. Newman, Caroline F. Wright, Andrew M. Schaefer, Roger F.L. James, Robert W. Taylor, Melanie Babcock, Arjune Sen, Emma Baple, Ellen M. McDonagh, Stephanie Grunewald, Loukas Moutsianas, Melissa A. Haendel, Olivera Spasic-Boskovic, Eleanor G. Seaby, Anna Need, Clarissa Pilkington, Sarah Wordsworth, Shamima Rahman, Christine Patch, Colin Wallis, Kristina Ibanez, Bishoy Habib, Eik Haraldsdottir, Huw B. Thomas, Razvan Sultana, Andrea H. Németh, Agata Wolejko, Claire Palles, Phil Beales, Adam C. Shaw, Letizia Vestito, Emily Li, Sarah Rose, Sarah Hunter, Angela Matchan, Genevieve Say, Dalia Kasperaviciute, Henry Houlden, Raymond T. O’Keefe, R. Andres Floto, Jill Clayton-Smith, John B. Taylor, Hywel J. Williams, Volker Straub, Val Davison, Helen Savage, John Chisholm, Eleanor Dewhurst, Charles Crichton, Andrea Haworth, Clare Turnbull, Carolyn Tregidgo, Carme Camps, Christopher Penkett, Emer O’Connor, Georgina Hall, Lyn S. Chitty, Sally Halsall, Andrew D. Mumford, Annette G. Wagner, Eleanor Williams, Mark Bale, Julius O. Jacobsen, Willem H. Ouwehand, Charu Deshpande, Gavin Burns, Smita Y. Patel, James Polke, Thiloka Ratnaike, Gavin Fuller, John Burn, Kenneth E. S. Poole, Emma Footitt, John R. Bradley, Suzanne Wood, Russell J. Grocock, Jenny C. Taylor, Louise Izatt, Kikkeri N. Naresh, Katherine R. Smith, Nigel Burrows, Katrina Newland, Peter N. Robinson, Sarju G. Mehta, Michael A. Simpson, Michael R. Barnes, Pilar Cacheiro, Olivia Niblock, Tracy Lester, Dimitris Polychronopoulos, Helen Brittain, John A. Sayer, Antonio Martin, Eshika Haque, Sean Humphray, Douglass M. Turnbull, Damian Smedley, Andrew Devereau, Stefan Gräf, Sian Ellard, Ivone U.S. Leong, Martin G. Reese, Matthias Wielscher, Louise C. Daugherty, Perry M. Elliott, F. Lucy Raymond, Cecilia Compton, David Bentley, Catherine Snow, James Welch, Frances Flinter, Dom McMullan, Mark J. Caulfield, Paul Aurora, Mark Gurnell, Mary Kasanicki, I. Karen Temple, Michel Michaelides, Deborah Ruddy, Leema Robert, Janice Yip, Grainne S. Gorman, Andrew C. Browning, Richard Quinton, Maureen Cleary, Jamie M. Ellingford, Angela Douglas, Christopher Boustred

المساهمون: Investigators, The 100,000 Genomes Project Pilot

المصدر: Mumford, A D 2021, ' 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care-Preliminary Report ', New England Journal of Medicine, vol. 385, no. 20, pp. 1868-1880 . https://doi.org/10.1056/NEJMoa2035790Test

مصطلحات موضوعية: Adult, Male, Proband, medicine.medical_specialty, Adolescent, Pilot Projects, Genomics, Polymerase Chain Reaction, Genome, State Medicine, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Health care, Human Phenotype Ontology, Humans, Medicine, Child, Exome sequencing, 030304 developmental biology, Family Characteristics, 0303 health sciences, Whole Genome Sequencing, Genome, Human, business.industry, Genetic Variation, Rare Diseases/diagnosis, General Medicine, Middle Aged, United Kingdom, 3. Good health, Child, Preschool, Family medicine, Medical genetics, Female, business, Bristol, 030217 neurology & neurosurgery, Rare disease

الوصف: BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::07e7a9cb72d07e6534b79e777083f769Test
https://doi.org/10.1056/nejmoa2035790Test

المؤلفون: Judith Hayward, Val Davison, Imran Rafi, Michelle Bishop

المصدر: British Journal of General Practice. 67:58-59

مصطلحات موضوعية: Genomics, Disease, Gene mutation, Bioinformatics, Genome, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Breast cancer, Neoplasms, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, 030212 general & internal medicine, Primary Health Care, business.industry, Editorials, Cancer, Genomic signature, Precision medicine, medicine.disease, United Kingdom, 030220 oncology & carcinogenesis, Family Practice, business

الوصف: > ‘ The NHS will need to be ready to use genomics as part of its routine care 1 But how will genomics impact on primary care and what is needed for primary care to be genomics-ready? While genetics focuses on DNA coding for single functional genes, genomics is the study of the entirety of our DNA, recognising the crucial regulatory role of non-coding DNA and the complex interactions between multiple genes and the environment. Genomics and variation is fundamental to precision medicine which, through its four components of predictive, preventive, personalised, and participatory medicine, aims to promote wellness as well as to more precisely treat disease. The transformational 100 000 Genomes Project funded by the Department of Health aspires to kick-start a UK genomics industry and set up a genomics medicine service within the NHS.1 GPs will play an important role within a genomics medicine service both in supporting patients through diagnostic and treatment processes and in using knowledge of genomics for disease prevention. There are 356 000 new cancer cases diagnosed in the UK each year.2 Testing of both the patient’s own genetic makeup (‘germline’ DNA) and the tumour DNA (‘somatic’ testing) are important here. A tumour’s genomic signature may be used to make a precise diagnosis, enabling more accurate prognosis and better tailored treatment. Examples include Herceptin® (trastuzumab) in breast cancer treatment and BRAF inhibitors in malignant melanoma. Treatment can also be based on germline genomic information; PARP inhibitors are more efficacious in the treatment of ovarian cancer in individuals who carry a BRCA gene mutation. Cancer follows …

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8574d134e18cac1f674b3fe7d7b3f04dTest
https://doi.org/10.3399/bjgp17x688945Test

المؤلفون: Dominic J. McMullan, Jenny Elizabeth Morton, Chirag Patel, Judith M. Walker, Lisa Cooper-Charles, Val Davison

المصدر: European Journal of Human Genetics. 19:634-639

مصطلحات موضوعية: Male, Candidate gene, Tics, Apraxias, Cystic Fibrosis Transmembrane Conductance Regulator, Translocation Breakpoint, Biology, Tourette syndrome, Article, Translocation, Genetic, Chromosome Breakpoints, Exon, Gene mapping, Endopeptidases, Genetics, medicine, Humans, In Situ Hybridization, Fluorescence, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Sequence Deletion, Comparative Genomic Hybridization, Breakpoint, Forkhead Transcription Factors, FOXP2, DNA, Exons, medicine.disease, Pedigree, Chromosomes, Human, Pair 7, Tourette Syndrome

الوصف: Gilles de la Tourette syndrome is a complex neuropsychiatric disorder with a strong genetic basis. We identified a male patient with Tourette syndrome-like tics and an apparently balanced de novo translocation [46,XY,t(2;7)(p24.2;q31)]. Further analysis using array comparative genomic hybridisation (CGH) revealed a cryptic deletion at 7q31.1-7q31.2. Breakpoints disrupting this region have been reported in one isolated and one familial case of Tourette syndrome. In our case, IMMP2L, a gene coding for a human homologue of the yeast inner mitochondrial membrane peptidase subunit 2, was disrupted by the breakpoint on 7q31.1, with deletion of exons 1-3 of the gene. The IMMP2L gene has previously been proposed as a candidate gene for Tourette syndrome, and our case provides further evidence of its possible role in the pathogenesis. The deleted region (7q31.1-7q31.2) of 7.2 Mb of genomic DNA also encompasses numerous genes, including FOXP2, associated with verbal dyspraxia, and the CFTR gene.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dd52f5af9826a5f282229c011e8a9c7eTest
https://doi.org/10.1038/ejhg.2010.238Test

المؤلفون: Richard M. Barber, Cyril Chapman, Fatimah Rahman, Salwati Shuib, Farida Latif, Val Davison, Malgosia Zatyka, Dominic J. McMullan, Eleanor Rattenberry, Eamonn R. Maher, Fiona Macdonald

المصدر: American Journal of Medical Genetics Part A. :2099-2105

مصطلحات موضوعية: Heart Defects, Congenital, Candidate gene, Genotype, Microarray, Gene Dosage, Telecanthus, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Gene mapping, Intellectual Disability, Genetics, medicine, Humans, SNP, Child, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Psychomotor retardation, Gene Expression Profiling, GTPase-Activating Proteins, Syndrome, Penetrance, Phenotype, Chromosome 3, Chromosomes, Human, Pair 3, Chromosome Deletion, medicine.symptom

الوصف: Distal deletion of chromosome 3p25-pter (3p- syndrome) produces a distinct clinical syndrome characterized by low birth weight, mental retardation, telecanthus, ptosis, and micrognathia. Congenital heart disease (CHD), typically atrioventricular septal defect (AVSD) occurs in about a third of patients. Previously we reported on an association between the presence of CHD and the proximal extent of the deletion such that a CHD susceptibility gene was mapped between D3S1263 and D3S3594. In addition, we and others have suggested several candidate genes for the psychomotor retardation usually seen with constitutional 3p25 deletions. In order to further investigate genotype-phenotype correlations in 3p- syndrome we analyzed 14 patients with cytogenetically detectable deletions of 3p25 (including one patient with a normal phenotype) using Affymetrix 250K SNP microarrays. Deletion size varied from approximately 6 to 12 Mb. Assuming complete penetrance, a candidate critical region for a CHD susceptibility gene was refined to approximately 200 kb and a candidate critical region for mental retardation was mapped to an approximately 1 Mb interval containing SRGAP3 but other 3p neurodevelopmental genes including CHL1, CNTN4, LRRN1, and ITPR1 mapped outside the candidate critical interval. We suggest that current evidence suggests that SRGAP3 is the major determinant of mental retardation in distal 3p deletions.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b8a3f430104592a7dc748a726acaf3c3Test
https://doi.org/10.1002/ajmg.a.32824Test

المؤلفون: Kim Smith, Samantha J. L. Knight, Edward Blair, Eddy Maher, Jenny C. Taylor, Regina Regan, Sara Dyer, James M. Buchanan, Carolyn Campbell, Sarah Wordsworth, Val Davison

المصدر: Genomic Medicine

مصطلحات موضوعية: medicine.medical_specialty, Cost effectiveness, Microarrays, MEDLINE, Comparative genomic hybridisation, Context (language use), Bioinformatics, 03 medical and health sciences, medicine, Genetics, Genetics(clinical), Medical diagnosis, Intensive care medicine, Genetics (clinical), Average cost, health care economics and organizations, Learning disability, 030304 developmental biology, Cost database, 0303 health sciences, business.industry, 030305 genetics & heredity, Cost-effectiveness analysis, 3. Good health, Cost-effectiveness, medicine.symptom, business, Research Article

الوصف: Array based comparative genomic hybridisation (aCGH) is a powerful technique for detecting clinically relevant genome imbalance and can offer 40 to > 1000 times the resolution of karyotyping. Indeed, idiopathic learning disability (ILD) studies suggest that a genome-wide aCGH approach makes 10–15% more diagnoses involving genome imbalance than karyotyping. Despite this, aCGH has yet to be implemented as a routine NHS service. One significant obstacle is the perception that the technology is prohibitively expensive for most standard NHS clinical cytogenetics laboratories. To address this, we investigated the cost-effectiveness of aCGH versus standard cytogenetic analysis for diagnosing idiopathic learning disability (ILD) in the NHS. Cost data from four participating genetics centres were collected and analysed. In a single test comparison, the average cost of aCGH was £442 and the average cost of karyotyping was £117 with array costs contributing most to the cost difference. This difference was not a key barrier when the context of follow up diagnostic tests was considered. Indeed, in a hypothetical cohort of 100 ILD children, aCGH was found to cost less per diagnosis (£3,118) than a karyotyping and multi-telomere FISH approach (£4,957). We conclude that testing for genomic imbalances in ILD using microarray technology is likely to be cost-effective because long-term savings can be made regardless of a positive (diagnosis) or negative result. Earlier diagnoses save costs of additional diagnostic tests. Negative results are cost-effective in minimising follow-up test choice. The use of aCGH in routine clinical practice warrants serious consideration by healthcare providers.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::425e9433fadb5dc02a422fc0d3adbe65Test
http://europepmc.org/articles/PMC2276893Test

المؤلفون: Pramila Ramani, Carmel McConville, Shaheen A. Chughtai, Dominic J. McMullan, J. E. Powell, Val Davison, Sara Dyer, Tracey Genus

المصدر: European Journal of Cancer. 42:1826-1834

مصطلحات موضوعية: Adult, Cancer Research, Pathology, medicine.medical_specialty, Adolescent, Genotype, Loss of Heterozygosity, Disease, Biology, Malignancy, Loss of heterozygosity, Neuroblastoma, medicine, Humans, Stage (cooking), Child, Allelotype, neoplasms, Aged, Infant, Newborn, Infant, Cancer, Middle Aged, medicine.disease, Survival Analysis, Phenotype, Oncology, Child, Preschool, Disease Progression, Cancer research

الوصف: Neuroblastoma is a heterogeneous tumour with a variety of clinical phenotypes, ranging from a localised tumour with excellent outcome (stage 1) to a metastatic, usually fatal malignancy (stage 4). In order to investigate the genetic relationship between these tumour subtypes, a loss of heterozygosity (LOH) analysis was carried out. Composite LOH allelotypes incorporating data from 96 loci on 5 chromosomes (1p, 3p, 4p, 11q, 14q), were constructed for 62 neuroblastomas. Neuroblastomas with similar allelotypes were clustered into groups and allelotype patterns correlated with clinical features. Three distinct genetic subgroups of neuroblastoma were observed. The largest group (50% of tumours) was characterised by specific allelotype patterns indicative of a stepwise accumulation of genetic alterations (11q LOH → 1p, 4p, and/or 14q LOH → 3p LOH), associated with progression from low to high stage disease. These tumours are distinct from MYCN amplified neuroblastomas which have a more rapid and aggressive disease course, and also a proportion of low stage tumours, often ganglioneuromas or ganglioneuroblastomas, with restricted growth potential.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dbe5df5982dbf232a902b3be2bf3c5c7Test
https://doi.org/10.1016/j.ejca.2006.03.016Test

المؤلفون: Farida Latif, Beeling Ng, Mark R. Morris, Takeshi Kishida, Mahera Abdulrahman, Masahiro Yao, Susan M. Gribble, Rebecca E. Foster, Nigel P. Carter, Michael S. Wiesener, Steven Ready, Eamonn R. Maher, Dean Gentle, José Luis Barbero, Elena Prigmore, Phil M. T. Weston, Val Davison, Carol Chu

مصطلحات موضوعية: Male, Cancer Research, Candidate gene, Tumor suppressor gene, Molecular Sequence Data, Chromosomal translocation, Biology, medicine.disease_cause, urologic and male genital diseases, Article, Translocation, Genetic, Exon, Genetics, medicine, Humans, neoplasms, Carcinoma, Renal Cell, Cell Line, Transformed, Middle Aged, medicine.disease, Molecular biology, female genital diseases and pregnancy complications, Clear cell renal cell carcinoma, Chromosome 3, Chromosomes, Human, Pair 6, Chromosomes, Human, Pair 3, Carcinogenesis, Clear cell

الوصف: The most frequent cause of familial clear cell renal cell carcinoma (RCC) is von Hippel-Lindau disease and the VHL tumor suppressor gene (TSG) is inactivated in most sporadic clear cell RCC. Although there is relatively little information on the mechanisms of tumorigenesis of clear cell RCC without VHL inactivation, a subset of familial cases harbors a balanced constitutional chromosome 3 translocation. To date nine different chromosome 3 translocations have been associated with familial or multicentric clear cell RCC; and in three cases chromosome 6 was also involved. To identify candidate genes for renal tumorigenesis we characterized a constitutional translocation, t(3;6)(q22;q16.1) associated with multicentric RCC without evidence of VHL target gene dysregulation. Analysis of breakpoint sequences revealed a 1.3-kb deletion on chromosome 6 within the intron of a 2 exon predicted gene (NT_007299.434). However, RT-PCR analysis failed to detect the expression of this gene in lymphoblast, fibroblast, or kidney tumor cell lines. No known genes were disrupted by the translocation breakpoints but several candidate TSGs (e.g., EPHB1, EPHA7, PPP2R3A RNF184, and STAG1) map within close proximity to the breakpoints.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::717a74a1fdeb84da347ded2114376fabTest
https://europepmc.org/articles/PMC2695133Test/

المؤلفون: A. Griffiths, Trevor Cole, A. Ng, S. E. Parkes, Val Davison, Richard Grundy, M. Griffiths, Jillian R. Mann, S. Larkin

المصدر: European journal of cancer (Oxford, England : 1990). 43(9)

مصطلحات موضوعية: Adult, Male, Cancer Research, Pediatrics, medicine.medical_specialty, Adolescent, Consanguinity, Wilms Tumor, Congenital Abnormalities, Cohort Studies, Marshall–Smith syndrome, medicine, Humans, Medical history, Sibling, Child, business.industry, Incidence (epidemiology), Cancer, Infant, Wilms' tumor, medicine.disease, Kidney Neoplasms, Pedigree, Oncology, Genetic Techniques, Child, Preschool, Cohort, Female, business, Follow-Up Studies

الوصف: Altogether 156 children treated for Wilms' tumour (WT) between 1970 and 1998 were studied. Sixty-six children, selected only by their attendance at clinic, were carefully examined and the findings compared to those from a case note review of 90 children. Congenital abnormalities were present in 45% of the examined cohort, in 19% of the case notes review group and in 30% overall. Novel findings included the association of WT with Marshall Smith syndrome, developmental delay in 3 of 4 cases of WT (one bilateral) and 1 sibling from consanguineous Pakistani families and another sibling also had leukaemia. The possibility of rare DNA repair or cancer predisposing disorders among these 4 families requires further study. Careful examination and history taking of an unselected patient cohort revealed a higher than expected incidence of clinical abnormalities which may be overlooked if not specifically sought.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::95e3e95fdae20ec04dfd1e9ec17a91cdTest
https://pubmed.ncbi.nlm.nih.gov/17499987Test

المؤلفون: Lisbeth Tranebjerg, Zeynep Tümer, Iben Bache, Maria Orera, Vera M. Kalscheuer, Elisabeth Blennow, Val Davison, Klaus Wagner, David R. FitzPatrick, Isidora Lopez-Pajares, Laurence Duprez, Maj Hultén, Sultan Cingoz, Sophie Dahoun, Niels Tommerup, Margarita Stefanova, Ingo Hansmann, Jan Murken, Maryse Bonduelle, Bruno Dallapiccola, M.-F. Croquette, Tony Parkin, Kirsten Winther, Kim Smith, Fiorella Shabtai, Kirsten Rasmussen, Catherine Turleau, Claes Lundsteen, Anita Niebuhr, Elvire Van Assche, Gotthold Barbi, Eberhard Schwinger, Carl Birger van der Hagen, Bruno Delobel, Philippe Jonveaux, Nadja Kokalj Vokac, Peter Jensen, Inge Liebaers, Mads F. Hjorth, Georges Bourrouillou, Merete Bugge, Carmen Ramos, Regine Schubert, Leopoldo Zelante, Werner Schempp, Eberhard Passarge, Carmen Ayuso, Herman Tournaye, James Lespinasse, Malcolm A. Ferguson-Smith, Ulf Kristoffersson, Jan Wahlstroem, Gert Bruun-Petersen, Hans-Christoph Duba, Karen Brøndum-Nielsen, Michel Vekemans, Elizabeth Grace, Raymond L. Stallings, Jean McGowan-Jordan

المصدر: University of Copenhagen

مصطلحات موضوعية: Infertility, Genetics, Chromosome Aberrations, Male, medicine.medical_specialty, Cytogenetics, Chromosome, Chromosomal translocation, Karyotype, Locus (genetics), Oligospermia, Biology, medicine.disease, Translocation, Genetic, Male infertility, Chromosomes, Human, Pair 1, Chromosome Inversion, medicine, Humans, Genetics (clinical), Infertility, Male, Chromosomal inversion

الوصف: In a search for potential infertility loci, which might be revealed by clustering of chromosomal breakpoints, we compiled 464 infertile males with a balanced rearrangement from Mendelian Cytogenetics Network database (MCNdb) and compared their karyotypes with those of a Danish nation-wide cohort. We excluded Robertsonian translocations, rearrangements involving sex chromosomes and common variants. We identified 10 autosomal bands, five of which were on chromosome 1, with a large excess of breakpoints in the infertility group. Some of these could potentially harbour a male-specific infertility locus. However, a general excess of breakpoints almost everywhere on chromosome 1 was observed among the infertile males: 26.5 versus 14.5% in the cohort. This excess was observed both for translocation and inversion carriers, especially pericentric inversions, both for published and unpublished cases, and was significantly associated with azoospermia. The largest number of breakpoints was reported in 1q21; FISH mapping of four of these breakpoints revealed that they did not involve the same region at the molecular level. We suggest that chromosome 1 harbours a critical domain whose integrity is essential for male fertility.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::45e7b3a73407cfbd694bd1f4fa97aaa8Test
https://avesis.deu.edu.tr/publication/details/290330f0-f425-49bd-b49a-b4246cce8d2e/oaiTest

المؤلفون: Pramila Ramani, Paul Davies, Richard Grundy, Sara Dyer, Emma Prebble, Val Davison, David W. Ellison

المصدر: The American journal of pathology. 161(6)

مصطلحات موضوعية: Ependymoma, Oncology, Adult, Male, medicine.medical_specialty, Pathology, Multivariate analysis, Adolescent, Biology, Chromosomes, Pathology and Forensic Medicine, Internal medicine, medicine, Humans, Pediatric ependymoma, Genetic Testing, Child, Survival rate, Genetic testing, Proportional Hazards Models, Chromosome Aberrations, medicine.diagnostic_test, Proportional hazards model, Brain Neoplasms, Cytogenetics, Infant, Nucleic Acid Hybridization, DNA, Neoplasm, medicine.disease, Survival Rate, Treatment Outcome, Child, Preschool, Female, Chromosome Deletion, Comparative genomic hybridization, Regular Articles

الوصف: The outcome of pediatric ependymomas is difficult to predict based on clinical and histological parameters. To address this issue, we have performed a comparative genomic hybridization screen of 42 primary and 11 recurrent pediatric ependymomas and correlated the genetic findings with clinical outcome. Three distinct genetic patterns were identified in the primary tumors and confirmed by hierarchical cluster analysis. The first group of structural tumors, showed few, mainly partial imbalances (n = 19). A second numerical group showed 13 or more chromosome imbalances with a nonrandom pattern of whole chromosome gains and losses (n = 5). The remaining tumors (n = 18) showed a balanced genetic profile that was significantly associated with a younger age at diagnosis (P < 0.0001), suggesting that ependymomas arising in infants are biologically distinct from those occurring in older children. Multivariate analysis showed that the structural group had a significantly worse outcome compared to tumors with a numerical (P = 0.05) or balanced profile (P = 0.02). Moreover genetic group and extent of surgical resection contributed significantly to outcome whereas histopathology, age, and other clinical parameters did not. We conclude that patterns of genetic imbalances in pediatric intracranial ependymomas may help to predict clinical outcome.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b046ed6eb2b7dc2166952ff614c1f8a6Test
https://pubmed.ncbi.nlm.nih.gov/12466129Test