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1. High-throughput genotyping of high-homology mutant mouse strains by next-generation sequencing

Author

Shaheen Akhtar, Joanna Bottomley, Edward Ryder, Daniel M Barrett, Michaela Bruntraeger, Sanger Mouse Genetics, James Bussell, Jonathan Burvill, Radka Platte, Debarati Sethi, and Diane Gleeson

Subjects
FASTQ format, Genotyping, Genotype, Genotyping Techniques, Mouse, Computational biology, Biology, Polymerase Chain Reaction, Genome, Article, General Biochemistry, Genetics and Molecular Biology, DNA sequencing, Mice, 03 medical and health sciences, PCR, polymerase chain reaction, Animals, CRISPR, CRISPR, clustered regularly interspaced short palindromic repeat, hom, homozygous, Allele, Molecular Biology, Alleles, QC, 030304 developmental biology, 0303 health sciences, fungi, 030302 biochemistry & molecular biology, sgRNA, single guide RNA, Mutant, food and beverages, High-Throughput Nucleotide Sequencing, NGS, next generation sequencing, het, heterozygous, Amplicon, WT, wild-type, Mice, Mutant Strains, QC, quality control, NHEJ, non-homologous end joining, NGS
Abstract

Highlights • Next generation sequencing is a scalable solution to genotyping mutant mice. • Ratios of wild type and mutant sequence counts are used to call the genotype. • Hundreds of samples can be multiplexed into one sequencing experiment. • Amplification of high-homology genes can be easily filtered out during analysis., Genotyping of knockout alleles in mice is commonly performed by end-point PCR or gene-specific/universal cassette qPCR. Both have advantages and limitations in terms of assay design and interpretation of results. As an alternative method for high-throughput genotyping, we investigated next generation sequencing (NGS) of PCR amplicons, with a focus on CRISPR-mediated exon deletions where antibiotic selection markers are not present. By multiplexing the wild type and mutant-specific PCR reactions, the genotype can be called by the relative sequence counts of each product. The system is highly scalable and can be applied to a variety of different allele types, including those produced by the International Mouse Phenotyping Consortium and associated projects. One potential challenge with any assay design is locating unique areas of the genome, especially when working with gene families or regions of high homology. These can result in misleading or ambiguous genotypes for either qPCR or end-point assays. Here, we show that genotyping by NGS can negate these issues by simple, automated filtering of undesired sequences. Analysis and genotype calls can also be fully automated, using FASTQ or FASTA input files and an in-house Perl script and SQL database.

Published
2021
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2. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author

Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St George’s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)

Subjects
0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019
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3. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author

Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care

Subjects
0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

Published
2018
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4. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data

Author

Michael Parker, Caroline F. Wright, G. Jawahar Swaminathan, Philip Jones, Stephen Clayton, Alejandro Sifrim, Daniel A. King, Netravathi Krishnappa, Laura E Mason, Vijaya Parthiban, Katherine I. Morley, Margriet van Kogelenberg, Matthew E. Hurles, David R. FitzPatrick, Jeremy F. McRae, Eugene Bragin, Elena Prigmore, Helen V. Firth, Kirsty Ambridge, Wendy D Jones, Diana Rajan, Ray Miller, Daniel M Barrett, Tanya Bayzetinova, A. Paul Bevan, Nigel P. Carter, Susan M. Gribble, Jeffrey C. Barrett, Tomas W Fitzgerald, Eleni A. Chatzimichali, Adrian Tivey, and Anna Middleton

Subjects
Male, medicine.medical_specialty, Heterozygote, Adolescent, Developmental Disabilities, Genome-wide association study, Disease, Bioinformatics, Clinical decision support system, Specimen Handling, 03 medical and health sciences, Medicine, Humans, Child, Exome sequencing, 030304 developmental biology, Medicine(all), 0303 health sciences, Incidental Findings, business.industry, Information Dissemination, Genome, Human, 030305 genetics & heredity, Infant, Newborn, Genetic Variation, Infant, General Medicine, Articles, medicine.disease, Human genetics, 3. Good health, Developmental disorder, Patient recruitment, Phenotype, Child, Preschool, Medical genetics, Female, business, Genome-Wide Association Study
Abstract

BACKGROUND: Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount.METHODS: The Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team.FINDINGS: Around 80 000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation.INTERPRETATION: Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene-phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial.FUNDING: Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health.

Published
2015
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5. Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders

Author

Víctor Faundes, William G. Newman, Laura Bernardini, Natalie Canham, Jill Clayton-Smith, Bruno Dallapiccola, Sally J. Davies, Michelle K. Demos, Amy Goldman, Harinder Gill, Rachel Horton, Bronwyn Kerr, Dhavendra Kumar, Anna Lehman, Shane McKee, Jenny Morton, Michael J. Parker, Julia Rankin, Lisa Robertson, I. Karen Temple, Siddharth Banka, Shelin Adam, Christèle du Souich, Alison M. Elliott, Jill Mwenifumbo, Tanya N. Nelson, Clara van Karnebeek, Jan M. Friedman, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, V.K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, and Matthew E. . Hurles

Subjects
0301 basic medicine, ASH1L, Male, Methyltransferase, Adolescent, Histone lysine methylation, KMT5B, Developmental Disabilities, Haploinsufficiency, Biology, Compound heterozygosity, histone lysine methyltransferase, Chromatin remodeling, chromatin remodeling, 03 medical and health sciences, histone lysine demethylase, Report, Genetics, Humans, Child, Genetics (clinical), Regulation of gene expression, Histone Demethylases, Developmental disorders, KMT2C, KMT2B, Histone-Lysine N-Methyltransferase, 030104 developmental biology, Histone, Overgrowth syndrome, Child, Preschool, Mutation, biology.protein, KDM5B, Female
Abstract

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

Published
2017
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6. Imaging multidrug resistance with 4-[18F]fluoropaclitaxel

Author

Jerry I. Hirsch, James McCumiskey, Rakesh Agarwal, John D. Wilson, Daniel M. Barrett, Karen A. Kurdziel, Joseph D. Kalen, and Harry D. Bear

Subjects
Cancer Research, Biodistribution, Paclitaxel, medicine.medical_treatment, Antineoplastic Agents, Pharmacology, chemistry.chemical_compound, Breast cancer, Neoplasms, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Chemotherapy, business.industry, Cancer, medicine.disease, Primary tumor, Drug Resistance, Multiple, Multiple drug resistance, chemistry, Drug Resistance, Neoplasm, Positron-Emission Tomography, Cancer research, Molecular Medicine, Personalized medicine, Radiopharmaceuticals, business
Abstract

Multidrug resistance (MDR) is a cause of treatment failure in many cancer patients. MDR refers to a phenotype whereby a tumor is resistant to a large number of natural chemotherapeutic drugs. Having prior knowledge of the presence of such resistance would decrease morbidity from unsuccessful therapy and allow for the selection of individuals who may benefit from the coadministration of MDR-inhibiting drugs. The Tc-99m-labeled single-photon-emitting radiotracers sestamibi and tetrofosmin have shown some predictive value. However, positron-emitting radiotracers, which allow for dynamic quantitative imaging, hold promise for a more accurate and specific identification of MDRtumors.MDR-expressing tumors are resistant to paclitaxel, which is commonly used as a chemotherapeutic agent. 4-[18F]Fluoropaclitaxel (FPAC) is a PET-radiolabeled analogue of paclitaxel. Preclinical studies have shown the uptake of FPAC to be inversely proportional to tumor MDR expression. FPAC PET imaging in normal volunteers shows biodistribution to be similar to that in nonhuman primates. Imaging in a breast cancer patient showed FPAC localization in a primary tumor that responded to chemotherapy, while failure to localize in mediastinal disease corresponded with only partial response.FPAC PET imaging shows promise for the noninvasive pretreatment identification of MDR-expressing tumors. While much additional work is needed, this work represents a step toward image-guided personalized medicine.

Published
2007
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7. Benign peripheral nerve tumors: treatment algorithm and reconstructive options

Author

Ali Al-Attar, Ivica Ducic, and Daniel M. Barrett

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Peripheral Nerve Tumors, Peripheral Nervous System Neoplasms, Medicine, Humans, Prospective Studies, Prospective cohort study, Aged, Pain Measurement, Nerve reconstruction, business.industry, Perioperative, Fascicle, Middle Aged, Plastic Surgery Procedures, Functional recovery, Surgery, Plastic surgery, Treatment Outcome, Neuropathic pain, Female, business, Algorithms
Abstract

Peripheral nerve tumors are mostly benign; however, their excision can result in profound deficits. Nerve reconstruction strategies offer techniques to minimize morbidity. In this prospective study, 20 consecutive patients with benign peripheral nerve tumors were treated using a single-stage surgical paradigm between 2003 and 2007. Nerve fascicles were microdissected off of the tumor; any fascicle that gave origin to the tumor (was inseparable from tumor) was reconstructed using nerve conduits. Patients were followed from 6 to 24 months. All patients had neuropathic pain before tumor excision; only 1 patient had pain persist postoperatively. Seventeen patients had complete functional recovery after nerve reconstruction. No perioperative complications occurred. Benign peripheral nerve tumors require highly specialized surgical care. Tumor excision with immediate nerve reconstruction, for fascicles inseparable from the tumor, optimizes outcomes. Nerve reconstruction with available conduits or allografts should be attempted to restore anatomic integrity to any killed fascicles, thereby minimizing possible deficits.

Published
2009

8. Inhibition of protein-tyrosine phosphatases by mild oxidative stresses is dependent on S-nitrosylation

Author

Stephen M. Black, Horia Todor, Ross B. Mikkelsen, Kathryn S. Dawson, Daniel M. Barrett, and Rupert Schmidt-Ullrich

Subjects
Cytoplasm, Time Factors, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein tyrosine phosphatase, Ascorbic Acid, medicine.disease_cause, Biochemistry, chemistry.chemical_compound, Cytosol, Cricetinae, Phosphorylation, Genes, Dominant, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Ionomycin, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Intracellular Signaling Peptides and Proteins, NG-Nitroarginine Methyl Ester, Ethylmaleimide, Signal transduction, Oxidation-Reduction, Plasmids, Signal Transduction, Nitrogen, Phosphatase, Immunoblotting, Biotin, CHO Cells, Nitric Oxide, Cell Line, Tumor, medicine, Animals, Humans, Molecular Biology, Binding Sites, Wild type, Cell Biology, S-Nitrosylation, Hydrogen Peroxide, Molecular biology, Oxygen, Dithiothreitol, Oxidative Stress, chemistry, Mutation, Calcium, Nitric Oxide Synthase, Protein Tyrosine Phosphatases, Oxidative stress
Abstract

Previous studies have shown that a Ca(2+)-dependent nitric-oxide synthase (NOS) is activated as part of a cellular response to low doses of ionizing radiation. Genetic and pharmacological inhibitor studies linked this NO signaling to the radiation-induced activation of ERK1/2. Herein, a mechanism for the radiation-induced activation of Tyr phosphorylation-dependent pathways (e.g. ERK1/2) involving the inhibition of protein-Tyr phosphatases (PTPs) by S-nitrosylation is tested. The basis for this mechanism resides in the redox-sensitive active site Cys in PTPs. These studies also examined oxidative stress induced by low concentrations of H(2)O(2). S-Nitrosylation of total cellular PTP and immunopurified SHP-1 and SHP-2 was detected as protection of PTP enzymatic activity from alkylation by N-ethylmaleimide and reversal by ascorbate. Both radiation and H(2)O(2) protected PTP activity from alkylation by a mechanism reversible by ascorbate and inhibited by NOS inhibitors or expression of a dominant negative mutant of NOS-1. Radiation and H(2)O(2) stimulated a transient increase in cytoplasmic free [Ca(2+)]. Radiation, H(2)O(2), and the Ca(2+) ionophore, ionomycin, also stimulated NOS activity, and this was associated with an enhanced S-nitrosylation of the active site Cys(453) determined by isolation of S-nitrosylated wild type but not active site Cys(453) --> Ser SHP-1 mutant by the "biotin-switch" method. Thus, one consequence of oxidative stimulation of NO generation is S-nitrosylation and inhibition of PTPs critical in cellular signal transduction pathways. These results support the conclusion that a mild oxidative signal is converted to a nitrosative one due to the better redox signaling properties of NO.

Published
2005

9. Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: The Deciphering Developmental Disorders Study

Author

Nicola S. Cooper, S Samant, H Purnell, Claire L. S. Turner, A Vandersteen, Alex Magee, Susan Tomkins, Louise C. Wilson, L Greenhalgh, IK Temple, Irina Colgiu, A Duncan, G Cross, Susan E. Holder, C Wragg, Deirdre E. Donnelly, Nadia Akawi, Linda Sneddon, Eamonn Sheridan, Wendy D Jones, I Ellis, David Bourn, Joanna Poulton, Ingrid Simonic, R Singzon, Lisa Bradley, Matthew E. Hurles, Meena Balasubramanian, Dominic J. McMullan, Trevor Cole, Gillian Roberts, J Thomson, Moira Blyth, G Hollingsworth, Neeti Ghali, Alex Henderson, Zara Skitt, E Roberts, G Woods, David Goudie, J Awada, Caroline Langman, U Anjum, Martin O. Pollard, Usha Kini, Stephen Clayton, J Burn, Daniel M Barrett, Vka Kumar, Angela E. Douglas, Natalie Canham, Ruth Armstrong, Denise Williams, C Shaw-Smith, Lorraine Gaunt, S Ingram, Edward Blair, K Brunstrom, O. W.J. Quarrell, Ben Hutton, Nora Shannon, S Wallwark, Laura E Mason, Sarah F. Smithson, Jeremy F. McRae, Amanda L. Collins, Shane McKee, Katrina Prescott, Lara Cresswell, Sofia Douzgou, L Islam, C Deshpande, J Waters, Anna Middleton, S-M Park, Tarjinder Singh, Liu He, M Tein, T Fendick, B Kaemba, Tara Montgomery, Michael Wright, Jenny Morton, J Roberts, Emma Hobson, Caroline Mackie Ogilvie, Katrina Tatton-Brown, Lucy Jenkins, A Coates, Abhijit Dixit, Deborah J. Shears, Kath Smith, D. Baty, D Lim, D Cilliers, Richard Gibbons, Ruth Newbury-Ecob, M Squires, Nicola K. Ragge, Anneke Seller, E Kivuva, Kay Metcalfe, Fiona Stewart, K Marks, Elisabeth Rosser, R Fisher, Andrew E. Fry, Joan Paterson, Diana Wellesley, Dian Donnai, Christopher P. Bennett, Jonathan Berg, Ganesh J. Swaminathan, Lucy Raymond, Sally Ann Lynch, Pradeep C. Vasudevan, Rosemarie Davidson, Melita Irving, John Dean, Margo Whiteford, Melissa Lees, S Payne, K-R Ong, Emma Gray, M Holder, Dragana Josifova, Claire Kirk, McConnell, Helen Cox, Sarju G. Mehta, Elena Prigmore, Emma Shearing, Anand Saggar, Angela Barnicoat, Alejandro Sifrim, Nicola Foulds, Katherine Martin, Joanna Kaplanis, Sahar Mansour, Kirsty Ambridge, Clowes, A Procter, Z Miedzybrodzka, Katherine Lachlan, S Schweiger, E Maher, Allyson Ross, Simon Brent, C Sequeira, Tabib Dabir, Netravathi Krishnappa, Andrew Smith, B Bernhard, Andrew Green, Sara Widaa, Daniel A. King, Astrid Weber, Harinder Gill, Frances Flinter, Ruth McGowan, Siddharth Banka, Susan E. McNerlan, Elizabeth M. Sweeney, L Nevitt, Michael Parker, Hood Mugalaasi, AP Bevan, L Harrison, Varghese, Lucy Hildyard, Murday, G Kirby, S Clasper, Sutton, Clare Taylor, Andrew Jackson, A Selby, E Wilkinson, Miranda Splitt, Stuart Aitken, Shelagh Joss, Fiona Connell, Julie Vogt, Jill Clayton-Smith, Alan Fryer, N Pratt, Parthiban Vijayarangakannan, Shehla Mohammed, Susan Price, Wayne Lam, Peter D. Turnpenny, C Tysoe, Raheleh Rahbari, Marc Tischkowitz, N Williams, Tessa Homfray, Maria Bitner-Glindzicz, Helen Murphy, Meriel M. McEntagart, Sian Ellard, M Ahmed, R O'Shea, Andrew R. Norman, Daniel Perrett, Harrison, Philip Greene, David Moore, R Hawkins, DT Pilz, FitzPatrick, P Batstone, Esther Kinning, Caroline F. Wright, Yanick J. Crow, Kate Chandler, C Donnelly, Leema Robert, Straub, Susan M. Gribble, Philip Jones, D de Vries, K Evans, Simon J. Davies, Diana Baralle, E Miles, Jeffrey C. Barrett, A Lampe, Joshua C. Randall, Bruce Castle, K McKay, D Rice, Becky Treacy, Richard H Scott, Rosemary Kelsell, Angela F. Brady, Julian R. Sampson, J Jarvis, Laura Yates, R Sandford, Hayley Archer, M Yau, Mohnish Suri, Caroline Pottinger, Dhavendra Kumar, R. Taylor, Alison Kraus, L Bourdon, Alan Donaldson, S Everest, S Kazembe, Sian Morgan, C Longman, Ingrid Scurr, Alison Male, Ajoy Sarkar, Helen Kingston, Emma McCann, Julie M. Phipps, Andrea H. Németh, A Pridham, D Bohanna, C Gardiner, Diana Johnson, Tomas W Fitzgerald, Eleni A. Chatzimichali, A Dobbie, Diana Rajan, Frances Elmslie, Mohsan Alvi, Pendaran Roberts, Bronwyn Kerr, M D'Alessandro, Elizabeth A. Jones, Simon Holden, U Maye, Helen V. Firth, J Rankin, H. Stewart, S Naik, Adrian Tivey, Chirag N. Patel, Tanya Bayzetinova, G Lowther, G Devlin, A Torokwa, DJ Bunyan, Judith A. Goodship, Sarah Hewitt, Emma Wakeling, Christoffer Nellåker, S Wilcox, Saba Sharif, MN Collinson, C Brewer, Jacqueline Eason, C McWilliam, Jane A. Hurst, Angus John Clarke, Mervyn Humphreys, and Stephen W. Hellens

Subjects
Genetics, 0303 health sciences, education.field_of_study, Genetic heterogeneity, Population, Biology, Phenotype, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, education, Indel, Gene, Exome, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P < 7 × 10−7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age.AbbreviationsPTVProtein-Truncating VariantDNMDe Novo MutationDDDevelopmental DisorderDDDDeciphering Developmental Disorders study

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