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7 results on '"Hywel J. Williams"'

1. Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulationResearch in context

Author

Louise C. Gregory, Carolina B. Ferreira, Sara K. Young-Baird, Hywel J. Williams, Magdalena Harakalova, Gijs van Haaften, Sofia A. Rahman, Carles Gaston-Massuet, Daniel Kelberman, GOSgene, Waseem Qasim, Sally A. Camper, Thomas E. Dever, Pratik Shah, Iain C.A.F. Robinson, and Mehul T. Dattani

Subjects
Medicine, Medicine (General), R5-920
Abstract

Background: The heterotrimeric GTP-binding protein eIF2 forms a ternary complex with initiator methionyl-tRNA and recruits it to the 40S ribosomal subunit for start codon selection and thereby initiates protein synthesis. Mutations in EIF2S3, encoding the eIF2γ subunit, are associated with severe intellectual disability and microcephaly, usually as part of MEHMO syndrome. Methods: Exome sequencing of the X chromosome was performed on three related males with normal head circumferences and mild learning difficulties, hypopituitarism (GH and TSH deficiencies), and an unusual form of glucose dysregulation. In situ hybridisation on human embryonic tissue, EIF2S3-knockdown studies in a human pancreatic cell line, and yeast assays on the mutated corresponding eIF2γ protein, were performed in this study. Findings: We report a novel hemizygous EIF2S3 variant, p.Pro432Ser, in the three boys (heterozygous in their mothers). EIF2S3 expression was detectable in the developing pituitary gland and pancreatic islets of Langerhans. Cells lacking EIF2S3 had increased caspase activity/cell death. Impaired protein synthesis and relaxed start codon selection stringency was observed in mutated yeast. Interpretation: Our data suggest that the p.Pro432Ser mutation impairs eIF2γ function leading to a relatively mild novel phenotype compared with previous EIF2S3 mutations. Our studies support a critical role for EIF2S3 in human hypothalamo-pituitary development and function, and glucose regulation, expanding the range of phenotypes associated with EIF2S3 mutations beyond classical MEHMO syndrome. Untreated hypoglycaemia in previous cases may have contributed to their more severe neurological impairment and seizures in association with impaired EIF2S3. Fund: GOSH, MRF, BRC, MRC/Wellcome Trust and NIGMS funded this study. Keywords: Hypopituitarism, Hypoglycaemia, Glucose dysregulation, Translation initiation, Protein synthesis, EIF2S3

Published
2019
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2. X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3

Author

Chiara Olcese, Mitali P. Patel, Amelia Shoemark, Santeri Kiviluoto, Marie Legendre, Hywel J. Williams, Cara K. Vaughan, Jane Hayward, Alice Goldenberg, Richard D. Emes, Mustafa M. Munye, Laura Dyer, Thomas Cahill, Jeremy Bevillard, Corinne Gehrig, Michel Guipponi, Sandra Chantot, Philippe Duquesnoy, Lucie Thomas, Ludovic Jeanson, Bruno Copin, Aline Tamalet, Christel Thauvin-Robinet, Jean- François Papon, Antoine Garin, Isabelle Pin, Gabriella Vera, Paul Aurora, Mahmoud R. Fassad, Lucy Jenkins, Christopher Boustred, Thomas Cullup, Mellisa Dixon, Alexandros Onoufriadis, Andrew Bush, Eddie M. K. Chung, Stylianos E. Antonarakis, Michael R. Loebinger, Robert Wilson, Miguel Armengot, Estelle Escudier, Claire Hogg, UK10K Rare Group, Serge Amselem, Zhaoxia Sun, Lucia Bartoloni, Jean-Louis Blouin, and Hannah M. Mitchison

Subjects
Science
Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease resulting in reduced mucus clearance and impaired lung function. Here, the authors show that mutations in PIH1D3 are responsible for an X-linked form of PCD, affecting assembly of a subset of inner arm dyneins.

Published
2017
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3. 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

Author

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, and Investigators, The 100,000 Genomes Project Pilot

Subjects
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
Abstract

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.).

Published
2021

4. Rapid genome sequencing for pediatrics

Author

Jana Jezkova, Sophie Shaw, Nicola V. Taverner, and Hywel J. Williams

Subjects
Genetics, Chromosome Mapping, High-Throughput Nucleotide Sequencing, Humans, Child, Pediatrics, Genetics (clinical)
Abstract

The advancements made in next-generation sequencing (NGS) technology over the past two decades have transformed our understanding of genetic variation in humans and had a profound impact on our ability to diagnose patients with rare genetic diseases. In this review, we discuss the recently developed application of rapid NGS techniques, used to diagnose pediatric patients with suspected rare diseases who are critically ill. We highlight the challenges associated with performing such clinical diagnostics tests in terms of the laboratory infrastructure, bioinformatic analysis pipelines, and the ethical considerations that need to be addressed. We end by looking at what future developments in this field may look like and how they can be used to augment the genetic data to further improve the diagnostic rates for these high-priority patients.

Published
2022

5. An example of the utility of genomic analysis for fast and accurate clinical diagnosis of complex rare phenotypes

Author

Polona, Le Quesne Stabej, Chela, James, Louise, Ocaka, Mehmet, Tekman, Stephanie, Grunewald, Emma, Clement, Horia C, Stanescu, Robert, Kleta, Deborah, Morrogh, Alistair, Calder, Hywel J, Williams, and Maria, Bitner-Glindzicz

Subjects
Mosaicism, Developmental Disabilities, Siblings, Research, PDZD7, Genomics, Autosomal recessive non-syndromic hearing loss, COL1A1 C-propeptide cleavage site, Consanguinity, Rare Diseases, Gene Expression Regulation, Child, Preschool, Next generation sequencing, Mutation, Exome Sequencing, Humans, Osteogenesis imperfecta, Hearing Loss
Abstract

Background We describe molecular diagnosis in a complex consanguineous family: four offspring presented with combinations of three distinctive phenotypes; non-syndromic hearing loss (NSHL), an unusual skeletal phenotype comprising multiple fractures, cranial abnormalities and diaphyseal expansion, and significant developmental delay with microcephaly. We performed Chromosomal Microarray Analysis on the offspring with either the skeletal or developmental delay phenotypes, and linkage analysis and whole exome sequencing (WES) on all four children, parents and maternal aunt. Results Chromosomal microarray and FISH analysis identified a de novo unbalanced translocation as a cause of the microcephaly and severe developmental delay. WES identified a NSHL-causing splice variant in an autosomal recessive deafness gene PDZD7 which resided in a linkage region and affected three of the children. In the two children diagnosed with an unusual skeletal phenotype, WES eventually disclosed a heterozygous COL1A1 variant which affects C-propetide cleavage site of COL1. The variant was inherited from an apparently unaffected mosaic father in an autosomal dominant fashion. After the discovery of the COL1A1 variant, the skeletal phenotype was diagnosed as a high bone mass form of osteogenesis imperfecta. Conclusions Next generation sequencing offers an unbiased approach to molecular genetic diagnosis in highly heterogeneous and poorly characterised disorders and enables early diagnosis as well as detection of mosaicism. Electronic supplementary material The online version of this article (doi:10.1186/s13023-017-0582-8) contains supplementary material, which is available to authorized users.

Published
2016

6. Contributors

Author

Michael J. Ackerman, Minhaz Uddin Ahmed, Sun Hee Ahn, R. Rand Allingham, Jude Alsarraj, Matthew L. Anderson, Brian H. Annex, Christina K. Augustine, Sergio E. Baranzini, Peter J. Barnes, Georgia M. Beasley, Richard C. Becker, Ivor J. Benjamin, D. Woodrow Benson, Jacob Fog Bentzon, Philip S. Bernard, Lars Bertram, Laura M. Beskow, Brigitta Bondy, J. Martijn Bos, Gabriella L. Boulting, Jerome S. Brody, April S. Brown, Kenneth H. Buetow, Lars Bullinger, Atul J. Butte, David J. Carey, George Carlson, David Chen, Maria Chahrour, E. Antonio Chiocca, Alex H. Cho, Carolyn Compton, Robert Cook-Deegan, Nicholas Craddock, Michael Coulter, Samir B. Damani, Jacqueline S. Danik, Sandeep Dave, Russell Dedrick, Frank R. DeLeo, Eleftherios P. Diamandis, Ayotunde O. Dokun, Gregory J. Downing, Stephen L. Eck, Lucas B. Edelman, Kevin C. Eggan, Erling Falk, Hawazin Faruki, Junjie Feng, Eleanora Anna Margaretha Festen, Jose C. Florez, Vance G. Fowler, Jennifer A. Freedman, Hudson H. Freeze, Stefan Fröhling, David J. Galas, Glenn S. Gerhard, Daniel H. Geschwind, Ad Geurts van Kessel, Robert B. Giffin, Geoffrey S. Ginsburg, Megan Goodall, Praveen Govender, Robert C. Green, Chris Gunter, Marta Gwinn, Susanne B. Haga, James R. Heath, Robert A. Hegele, John Holton, Leroy Hood, Kent W. Hunter, Daehee Hwang, Gail Javitt, Gina Jefferson, Sam John, Keith J. Johnson, Toby Johnson, Tisha R. Joy, Sekar Kathiresan, Hasmeena Kathuria, Arabindra B. Katwal, Kensaku Kawamoto, Andrea Kelly, Muin J. Khoury, Jin Woo Kim, Stephen F. Kingsmore, Tod Klingler, Scott D. Kobayashi, Isaac S. Kohane, Virginia Byers Kraus, Roland P. Kuiper, Myla Lai-Goldman, Neil E. Lamb, Sevdalina Nikolova Lambova, Matthew B. Lanktree, Sean E. Lawler, David H. Ledbetter, Charles Lee, Inyoul Lee, Karine G. Le Roch, Samuel Levy, Sophie Limou, Wennuan Liu, Yutao Liu, Barry London, Jeffrey P. MacKeigan, Elaine R. Mardis, Hector Marquez, Marco Marra, Christa Lese Martin, Lisa J. Martin, Steven A. McCarroll, John McHutchison, Howard L. McLeod, Asunción Mejías, Eric B. Meltzer, M. Anthony Moody, Ryan D. Morin, M. Arthur Moseley, Joanna L. Mountain, Ulf Müller-Ladner, Patricia B. Munroe, Bobby G. Ng, Paul W. Noble, Michael C. O’Donovan, Kunle Odunsi, Gilbert S. Omenn, Steve R. Ommen, Lori A. Orlando, Albert D.M.E. Osterhaus, Michael J. Owen, Neelroop N. Parikshak, Keyur Patel, Maria P. Pavlou, Nina P. Paynter, Tanja Pejovic, Michael X. Pham, Robert M. Plenge, Mihai V. Podgoreanu, Nadia Ponts, Nathan D. Price, Bruce Quinn, Francisco J. Quintana, Daniel J. Rader, Octavio Ramilo, Heidi L. Rehm, Benjamin Rhodes, Paul M. Ridker, Erin Rooney Riggs, Jeffrey S. Ross, Wendy S. Rubinstein, Carol J. Saunders, Joan Scott, Nicholas A. Shackel, Svati H. Shah, Richard Simon, Sanjay M. Sisodiya, Saskia L. Smits, John A. Stamatoyannopoulos, Glenn D. Steele, Mark P. Steele, Tessandra Stewart, Giovana R. Thomas, Eric J. Topol, Sean R. Tunis, Aubrey R. Turner, Douglas S. Tyler, David L. Veenstra, Ramprasath Venkatachalam, Deepak Voora, Timothy J. Vyse, Christopher A. Walsh, Katherine Walsh, Hao Wang, Jun Wang, Rinse K. Weersma, Howard L. Weiner, Scott T. Weiss, C. William Wester, David N. Wholley, Janey L. Wiggs, Cisca Wijmenga, Huntington F. Willard, Hywel J. Williams, Marc S. Williams, Cheryl A. Winkler, Janet Woodcock, Christopher W. Woods, Pae C. Wu, Jianfeng Xu, James Yee, Hyuntae Yoo, Timothy Yu, Jing Zhang, and Yurong Zhang

Published
2013

7. Further evidence for the association of MMP9 with nephropathy in type 2 diabetes and application of DNA pooling technology to candidate gene screening

Author

Sunita, Nair, Aled O, Phillips, Nadine, Norton, Gillian, Spurlock, Hywel J, Williams, Kathrine J, Craig, John D, Williams, Nigel M, Williams, and Timothy, Bowen

Subjects
Male, Genotype, Exons, Sequence Analysis, DNA, Middle Aged, Polymorphism, Single Nucleotide, Transforming Growth Factor beta1, Diabetes Mellitus, Type 2, Gene Frequency, Matrix Metalloproteinase 9, Humans, Diabetic Nephropathies, Female, Glucuronosyltransferase, Promoter Regions, Genetic, Hyaluronan Synthases, Aged, Microsatellite Repeats, Oligonucleotide Array Sequence Analysis
Abstract

Diabetic nephropathy is characterised by extracellular matrix (ECM) expansion, a key modulator of which is TGF-b1. Glucose-stimulated transcriptional activation of the TGF-b1 gene is an important component of the pathogenesis of nephropathy, following which latent TGF-b1 protein is synthesised. Matrix metalloproteinase 9 (MMP9) remodels the ECM and has been implicated in TGF-b1 activation. The ECM glycosaminoglycan hyaluronan (HA) influences TGF-b1 generation and can modulate its signal transduction activity; renal HA is synthesised by HA synthases HAS2 and HAS3.We report the first screening of the genes encoding HAS2 and HAS3 for sequence variants predisposing to nephropathy in UK type 2 diabetes patients, together with the MMP9 and TGF-b1 genes. Also for the first time, we used validated DNA pools to carry out association analyses of single nucleotide polymorphisms on nephropathic and non-nephropathic cohorts from a total of 199 type 2 diabetes patients, to increase the throughput and decrease the cost of genotype analysis.None of the 23 single nucleotide polymorphisms analysed in DNA pools were found to be associated with diabetic nephropathy. However, genotyping of alleles at the MMP9 promoter microsatellite locus D20S838 in individual genomic DNA samples supported previous evidence of association between this locus and diabetic nephropathy.The use of DNA pooling technology increased the throughput and decreased the cost of our association analysis of nephropathy in our type 2 diabetes sample, which demonstrated sufficient sensitivity to support previous positive findings of association with a microsatellite in the MMP9 promoter region.

Published
2008

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