Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram and Thiamine-responsive megaloblastic anaemia

Research output: Contribution to journalArticle

Authors

  • Ataf Sabir
  • Piers Fulton
  • Denise Williams
  • Carol Hardy
  • Gabriella Milan
  • Francesca Favaretto
  • Patrick Yu-Wai-Man
  • Julia Rohayem
  • Miguel López de Heredia
  • Tamara Hershey
  • Lisbeth Tranebjaerg
  • Jian-Hua Chen
  • Annabel Chaussenot
  • Virginia Nunes
  • Bess Marshall
  • Susan McAfferty
  • Vallo Tillmann
  • Pietro Maffei
  • Veronique Paquis-Flucklinger
  • Tarekign Geberhiwot
  • Wojciech Mlynarski
  • Kay Parkinson
  • Virginie Picard
  • Gema Esteban Bueno
  • Amy Arnold
  • Caitlin Richens
  • Richard Paisey
  • Fumi Urano
  • Robert Semple
  • Richard Sinnott

External organisations

  • Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
  • West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Edgbaston, Birmingham, UK.
  • Department of Medicine (DIMED), University of Padua, Padua, Italy.
  • Newcastle University
  • Centrum für Reproduktionsmedizin und Andrologie, WHO Kollaborationszentrum, EAA, Ausbildungszentrum, Universitätsklinikum Münster, Münster, Germany.
  • IDIBELL, Hospital Duran i Reynals, 3ª Planta, Gran Via de L'Hospitalet, 199, E-08908- L'Hospitalet de Llobregat, Centro de Investigación en Red de Enfermedades Raras (CIBERER), U-730, Hospital Duran i Reynals, Barcelona, Spain, 3ª Planta, Gran Via de L'Hospitalet, 199, E-08908-L'Hospitalet de Llobregat, Barcelona, Spain.
  • Departments of Psychiatry, Neurology and Radiology, Washington University School of Medicine, St. Louis, MO, USA.
  • Department of Clinical Genetics, University Hospital/The Kennedy Centre, DK- 2600, Denmark.
  • University of Cambridge
  • School of Medicine, IRCAN, UMR CNRS 7284/INSERM U1081/UNS, Nice Sophia-Antipolis University, 28 av de Valombrose, 06107 Nice Cedex 2, France.
  • Department of Pediatrics, Washington University School of Medicine, One Children's Place, St. Louis, MO, USA.
  • University of Glasgow
  • Tartu University Children's Hospital, Lunini 6, Tartu, Estonia.
  • Department of Metabolism, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, UK.
  • Department of Paediatrics, Medical University of Lodz, 4 Kosciuszki Avenue, Lodz, Poland.
  • Alström Syndrome Europe, Woodpecker Cottage, Roundham Road, Paignton, S. Devon, UK.
  • Association syndrome de Wolfram, Residence Gauguin, 56390 Grand-Champ, France. Área de.
  • Unidad de Géstion Clínica de Garrucha, Área de Gestión Sanitaria Norte de Almería, Avd. Dra. Parra, s/n 04600 Huércal-Overa (Almería), Spain.
  • Birmingham Women's and Children's Hospital, Steelhouse Lane, Birmingham, UK.
  • Diabetes Research Unit, Horizon Centre, Torbay Hospital NHS Foundation Trust, 8 Lawes Bridge, Torquay, Devon, UK.
  • Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA.
  • The University of Melbourne, Level 3, Doug McDonell Building, Parkville, Australia.
  • Birmingham Children’s Hospital, Birmingham, UK

Abstract

We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström and Thiamine-responsive megaloblastic anaemia syndromes respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype phenotype relations for the WFS1 gene. The presence of bi-allelic loss of function variants predicted Wolfram syndrome defined by insulin dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75-83%) and specificity of 92% (83-97%). The presence of minor loss of function variants in WFS1 predicted isolated diabetes, isolated deafness or isolated congenital cataracts without development of the full syndrome (sensitivity 100% (93-100%), specificity 78% (73-82%). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as Next Generation Sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org. This article is protected by copyright. All rights reserved.

Details

Original languageEnglish
Pages (from-to)764-777
JournalHuman Mutation
Volume38
Issue number7
Early online date1 Jun 2017
Publication statusPublished - Jul 2017

Keywords

  • Genotype-phenotype analysis, Wolfram syndrome, Alström syndrome, Thiamine responsive megaloblastic anaemia syndrome, Monogenic diabetes, Locus-specific database