Monogenic diabetes syndromes: Locus‐specific databases for Alström,Wolfram, and Thiamine‐responsive megaloblastic anemia期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

Monogenic diabetes syndromes: Locus‐specific databases for Alström,Wolfram, and Thiamine‐responsive megaloblastic anemia

Authors:	Dewi Astuti Ataf Sabir Piers Fulton Malgorzata Zatyka 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 Renuka Dias Amy Arnold Caitlin Richens Richard Paisey Fumihiko Urano Robert Semple Richard Sinnott Timothy G. Barrett

Affiliation:	1. Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK;2. West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Edgbaston, Birmingham, UK;3. Department of Medicine (DIMED), University of Padua, Padua, Italy;4. Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK;5. Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK;6. NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK;7. Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK;8. Centrum für Reproduktionsmedizin und Andrologie, WHO Kollaborationszentrum, EAA, Ausbildungszentrum, Universit?tsklinikum Münster, Münster, Germany;9. IDIBELL, Hospital Duran i Reynals, 3a Planta, Gran Via de L'Hospitalet, 199, E‐08908‐ L'Hospitalet de Llobregat, Barcelona, Spain;10. Centro de Investigación en Red de Enfermedades Raras (CIBERER), U‐730, Hospital Duran i Reynals, Barcelona, Spain;11. Departments of Psychiatry, Neurology and Radiology, Washington University School of Medicine, St. Louis, Missouri;12. Department of Clinical Genetics, University Hospital/The Kennedy Centre, Glostrup, Denmark;13. Institute of Clinical Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark;14. University of Cambridge Metabolic Research Laboratories, Wellcome Trust‐MRC Institute of Metabolic Science, Cambridge, UK;15. School of Medicine, IRCAN, UMR CNRS 7284/INSERM U1081/UNS, Nice Sophia‐Antipolis University, Nice, France;16. Genetics Section, Physiological Sciences Department, Health Sciences and Medicine FacultyUniversity of Barcelona;17. Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri;18. IT Services, University of Glasgow, Glasgow, UK;19. Tartu University Children's Hospital, Tartu, Estonia;20. Department of Metabolism, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, UK;21. Department of Paediatrics, Medical University of Lodz, Lodz, Poland;22. Alstr?m Syndrome Europe, Paignton, S. Devon, UK;23. Association syndrome de Wolfram, Grand‐Champ, France;24. Unidad de Géstion Clínica de Garrucha, Almería, Spain;25. Birmingham Women's and Children's Hospital, Birmingham, UK;26. Diabetes Research Unit, Horizon Centre, Torbay Hospital NHS Foundation Trust, Devon, UK;27. Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri;28. Department of information and computing systems, The University of Melbourne, Parkville, Australia

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 anemia 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 biallelic 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 .

Keywords:	Alströ m syndrome genotype– phenotype analysis locus‐specific database Monogenic diabetes Thiamine‐responsive megaloblastic anemia syndrome Wolfram syndrome

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