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Detection of Variants in Dystroglycanopathy-Associated Genes Through the Application of Targeted Whole-Exome Sequencing Analysis to a Large Cohort of Patients With Unexplained Limb-Girdle Muscle Weakness Publisher Pubmed



Johnson K1 ; Bertoli M1, 2 ; Phillips L1 ; Topf A1 ; Van Den Bergh P3 ; Vissing J4 ; Witting N4 ; Nafissi S5 ; Jamalomidi S5 ; Lusakowska A6 ; Kosterapruszczyk A6 ; Potulskachromik A6 ; Deconinck N7, 8 ; Wallgrenpettersson C9 Show All Authors
Authors
  1. Johnson K1
  2. Bertoli M1, 2
  3. Phillips L1
  4. Topf A1
  5. Van Den Bergh P3
  6. Vissing J4
  7. Witting N4
  8. Nafissi S5
  9. Jamalomidi S5
  10. Lusakowska A6
  11. Kosterapruszczyk A6
  12. Potulskachromik A6
  13. Deconinck N7, 8
  14. Wallgrenpettersson C9
  15. Strangkarlsson S9, 10
  16. Colomer J11
  17. Claeys KG12, 13, 14
  18. De Ridder W15, 16, 17
  19. Baets J15, 16, 17
  20. Von Der Hagen M18
  21. Fernandeztorron R1, 19, 20, 21
  22. Zulaica Ijurco M19, 20
  23. Espinal Valencia JB19, 20
  24. Hahn A22
  25. Durmus H23
  26. Willis T24
  27. Xu L25, 26
  28. Valkanas E25, 26
  29. Mullen TE25, 26
  30. Lek M25, 26
  31. Macarthur DG25, 26
  32. Straub V1, 2
Show Affiliations
Authors Affiliations
  1. 1. Newcastle University, John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle upon Tyne, United Kingdom
  2. 2. Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
  3. 3. University Hospital St-Luc, University of Louvain, Neuromuscular Reference Centre, Brussels, Belgium
  4. 4. University of Copenhagen, Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen, Denmark
  5. 5. Tehran University of Medical Sciences, Iranian Center for Neurological Research, Shariati Hospital, Tehran, Iran
  6. 6. Medical University of Warsaw, Department of Neurology, Warsaw, Poland
  7. 7. Ghent University Hospital, De Pintelaan 185, Ghent, Belgium
  8. 8. Hopital Universitaire des Enfants Reine Fabiola, ULB, Paediatric Neurology Department, Brussels, Belgium
  9. 9. University of Helsinki, The Folkhaelsan Department of Medical Genetics, The Folkhaelsan Institute of Genetics, and the Department of Medical and Clinical Genetics, Topeliuksenkatu 20, Helsinki, Finland
  10. 10. Helsinki University Hospital and University of Helsinki, Children's Hospital, Helsinki, Finland
  11. 11. Hospital Sant Joan de Deu, Unitat de Patologia Neuromuscular, Servei de Neurologia, Barcelona, Spain
  12. 12. University Hospitals Leuven, Department of Neurology, Leuven, Belgium
  13. 13. University of Leuven (KU Leuven), Laboratory for Muscle Diseases and Neuropathies, Department of Neurosciences, Leuven, Belgium
  14. 14. RWTH Aachen University Hospital, Department of Neurology and Institute of Neuropathology, Aachen, Germany
  15. 15. University of Antwerp, Neurogenetics Group, VIB-UA, Center for Molecular Neurology, Antwerp, Belgium
  16. 16. University of Antwerp, Laboratory of Neuromuscular Pathology, Institute Born-Bunge, Antwerp, Belgium
  17. 17. Antwerp University Hospital, Neuromuscular Reference Centre, Department of Neurology, Antwerp, Belgium
  18. 18. Technische Universitat Dresden, Abteilung Neuropadiatrie, Medizinische Fakultat Carl Gustav Carus, Dresden, Germany
  19. 19. Biodonostia Health Research Institute, Neuroscience Area, San Sebastian, Spain
  20. 20. Ministry of Economy and Competitiveness, Center for Biomedical Research in the Neurodegenerative Diseases (CIBERNED) Network, Instituto Carlos III, Madrid, Spain
  21. 21. Hospital de Mendaro, Osakidetza, Servicio de Neurologia, Mendaro, Spain
  22. 22. Justus-Liebig University, Department of Child Neurology, Gießen, Germany
  23. 23. Istanbul University, Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey
  24. 24. The Robert Jones and Agnes Hunt Orthopaedic Hospital, NHS Foundation Trust, Oswestry, United Kingdom
  25. 25. Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, MA, United States
  26. 26. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States

Source: Skeletal Muscle Published:2018


Abstract

Background: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration. Methods: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250ng DNA was completed using an Illumina exome capture and a 38Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants. Results: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase. Conclusions: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases. © 2018 The Author(s).
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