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Sequential Targeted Exome Sequencing of 1001 Patients Affected by Unexplained Limb-Girdle Weakness Publisher Pubmed



Topf A1 ; Johnson K1, 67 ; Bates A1 ; Phillips L1 ; Chao KR2, 3 ; England EM2, 3 ; Laricchia KM2, 3 ; Mullen T2, 3 ; Valkanas E2, 3 ; Xu L2, 3 ; Bertoli M1, 68 ; Blain A1 ; Casasus AB1 ; Duff J1 Show All Authors
Authors
  1. Topf A1
  2. Johnson K1, 67
  3. Bates A1
  4. Phillips L1
  5. Chao KR2, 3
  6. England EM2, 3
  7. Laricchia KM2, 3
  8. Mullen T2, 3
  9. Valkanas E2, 3
  10. Xu L2, 3
  11. Bertoli M1, 68
  12. Blain A1
  13. Casasus AB1
  14. Duff J1
  15. Mroczek M1
  16. Specht S1
  17. Lek M2, 3, 69
  18. Ensini M1, 70
  19. Macarthur DG2, 3, 71, 72
  20. Akay E4, 73
  21. Alonsoperez J5
  22. Baets J6, 7
  23. Barisic N8
  24. Bastian A9, 10
  25. Borell S11
  26. Chamova T12
  27. Claeys K13
  28. Colomer J14
  29. Coppens S15, 16
  30. Deconinck N17, 18
  31. De Ridder W6, 7
  32. Diazmanera J5, 19
  33. Dominguezgonzalez C19, 20
  34. Duncan A21
  35. Durmus H22
  36. Fahmy NA23
  37. Farrugia ME24
  38. Fernandeztorron R25, 26, 27
  39. Gonzalezquereda L19, 28
  40. Haberlova J29
  41. Von Der Hagen M30
  42. Hahn A31
  43. Jakovcevic A32
  44. Jericopascual I33
  45. Kapetanovic S34
  46. Kenina V35
  47. Kirschner J11
  48. Klein A36, 37
  49. Kolbel H38
  50. Kosterapruszczyk A39
  51. Kulshrestha R40
  52. Lahdetie J41
  53. Layegh M42
  54. Longman C21
  55. Lopezde Munain A25, 26, 27, 43
  56. Loscher W44
  57. Lusakowska A39
  58. Maddison P4
  59. Magot A45
  60. Majumdar A46
  61. Marti P19, 47, 48
  62. Martinezarroyo A49
  63. Mazanec R29
  64. Mercier S45
  65. Mongini T50
  66. Muelas N19, 47, 48
  67. Nascimento A14
  68. Nafissi S42
  69. Omidi S42
  70. Ortez C14
  71. Paquay S51
  72. Pereon Y45
  73. Peric S52
  74. Ponzalino V50
  75. Rakocevic Stojanovic V52
  76. Remiche G53
  77. Rodriguezsainz A49
  78. Rudnik S54
  79. Sanchezalbisua I55
  80. Santos M56
  81. Schara U38
  82. Shatillo A57
  83. Sertic J58
  84. Stephani U59
  85. Strangkarlsson S60, 61
  86. Sznajer Y62
  87. Tanev A12
  88. Tournev I12, 63
  89. Van Den Bergh P51
  90. Van Parijs V51
  91. Vilchez J19, 47, 48
  92. Vill K64
  93. Vissing J65
  94. Wallgrenpettersson C60, 66
  95. Wanschitz J44
  96. Willis T40
  97. Witting N65
  98. Zulaica M25, 26
  99. Straub V1
Show Affiliations
Authors Affiliations
  1. 1. John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
  2. 2. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
  3. 3. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
  4. 4. Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
  5. 5. Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  6. 6. Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerpen, Belgium
  7. 7. Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
  8. 8. Clinical Medical Centre Zagreb, University of Zagreb, Zagreb Medical School, Zagreb, Croatia
  9. 9. Colentina University Hospital-CDPC-CCC, Bucharest, Romania
  10. 10. University of Medicine and Pharmacy Carol Davila Bucharest, Faculty of Dental Medicine, Bucharest, Romania
  11. 11. Department of Neuropediatrics, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  12. 12. Department of Neurology, UMHAT, Alexandrovska Medical University, Sofia, Bulgaria
  13. 13. Department of Neurology, University Hospitals Leuven, and Laboratory for Muscle Diseases and Neuropathies, KU Leuven, Leuven, Belgium
  14. 14. Unitat de Patologia Neuromuscular, Servei de Neurologia, Hospital Sant Joan de Deu, ISCIII, CIBERER, Barcelona, Spain
  15. 15. Department of Pediatric Neurology, Neuromuscular Reference Center, Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium
  16. 16. Department of Pediatric Neurology, Neuromuscular Reference Center, Hopital Universitaire des Enfants Reine Fabiola, Universite Libre de Bruxelles, Brussels, Belgium
  17. 17. Neuromuscular Reference Center, Universitair Ziekenhuis Gent (UZ Gent), Ghent, Belgium
  18. 18. Neuromuscular Reference Center, Hopital Universitaire des Enfants Reine Fabiola (HUDERF), ULB, Brussels, Belgium
  19. 19. Centro de Investigacion Biomedica en Red en Enfermedades Raras (CIBERER), Madrid, Spain
  20. 20. Instituto de Investigacion Hospital 12 de Octubre Centro de Actividades Ambulatorias, Madrid, Spain
  21. 21. West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, United Kingdom
  22. 22. Department of Neurology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
  23. 23. Neuromuscular Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
  24. 24. Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, United Kingdom
  25. 25. Neuroscience Area, Biodonostia Research Institute, San Sebastian, Gipuzkoa, Spain
  26. 26. Department of Neurology, Hospital Universitario Donostia, OSAKIDETZA, San Sebastian, Gipuzkoa, Spain
  27. 27. CIBERNED, Instituto de Salud Carlos III, Ministry of Science, Innovation and Universities, Madrid, Spain
  28. 28. Genetics Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  29. 29. Department of Neurology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
  30. 30. Department of Neuropediatrics, Medical Faculty Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany
  31. 31. Department of Child Neurology, Justus-Liebig-University Giessen, Gießen, Germany
  32. 32. Department of Pathology and Cytology, University Hospital Center Zagreb, School of Medicine Zagreb, Zagreb, Croatia
  33. 33. Department of Neurology, Complejo Hospitalario de Navarra, IdisNa, Pamplona, Spain
  34. 34. Neuromuscular Consult Unit, Hospital Universitario Basurto, Bilbao, Spain
  35. 35. Riga East University Hospital, Rare Disease Unit, Riga, Latvia
  36. 36. Department of Neuropediatrics, University Childrens Hospital Basel, Basel, Switzerland
  37. 37. Department of Neuropediatrics Inselspital Bern, Bern, Switzerland
  38. 38. Department of Neuropediatrics, Centre for Neuromuscular Disorders in Children and Adolescents, Children’s Hospital University Clinic Essen, University of Duisburg, Essen, Germany
  39. 39. Department of Neurology, Medical University of Warsaw, Warsaw, Poland
  40. 40. The Muscle Team, RJAH Orthopaedic Hospital NHS Foundation Trust, Oswestry, United Kingdom
  41. 41. Deptartment Pediatric Neurology, University of Turku and Turku University Central Hospital, Turku, Finland
  42. 42. Department of Neurology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
  43. 43. Department of Neurosciences, University of the Basque Country UPV-EHU, San Sebastian, Spain
  44. 44. Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
  45. 45. Centre de Reference Maladies Neuromusculaires AOC, Hotel-Dieu, University Hospital, Nantes, France
  46. 46. Department of Paediatric Neurology, Bristol Children’s Hospital, Bristol, United Kingdom
  47. 47. Neuromuscular Reference Centre, Neurology Department, Hospital Universitari i Politecnic La Fe, Valencia, Spain
  48. 48. Neuromuscular Disorders Unit, Instituto de Investigacion Sanitaria La Fe, Valencia, Spain
  49. 49. Departamento de Neurologia, Hospital Galdakao, Galdakao, Spain
  50. 50. Neuromuscular Unit, Department of Neurosciences, University of Turin, Turin, Italy
  51. 51. Cliniques Universitaires St-Luc, Centre de Reference Neuromusculaire, Universite de Louvain, Brussels, Belgium
  52. 52. Faculty of Medicine, University of Belgrade, Neurology Clinic, Clinical Center of Serbia, Belgrade, Serbia
  53. 53. Centre de Reference Neuromusculaire Erasme-HUDERF, Department of Neurology, CUB Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium
  54. 54. Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
  55. 55. Department of Child Neurology, Children’s Hospital, University of Tubingen, Tubingen, Germany
  56. 56. Centro Hospitalar Universitario Porto, Porto, Portugal
  57. 57. Institute of Neurology, Psychiatry and Narcology of NAMS of Ukraine, Kharkiv, Ukraine
  58. 58. Department of Laboratory Diagnostics, Clinical Medical Centre Zagreb, University of Zagreb, Zagreb Medical School, Zagreb, Croatia
  59. 59. Klinik fur Neuropadiatrie, University Medical Center Schleswig-Holstein, Kiel, Germany
  60. 60. Folkhaelsan Department of Medical Genetics, Helsinki, Finland
  61. 61. Department of Clinical Genetics, HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  62. 62. Cliniques Universitaires St-Luc, Centre de Genetique Humaine, Universite de Louvain, Brussels, Belgium
  63. 63. Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria
  64. 64. Dr. v. Hauner Children’s Hospital, Department of Pediatric Neurology and Developmental Medicine, LMU—University of Munich, Munich, Germany
  65. 65. Copenhagen Neuromuscular Center Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  66. 66. Department of Medical Genetics, University of Helsinki, Helsinki, Finland
  67. 67. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
  68. 68. Northern Genetics Service, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
  69. 69. Department of Genetics, Yale University School of Medicine, New Haven, CT, United States
  70. 70. Directorate-General for Research and Innovation, Directorate E, Unit E2 Combatting Diseases, Brussels, Belgium
  71. 71. Centre for Population Genomics, Garvan Institute of Medical Research, Sydney, Australia
  72. 72. Centre for Population Genomics, Murdoch Children’s Research Institute, Melbourne, Australia
  73. 73. Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

Source: Genetics in Medicine Published:2020


Abstract

Purpose: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Methods: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. Results: We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. Conclusion: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes. © 2020, The Author(s).