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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

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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