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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

Lookup NU author(s): Dr Katherine JohnsonORCiD, Dr Marta Bertoli, Lauren Charlotte Phillips Phillips, Dr Ana TopfORCiD, Roberto Fernandez-Torron, Professor Volker StraubORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2018 The Author(s). 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.

Publication metadata

Author(s): Johnson K, Bertoli M, Phillips L, Topf A, Van den Bergh P, Vissing J, Witting N, Nafissi S, Jamal-Omidi S, Lusakowska A, Kostera-Pruszczyk A, Potulska-Chromik A, Deconinck N, Wallgren-Pettersson C, Strang-Karlsson S, Colomer J, Claeys KG, De Ridder W, Baets J, von der Hagen M, Fernandez-Torron R, Zulaica Ijurco M, Espinal Valencia JB, Hahn A, Durmus H, Willis T, Xu L, Valkanas E, Mullen TE, Lek M, MacArthur DG, Straub V

Publication type: Article

Publication status: Published

Journal: Skeletal Muscle

Year: 2018

Volume: 8

Issue: 1

Online publication date: 30/07/2018

Acceptance date: 13/07/2018

Date deposited: 15/08/2018

ISSN (electronic): 2044-5040

Publisher: BioMed Central Ltd.


DOI: 10.1186/s13395-018-0170-1


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