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

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dc.contributor.author Johnson, Katherine
dc.contributor.author Bertoli, Marta
dc.contributor.author Phillips, Lauren
dc.contributor.author Topf, Ana
dc.contributor.author Van den Bergh, Peter
dc.contributor.author Vissing, John
dc.contributor.author Witting, Nanna
dc.contributor.author Nafissi, Shahriar
dc.contributor.author Jamal-Omidi, Shirin
dc.contributor.author Lusakowska, Anna
dc.contributor.author Kostera-Pruszczyk, Anna
dc.contributor.author Potulska-Chromik, Anna
dc.contributor.author Deconinck, Nicolas
dc.contributor.author Wallgren-Pettersson, Carina
dc.contributor.author Strang-Karlsson, Sonja
dc.contributor.author Colomer, Jaume
dc.contributor.author Claeys, Kristl G.
dc.contributor.author De Ridder, Willem
dc.contributor.author Baets, Jonathan
dc.contributor.author von der Hagen, Maja
dc.contributor.author Fernandez-Torron, Roberto
dc.contributor.author Zulaica Ijurco, Miren
dc.contributor.author Espinal Valencia, Juan Bautista
dc.contributor.author Hahn, Andreas
dc.contributor.author Durmus, Hacer
dc.contributor.author Willis, Tracey
dc.contributor.author Xu, Liwen
dc.contributor.author Valkanas, Elise
dc.contributor.author Mullen, Thomas E.
dc.contributor.author Lek, Monkol
dc.contributor.author MacArthur, Daniel G.
dc.contributor.author Straub, Volker
dc.date.accessioned 2018-08-16T08:17:01Z
dc.date.available 2018-08-16T08:17:01Z
dc.date.issued 2018-07-30
dc.identifier.citation 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 , K G , De Ridder , W , Baets , J , von der Hagen , M , Fernandez-Torron , R , Zulaica Ijurco , M , Espinal Valencia , J B , Hahn , A , Durmus , H , Willis , T , Xu , L , Valkanas , E , Mullen , T E , Lek , M , MacArthur , D G & Straub , V 2018 , ' 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 ' , Skeletal Muscle , vol. 8 , 23 . https://doi.org/10.1186/s13395-018-0170-1
dc.identifier.other PURE: 115120885
dc.identifier.other PURE UUID: e4c03994-4b99-4de0-983e-be7f58596208
dc.identifier.other WOS: 000440184300001
dc.identifier.other Scopus: 85050774047
dc.identifier.uri http://hdl.handle.net/10138/238491
dc.description.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 alpha-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 250 ng DNA was completed using an Illumina exome capture and a 38 Mb 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. en
dc.format.extent 12
dc.language.iso eng
dc.relation.ispartof Skeletal Muscle
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject Whole-exome sequencing
dc.subject Dystroglycanopathies
dc.subject Limb-girdle muscle weakness
dc.subject CONGENITAL MUSCULAR-DYSTROPHY
dc.subject WALKER-WARBURG-SYNDROME
dc.subject EYE-BRAIN DISEASE
dc.subject ALPHA-DYSTROGLYCAN
dc.subject MENTAL-RETARDATION
dc.subject POMT2 MUTATIONS
dc.subject SKELETAL-MUSCLE
dc.subject DEFECTIVE GLYCOSYLATION
dc.subject ABNORMAL GLYCOSYLATION
dc.subject GLYCOPROTEIN COMPLEX
dc.subject 3111 Biomedicine
dc.subject 1182 Biochemistry, cell and molecular biology
dc.title 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 en
dc.type Article
dc.contributor.organization Medicum
dc.contributor.organization Department of Medical and Clinical Genetics
dc.contributor.organization University of Helsinki
dc.contributor.organization Clinicum
dc.contributor.organization Children's Hospital
dc.contributor.organization HUS Children and Adolescents
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1186/s13395-018-0170-1
dc.relation.issn 2044-5040
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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