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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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

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
Author: Johnson, Katherine; Bertoli, Marta; Phillips, Lauren; Topf, Ana; Van den Bergh, Peter; Vissing, John; Witting, Nanna; Nafissi, Shahriar; Jamal-Omidi, Shirin; Lusakowska, Anna; Kostera-Pruszczyk, Anna; Potulska-Chromik, Anna; Deconinck, Nicolas; Wallgren-Pettersson, Carina; Strang-Karlsson, Sonja; Colomer, Jaume; Claeys, Kristl G.; De Ridder, Willem; Baets, Jonathan; von der Hagen, Maja; Fernandez-Torron, Roberto; Zulaica Ijurco, Miren; Espinal Valencia, Juan Bautista; Hahn, Andreas; Durmus, Hacer; Willis, Tracey; Xu, Liwen; Valkanas, Elise; Mullen, Thomas E.; Lek, Monkol; MacArthur, Daniel G.; Straub, Volker
Contributor: University of Helsinki, Medicum
University of Helsinki, Clinicum
Date: 2018-07-30
Language: eng
Number of pages: 12
Belongs to series: Skeletal Muscle
ISSN: 2044-5040
URI: http://hdl.handle.net/10138/238491
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.
Subject: Whole-exome sequencing
Dystroglycanopathies
Limb-girdle muscle weakness
CONGENITAL MUSCULAR-DYSTROPHY
WALKER-WARBURG-SYNDROME
EYE-BRAIN DISEASE
ALPHA-DYSTROGLYCAN
MENTAL-RETARDATION
POMT2 MUTATIONS
SKELETAL-MUSCLE
DEFECTIVE GLYCOSYLATION
ABNORMAL GLYCOSYLATION
GLYCOPROTEIN COMPLEX
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
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