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

Katherine Johnson; Marta Bertoli; Lauren Phillips; Ana Töpf; Peter Van den Bergh; John Vissing; Nanna Witting; Shahriar Nafissi; Shirin Jamal-Omidi; Anna Łusakowska; Anna Kostera-Pruszczyk; Anna Potulska-Chromik; Nicolas Deconinck; Carina Wallgren-Pettersson; Sonja Strang-Karlsson; Jaume Colomer; Kristl G Claeys; Willem De Ridder; Jonathan Baets; Maja von der Hagen; Roberto Fernández-Torrón; Miren Zulaica Ijurco; Juan Bautista Espinal Valencia; Andreas Hahn; Hacer Durmus; Tracey Willis; Liwen Xu; Elise Valkanas; Thomas E Mullen; Monkol Lek; Daniel G MacArthur; Volker Straub

doi:10.1186/s13395-018-0170-1

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

Katherine Johnson, Marta Bertoli, Lauren Phillips, Ana Töpf, Peter Van den Bergh, John Vissing, Nanna Witting, Shahriar Nafissi, Shirin Jamal-Omidi, Anna Łusakowska, Anna Kostera-Pruszczyk, Anna Potulska-Chromik, Nicolas Deconinck, Carina Wallgren-Pettersson, Sonja Strang-Karlsson, Jaume Colomer, Kristl G Claeys, Willem De Ridder, Jonathan Baets, Maja von der HagenRoberto Fernández-Torrón, Miren Zulaica Ijurco, Juan Bautista Espinal Valencia, Andreas Hahn, Hacer Durmus, Tracey Willis, Liwen Xu, Elise Valkanas, Thomas E Mullen, Monkol Lek, Daniel G MacArthur, Volker Straub

Department of Clinical Medicine

16 Citations (Scopus)

28 Downloads (Pure)

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 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.

Original language	English
Article number	23
Journal	Skeletal Muscle
Volume	8
Number of pages	12
ISSN	2044-5040
DOIs	https://doi.org/10.1186/s13395-018-0170-1
Publication status	Published - 30 Jul 2018

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Child
Child, Preschool
Dystroglycans/metabolism
Female
Genetic Predisposition to Disease
Genetic Variation
Glycosylation
Heterozygote
Homozygote
Humans
Male
Middle Aged
Muscle Proteins/genetics
Muscular Dystrophies, Limb-Girdle/genetics
Mutation
Phenotype
Whole Exome Sequencing/methods
Young Adult

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Johnson, K., Bertoli, M., Phillips, L., Töpf, A., Van den Bergh, P., Vissing, J., Witting, N., Nafissi, S., Jamal-Omidi, S., Łusakowska, 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., ... 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, 8, [23]. https://doi.org/10.1186/s13395-018-0170-1

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. / Johnson, Katherine; Bertoli, Marta; Phillips, Lauren et al.

In: Skeletal Muscle, Vol. 8, 23, 30.07.2018.

Research output: Contribution to journal › Journal article › Research › peer-review

Johnson, K, Bertoli, M, Phillips, L, Töpf, A, Van den Bergh, P, Vissing, J, Witting, N, Nafissi, S, Jamal-Omidi, S, Łusakowska, 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, Fernández-Torrón, 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 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

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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",

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 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.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Dystroglycans/metabolism, Female, Genetic Predisposition to Disease, Genetic Variation, Glycosylation, Heterozygote, Homozygote, Humans, Male, Middle Aged, Muscle Proteins/genetics, Muscular Dystrophies, Limb-Girdle/genetics, Mutation, Phenotype, Whole Exome Sequencing/methods, Young Adult",

author = "Katherine Johnson and Marta Bertoli and Lauren Phillips and Ana T{\"o}pf and {Van den Bergh}, Peter and John Vissing and Nanna Witting and Shahriar Nafissi and Shirin Jamal-Omidi and Anna {\L}usakowska and Anna Kostera-Pruszczyk and Anna Potulska-Chromik and Nicolas Deconinck and Carina Wallgren-Pettersson and Sonja Strang-Karlsson and Jaume Colomer and Claeys, {Kristl G} and {De Ridder}, Willem and Jonathan Baets and {von der Hagen}, Maja and Roberto Fern{\'a}ndez-Torr{\'o}n and {Zulaica Ijurco}, Miren and {Espinal Valencia}, {Juan Bautista} and Andreas Hahn and Hacer Durmus and Tracey Willis and Liwen Xu and Elise Valkanas and Mullen, {Thomas E} and Monkol Lek and MacArthur, {Daniel G} and Volker Straub",

year = "2018",

month = jul,

day = "30",

doi = "10.1186/s13395-018-0170-1",

language = "English",

volume = "8",

journal = "Skeletal Muscle",

issn = "2044-5040",

publisher = "BioMed Central Ltd.",

}

TY - JOUR

T1 - 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

AU - Johnson, Katherine

AU - Bertoli, Marta

AU - Phillips, Lauren

AU - Töpf, Ana

AU - Van den Bergh, Peter

AU - Vissing, John

AU - Witting, Nanna

AU - Nafissi, Shahriar

AU - Jamal-Omidi, Shirin

AU - Łusakowska, Anna

AU - Kostera-Pruszczyk, Anna

AU - Potulska-Chromik, Anna

AU - Deconinck, Nicolas

AU - Wallgren-Pettersson, Carina

AU - Strang-Karlsson, Sonja

AU - Colomer, Jaume

AU - Claeys, Kristl G

AU - De Ridder, Willem

AU - Baets, Jonathan

AU - von der Hagen, Maja

AU - Fernández-Torrón, Roberto

AU - Zulaica Ijurco, Miren

AU - Espinal Valencia, Juan Bautista

AU - Hahn, Andreas

AU - Durmus, Hacer

AU - Willis, Tracey

AU - Xu, Liwen

AU - Valkanas, Elise

AU - Mullen, Thomas E

AU - Lek, Monkol

AU - MacArthur, Daniel G

AU - Straub, Volker

PY - 2018/7/30

Y1 - 2018/7/30

N2 - 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 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.

AB - 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 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Child

KW - Child, Preschool

KW - Dystroglycans/metabolism

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Glycosylation

KW - Heterozygote

KW - Homozygote

KW - Humans

KW - Male

KW - Middle Aged

KW - Muscle Proteins/genetics

KW - Muscular Dystrophies, Limb-Girdle/genetics

KW - Mutation

KW - Phenotype

KW - Whole Exome Sequencing/methods

KW - Young Adult

U2 - 10.1186/s13395-018-0170-1

DO - 10.1186/s13395-018-0170-1

M3 - Journal article

C2 - 30060766

SN - 2044-5040

VL - 8

JO - Skeletal Muscle

JF - Skeletal Muscle

M1 - 23

ER -

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

Abstract

Keywords

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