Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness
Abstract Background Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of α-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of α-glucosidase can often be detected using an inexpensive and readily accessible d...
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doaj-b22d8d5ac3fd41be9eca559f06d136302020-11-24T20:51:04ZengBMCOrphanet Journal of Rare Diseases1750-11722017-11-0112111110.1186/s13023-017-0722-1Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weaknessKatherine Johnson0Ana Töpf1Marta Bertoli2Lauren Phillips3Kristl G. Claeys4Vidosava Rakocevic Stojanovic5Stojan Perić6Andreas Hahn7Paul Maddison8Ela Akay9Alexandra E. Bastian10Anna Łusakowska11Anna Kostera-Pruszczyk12Monkol Lek13Liwen Xu14Daniel G. MacArthur15Volker Straub16John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, International Centre for LifeJohn Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, International Centre for LifeJohn Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, International Centre for LifeJohn Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, International Centre for LifeDepartment of Neurology and Institute of Neuropathology, RWTH Aachen University HospitalNeurology Clinic CCS, School of Medicine, University of BelgradeNeurology Clinic CCS, School of Medicine, University of BelgradeDepartment of Child Neurology, Justus-Liebig UniversityQueen’s Medical CentreQueen’s Medical CentreClinical Hospital Colentina, Carol Davila University of Medicine and PharmacyDepartment of Neurology, Medical University of WarsawDepartment of Neurology, Medical University of WarsawAnalytic and Translational Genetics Unit, Massachusetts General HospitalAnalytic and Translational Genetics Unit, Massachusetts General HospitalAnalytic and Translational Genetics Unit, Massachusetts General HospitalJohn Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, International Centre for LifeAbstract Background Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of α-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of α-glucosidase can often be detected using an inexpensive and readily accessible dried blood spot test when Pompe disease is suspected. Like several neuromuscular disorders, Pompe disease typically presents with progressive weakness of limb-girdle muscles and respiratory insufficiency. Due to the phenotypic heterogeneity of these disorders, however, it is often difficult for clinicians to reach a diagnosis for patients with Pompe disease. Six hundred and six patients from a European population were recruited onto our study. Inclusion criteria stipulated that index cases must present with limb-girdle weakness or elevated serum creatine kinase activity. Whole exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. A panel of 169 candidate genes for limb-girdle weakness was analysed for disease-causing variants. Results A total of 35 variants within GAA were detected. Ten distinct variants in eight unrelated index cases (and four siblings not sequenced in our study) were considered disease-causing, with the patients presenting with heterogeneous phenotypes. The eight unrelated individuals were compound heterozygotes for two variants. Six patients carried the intronic splice site c.-13 T > G transversion and two of the six patients also carried the exonic p.Glu176ArgfsTer45 frameshift. Four of the ten variants were novel in their association with Pompe disease. Conclusions Here, we highlight the advantage of using whole exome sequencing as a tool for detecting, diagnosing and treating patients with rare, clinically variable genetic disorders.http://link.springer.com/article/10.1186/s13023-017-0722-1Whole exome sequencingSequence variantsPompe disease |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Katherine Johnson Ana Töpf Marta Bertoli Lauren Phillips Kristl G. Claeys Vidosava Rakocevic Stojanovic Stojan Perić Andreas Hahn Paul Maddison Ela Akay Alexandra E. Bastian Anna Łusakowska Anna Kostera-Pruszczyk Monkol Lek Liwen Xu Daniel G. MacArthur Volker Straub |
spellingShingle |
Katherine Johnson Ana Töpf Marta Bertoli Lauren Phillips Kristl G. Claeys Vidosava Rakocevic Stojanovic Stojan Perić Andreas Hahn Paul Maddison Ela Akay Alexandra E. Bastian Anna Łusakowska Anna Kostera-Pruszczyk Monkol Lek Liwen Xu Daniel G. MacArthur Volker Straub Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness Orphanet Journal of Rare Diseases Whole exome sequencing Sequence variants Pompe disease |
author_facet |
Katherine Johnson Ana Töpf Marta Bertoli Lauren Phillips Kristl G. Claeys Vidosava Rakocevic Stojanovic Stojan Perić Andreas Hahn Paul Maddison Ela Akay Alexandra E. Bastian Anna Łusakowska Anna Kostera-Pruszczyk Monkol Lek Liwen Xu Daniel G. MacArthur Volker Straub |
author_sort |
Katherine Johnson |
title |
Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness |
title_short |
Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness |
title_full |
Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness |
title_fullStr |
Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness |
title_full_unstemmed |
Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness |
title_sort |
identification of gaa variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness |
publisher |
BMC |
series |
Orphanet Journal of Rare Diseases |
issn |
1750-1172 |
publishDate |
2017-11-01 |
description |
Abstract Background Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of α-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of α-glucosidase can often be detected using an inexpensive and readily accessible dried blood spot test when Pompe disease is suspected. Like several neuromuscular disorders, Pompe disease typically presents with progressive weakness of limb-girdle muscles and respiratory insufficiency. Due to the phenotypic heterogeneity of these disorders, however, it is often difficult for clinicians to reach a diagnosis for patients with Pompe disease. Six hundred and six patients from a European population were recruited onto our study. Inclusion criteria stipulated that index cases must present with limb-girdle weakness or elevated serum creatine kinase activity. Whole exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. A panel of 169 candidate genes for limb-girdle weakness was analysed for disease-causing variants. Results A total of 35 variants within GAA were detected. Ten distinct variants in eight unrelated index cases (and four siblings not sequenced in our study) were considered disease-causing, with the patients presenting with heterogeneous phenotypes. The eight unrelated individuals were compound heterozygotes for two variants. Six patients carried the intronic splice site c.-13 T > G transversion and two of the six patients also carried the exonic p.Glu176ArgfsTer45 frameshift. Four of the ten variants were novel in their association with Pompe disease. Conclusions Here, we highlight the advantage of using whole exome sequencing as a tool for detecting, diagnosing and treating patients with rare, clinically variable genetic disorders. |
topic |
Whole exome sequencing Sequence variants Pompe disease |
url |
http://link.springer.com/article/10.1186/s13023-017-0722-1 |
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