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Diagnosis and aetiology of congenital muscular dystrophy: we are halfway there

O'Grady, GL; Lek, M; Lamande, SR; Waddell, L; Oates, EC; Punetha, J; Ghaoui, R; ... North, K; + view all (2016) Diagnosis and aetiology of congenital muscular dystrophy: we are halfway there. Annals of Neurology , 80 (1) pp. 101-111. 10.1002/ana.24687. Green open access

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Abstract

OBJECTIVES: To evaluate the diagnostic outcomes in a large cohort of congenital muscular dystrophy (CMD) patients using traditional and Next Generation Sequencing (NGS) technologies. METHODS: 123 CMD patients were investigated using the traditional approaches of histology, immunohistochemical analysis of muscle biopsy and candidate gene sequencing. Undiagnosed patients available for further testing were investigated using NGS. RESULTS: Muscle biopsy and immunohistochemical analysis found deficiencies of laminin α2, α-dystroglycan or collagen VI in 50% of patients. Candidate gene sequencing and chromosomal microarray established a genetic diagnosis in 32% (39/123). Of 85 patients presenting in the last 20 years, 28 of 51 who lacked a confirmed genetic diagnosis (55%) consented to NGS studies, leading to confirmed diagnoses in a further 11 patients. Using the combination of approaches, a confirmed genetic diagnosis was achieved in 51% (43/85). The diagnoses within the cohort were heterogeneous. 45/59 probands with confirmed or probable diagnoses had variants in genes known to cause CMD (76%), and 11/59 (19%) had variants in genes associated with congenital myopathies, reflecting overlapping features of these conditions. One patient had a congenital myasthenic syndrome and two had microdeletions. Within the cohort, five patients had variants in novel (PIGY and GMPPB) or recently published genes (GFPT1 and MICU1) and seven had variants in TTN or RYR1; large genes that are technically difficult to Sanger sequence. INTERPRETATION: These data support NGS as a first-line tool for genetic evaluation of patients with a clinical phenotype suggestive of CMD, with muscle biopsy reserved as a second-tier investigation. This article is protected by copyright. All rights reserved.

Type: Article
Title: Diagnosis and aetiology of congenital muscular dystrophy: we are halfway there
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/ana.24687
Publisher version: http://doi.org/10.1002/ana.24687
Language: English
Additional information: © 2016 American Neurological Association. This is the peer reviewed version of the following article: O'Grady, GL; Lek, M; Lamande, SR; Waddell, L; Oates, EC; Punetha, J; Ghaoui, R; (2016) Diagnosis and aetiology of congenital muscular dystrophy: we are halfway there. Annals of Neurology , 80 (1) pp. 101-111. 10.1002/ana.24687, which has been published in final form at http://doi.org/10.1002/ana.24687. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1494607
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