Diagnostic use of Massively Parallel Sequencing in Neuromuscular Diseases: Towards an Integrated Diagnosis

Biancalana, Valérie; Laporte, Jocelyn

doi:10.3233/jnd-150092

Cited by 18 publications

(12 citation statements)

References 58 publications

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“…Since the identification of dominant mutations in the skeletal muscle ryanodine receptor (RYR1) gene as the cause of Malignant Hyperthermia (MH) in 1991 and CCD in 1993 9,10 , mutations in more than 20 genes have been identified. Introduction of next generation sequencing (NGS) techniques into routine clinical diagnosis 11 has resulted in an improved detection rate of mutations in genes such as RYR1, nebulin (NEB) or titin (TTN), due to their sheer size previously only studied with Sanger sequencing in few patients. These novel techniques have led to the recognition that different mutations in the same gene may give rise to variable histopathological phenotypes, whilst mutations in different genes may cause the same histopathological feature, often due to functional association of the defective proteins.…”

Section: Introductionmentioning

confidence: 99%

Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

et al. 2018

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The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course. Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects. Central core disease (CCD), multi-minicore disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories. However, these entities seem to belong to a much wider phenotypic spectrum. To date, congenital myopathies have been attributed to mutations in over 20 genes, which encode proteins implicated in skeletal muscle Ca homeostasis, excitation-contraction coupling, thin-thick filament assembly and interactions, and other mechanisms. RYR1 mutations are the most frequent genetic cause, and CCD and MmD are the most common subgroups. Next-generation sequencing has vastly improved mutation detection and has enabled the identification of novel genetic backgrounds. At present, management of congenital myopathies is largely supportive, although new therapeutic approaches are reaching the clinical trial stage.

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Section: Introductionmentioning

confidence: 99%

Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

et al. 2018

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“…In terms of cost and time effectiveness, and several quality control parameters, targeted sequencing has been accepted by several large‐scale studies as the method‐of‐choice in the neuromuscular disease (NMD) diagnostics (Ankala et al., ; Biancalana & Laporte, ; Gorokhova et al., ; Savarese et al., ; Vasli et al., ). However, defining the optimal size of the gene panel remains the biggest challenge in targeted sequencing (Volk & Kubisch, ).…”

Section: Introductionmentioning

confidence: 99%

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies

et al. 2018

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Spinal muscular atrophies (SMAs) are a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48.8% carried a homozygous SMN1 deletion, 2.8% a subtle mutation, and an SMN1 deletion, whereas 48.4% remained undiagnosed. Recently, several other genes implicated in SMA/LMND have been reported. Despite several efforts to establish a diagnostic algorithm for non-5q-SMA (SMA without deletion or point mutations in SMN1 [5q13.2]), data from large-scale studies are not available. We tested the clinical utility of targeted sequencing in non-5q-SMA by developing two different gene panels. We first analyzed 30 individuals with a small panel including 62 genes associated with LMND using IonTorrent-AmpliSeq target enrichment. Then, additional 65 individuals were tested with a broader panel encompassing up to 479 genes implicated in neuromuscular diseases (NMDs) with Agilent-SureSelect target enrichment. The NMD panel provided a higher diagnostic yield (33%) than the restricted LMND panel (13%). Nondiagnosed cases were further subjected to exome or genome sequencing. Our experience supports the use of gene panels covering a broad disease spectrum for diseases that are highly heterogeneous and clinically difficult to differentiate.

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“…Next generation sequencing techniques (NGS) provide a potential way to overcome diagnostic delays due to genetic heterogeneity and also the possibility to identify novel genetic causes of muscle disorders [ 13 , 14 ]. Several studies have reported on the application of gene panels [ 15 – 23 ] or WES [ 24 , 25 ] for the diagnosis in undiagnosed muscle disease, achieving diagnostic rates from 16 to 76%, with the highest diagnostic rate achieved in patients with no prior genetic testing [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Exome sequences versus sequential gene testing in the UK highly specialised Service for Limb Girdle Muscular Dystrophy

Harris

Töpf

Barresi

et al. 2017

Orphanet J Rare Dis

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BackgroundLimb girdle muscular dystrophies are a group of rare and genetically heterogeneous diseases that share proximal weakness as a common feature; however they are often lacking very specific phenotypic features to allow an accurate differential diagnosis based on the clinical signs only, limiting the diagnostic rate using phenotype driven genetic testing. Next generation sequencing provides an opportunity to obtain molecular diagnoses for undiagnosed patients, as well as identifying novel genetic causes of muscle diseases. We performed whole exome sequencing (WES) on 104 affected individuals from 75 families in who standard gene by gene testing had not yielded a diagnosis. For comparison we also evaluated the diagnostic rate using sequential gene by gene testing for 91 affected individuals from 84 families over a 2 year period.ResultsPatients selected for WES had undergone more extensive prior testing than those undergoing standard genetic testing and on average had had 8 genes screened already. In this extensively investigated cohort WES identified the genetic diagnosis in 28 families (28/75, 37%), including the identification of the novel gene ZAK and two unpublished genes. WES of a single affected individual with sporadic disease yielded a diagnosis in 13/38 (34%) of cases. In comparison, conventional gene by gene testing provided a genetic diagnosis in 28/84 (33%) families. Titinopathies and collagen VI related dystrophy were the most frequent diagnoses made by WES. Reasons why mutations in known genes were not identified previously included atypical phenotypes, reassignment of pathogenicity of variants, and in one individual mosaicism for a COL6A1 mutation which was undetected by prior direct sequencing.ConclusionWES was able to overcome many limitations of standard testing and achieved a higher rate of diagnosis than standard testing even in this cohort of extensively investigated patients. Earlier application of WES is therefore likely to yield an even higher diagnostic rate. We obtained a high diagnosis rate in simplex cases and therefore such individuals should be included in exome or genome sequencing projects. Disease due to somatic mosaicism may be increasingly recognised due to the increased sensitivity of next generation sequencing techniques to detect low level mosaicism.Electronic supplementary materialThe online version of this article (10.1186/s13023-017-0699-9) contains supplementary material, which is available to authorized users.

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Diagnostic use of Massively Parallel Sequencing in Neuromuscular Diseases: Towards an Integrated Diagnosis

Cited by 18 publications

References 58 publications

Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies

Exome sequences versus sequential gene testing in the UK highly specialised Service for Limb Girdle Muscular Dystrophy

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