The Impact of Next-Generation Sequencing on the Diagnosis, Treatment, and Prevention of Hereditary Neuromuscular Disorde
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LEADING ARTICLE
The Impact of Next‑Generation Sequencing on the Diagnosis, Treatment, and Prevention of Hereditary Neuromuscular Disorders Sarah J. Beecroft1,2 · Phillipa J. Lamont3 · Samantha Edwards1,2 · Hayley Goullée1,2 · Mark R. Davis4 · Nigel G. Laing1,2,3 · Gianina Ravenscroft1,2 Accepted: 5 September 2020 © Springer Nature Switzerland AG 2020
Abstract The impact of high-throughput sequencing in genetic neuromuscular disorders cannot be overstated. The ability to rapidly and affordably sequence multiple genes simultaneously has enabled a second golden age of Mendelian disease gene discovery, with flow-on impacts for rapid genetic diagnosis, evidence-based treatment, tailored therapy development, carrier-screening, and prevention of disease recurrence in families. However, there are likely many more neuromuscular disease genes and mechanisms to be discovered. Many patients and families remain without a molecular diagnosis following targeted panel sequencing, clinical exome sequencing, or even genome sequencing. Here we review how massively parallel, or next-generation, sequencing has changed the field of genetic neuromuscular disorders, and anticipate future benefits of recent technological innovations such as RNA-seq implementation and detection of tandem repeat expansions from short-read sequencing.
Key Points
1 Introduction
High-throughput massively parallel sequencing has revolutionised genetic diagnosis and disease gene discovery.
Monogenic neuromuscular disorders affect one or more parts of the neuromuscular system, comprising the skeletal muscle, neuromuscular junction, nerve, and brain [1, 2]. Although these diseases vary widely in presentation and severity, their uniting feature is impairment of voluntary movement [2]. The onset of neurogenetic disorders ranges from in utero (e.g. foetal akinesia [3]) to old age (e.g. motor neuron disease [4], late-onset ataxia [5]). Some are rapidly progressive (e.g. motor neuron disease [4]), while others are almost static (e.g. spinal muscular atrophy with lower extremity predominance [6]). Although individually rare, their combined incidence exceeds one in 3000 [7]. Neuromuscular disorders often result in chronic, severe disability and early mortality [7–9], and have a high burden of disease [10]. Indirect costs associated with patient and caregiver productivity losses comprise a significant burden that can be double the direct costs [11]. Neuromuscular disorders exhibit considerable clinical and genetic heterogeneity, having been associated with ≈ 600 genes to date (https://www.musclegenetable.fr/) [2, 12]. Differentiating between neuromuscular disorders based on their clinical presentation is challenging, and a clinically similar phenotype can be associated with multiple genes. A European survey of eight rare diseases, including four neuromuscular diseases, showed that 25% of patients waited
The paradigm shift caused by massively parallel sequencing has blurred the boundaries between previously distinct disease entities. Limitations in technology a
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