Abstract
The diagnosis of neuromuscular diseases (NMDs) has been progressively evolving from the grouping of clinical symptoms and signs towards the molecular definition. Optimal clinical, biochemical, electrophysiological, electrophysiological, and histopathological characterization is very helpful to achieve molecular diagnosis, which is essential for establishing prognosis, treatment and genetic counselling. Currently, the genetic approach includes both the gene-targeted analysis in specific clinically recognizable diseases, as well as genomic analysis based on next-generation sequencing, analyzing either the clinical exome/genome or the whole exome or genome. However, as of today, there are still many patients in whom the causative genetic variant cannot be definitely established and variants of uncertain significance are often found. In this review, we address these drawbacks by incorporating two additional biological omics approaches into the molecular diagnostic process of NMDs. First, functional genomics by introducing experimental cell and molecular biology to analyze and validate the variant for its biological effect in an in-house translational diagnostic program, and second, incorporating a multi-omics approach including RNA-seq, metabolomics, and proteomics in the molecular diagnosis of neuromuscular disease. Both translational diagnostics programs and omics are being implemented as part of the diagnostic process in academic centers and referral hospitals and, therefore, an increase in the proportion of neuromuscular patients with a molecular diagnosis is expected. This improvement in the process and diagnostic performance of patients will allow solving aspects of their health problems in a precise way and will allow them and their families to take a step forward in their lives.
Highlights
Inherited neuromuscular disorders (NMDs) are a group of diseases that affect the muscle and the peripheral nervous system (PNS)
Stenton et al suggested a multi-omics approach to the diagnosis of Mendelian disease [82] in which genomic data obtained from whole exome sequencing (WES) and whole genome sequencing (WGS) negative studies are analyzed in parallel with transcriptomic and proteomic data
Two aspects still make etiological diagnosis difficult in a significant number of patients in whom a genetic neuromuscular diseases (NMDs) is suspected: (i) first, the increase in genes associated with recognized phenotypes and nosological entities, and the overlapping of phenotypes; and (ii) second, the difficulty that sometimes arises as a result of the uncertainty in the pathogenic significance of the genetic variant(s) in a candidate gene, or the incongruity between genotype and phenotype despite finding a pathogenic variant
Summary
Inherited neuromuscular disorders (NMDs) are a group of diseases that affect the muscle and the peripheral nervous system (PNS). The diagnosis of NMDs is based on the appropriate combination of clinical and neurological examinations, electrophysiological studies of the peripheral nervous system, histopathology of the muscle biopsy (and sometimes of the nerve biopsy), and gene/genome studies. This clinical approach is especially relevant to address difficult differential diagnoses and complex phenotypes or diseases [2]. According to the GeneTable of Neuromuscular Disorders (http://www.musclegenetable.fr/ (accessed on 20 January 2021)) [3], by December 2020, almost 600 genes had been associated with NMD.
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