The Increasing Impact of Translational Research in the Molecular Diagnostics of Neuromuscular Diseases

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.

Genetic approaches and pathogenic pathways in the clinical management of Charcot-Marie-Tooth disease

“…Nevertheless, this is a very expensive and time-consuming workflow, especially in those cases where the causative gene is individually rare. With the evolution of next generation sequencing (NGS, or massive parallel sequencing) techniques, it is now possible to analyze all CMT genes by a selection of genes (panels), the exome (containing only the protein-coding sequences), or the genome, and this strategy has become the most cost-efficient approach [14,28,29] . This means that, as technology has advanced and the cost has dropped, these approaches have replaced the traditional screening gene by gene.…”

Diagnostic strategies in patients with undiagnosed and rare diseases

“…In silico prediction of the pathogenicity of a VUS can be improved with several tools such as literature review and data mining, pathogenicity predictors, and 3D protein modeling [13] . After that, functional genomics can be used for the validation of the genetic variant through molecular and cellular experiments (e.g., subcellular localization studies, expression levels, and specific studies related to protein function) [13,54] . At Sant Joan de Déu (SJD) Hospital and Research Institute, we developed the in-house Translational Diagnostics Program (TDP) to functionally validate both candidate VUS and variants found in patients with phenotype-genotype incongruity [13,55] .…”

Current Status of Genetic Counselling for Rare Diseases in Spain

“…In fact, lots of investments and actions were made to promote research in the RD field, neglecting improvements in the clinical, daily life of patients that need continuous support and advice regarding their disease. Collaborations between research centres and hospitals allowed concentrating efforts in particular diseases, such as neuromuscular [ 54 , 55 ], retinal [ 56 , 57 ] and cardiovascular [ 58 ] rare diseases among others, to provide the most comprehensive management, including Genetic Counselling, although this effort should be extended to ideally all RD.…”