Abstract
Next-generation sequencing (NGS) has revealed large numbers of genetic variants in LGMD-related genes, with most of them classified as variants of uncertain significance (VUSs). VUSs are genetic changes with unknown pathological impact and present a major challenge in genetic test interpretation and disease diagnosis. Understanding the phenotypic consequences of VUSs can provide clinical guidance regarding LGMD risk and therapy. In this review, we provide a brief overview of the subtypes of LGMD, disease diagnosis, current classification systems for investigating VUSs, and a potential deep mutational scanning approach to classify VUSs in LGMD-related genes.
Highlights
In the remainder of this review, we propose a deep mutational scanning protocol using sarcoglycans as an example to discuss the feasibility of applying this technology on Limb-girdle muscular dystrophies (LGMDs)
Next-generation sequencing is steadily becoming more common in accurate disease diagnosis
As we described in this review, there are several approaches that are currently being used for VUS classification
Summary
Limb-girdle muscular dystrophies (LGMDs) are the fourth most common form of genetic muscle disease. They are defined by progressive weakness that predominantly affects the pelvic and shoulder girdle muscles, with age of onset ranging from early childhood to late adulthood. Whole-exome sequencing (WES, one strategy of NGS) followed by targeted analysis was reported to identify disease-causing mutations that were previously missed using incomplete Sanger sequencing [5], increasing the diagnostic success rate to 45% in a cohort of patients with LGMDs in Australia [6]. Nallamilli et al [7] conducted NGS-based gene-panel testing on a cohort of 4656 patients from the United States with clinically suspected LGMDs, diagnostic variants were interpreted.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
