Identifying the genetic basis of neuromuscular disease is crucial to guide patient care. It enables us to provide more accurate prognostic information to families, and prevent complications, such as heart and lung involvement. By using next generation sequencing (NGS) such as whole exome sequencing (WES) and Neurogenetic Subexomic Supercapture (NSES, also known as targeted neuromuscular panel), this approach has dramatically transformed how we diagnose and deliver health care to Australian myopathy and muscular dystrophy patients – now greater numbers of patients can achieve accurate and timely diagnosis, receive appropriate disease-specific treatments and gain access to informed family planning while still fertile.
Despite these recent advances in genetic testing, more than 50% of patients with hereditary neuromuscular disorders remain undiagnosed. RNA studies via RNA sequencing (also known as transciptome sequencing) is the next step of the diagnostic pathway. This project aims to apply this newest form of NGS testing strategy to clinical practice. We will examine the utility of RNA sequencing (RNA-seq) as a complementary diagnostic tool in a cohort of families with inherited myopathy or limb-girdle muscular dystrophy (LGMD) that have remained undiagnosed despite next generation sequencing (NGS) and who have muscle biopsies available. Previous studies have shown that RNA-seq can provide a substantial diagnosis rate in patients for whom exome or whole genome analysis has not yielded a molecular diagnosis. By taking from my experience of using RNA sequencing, I hope to develop a new diagnostic algorithm with the completion of the project that incorporates NGS and RNA sequencing into the diagnostic pathway for patients with neuromuscular disorders. The ultimate aim of the project is to help inform best practice guidelines for the diagnosis and management of patients with inherited myopathies and LGMD in Australia.