Rare and Neuromuscular Diseases:
Gene discovery and mechanistic insights
Researchers at the Harry Perkins Institute of Medical Research and The University of Western Australia (UWA) have discovered the genetic cause of a rare muscle disease that causes muscle weakness, droopy eyelids and difficulty swallowing.Â
neuromuscular diseases:
MYOPATHIES
DYSTROPHIES
RHABDOMYOLYSIS
NEUROPATHIES
Ataxias
Movement
disorders
Fetal akinesia
others rare diseases
ABOUT THE PROGRAM
More than 50% of patients with a rare disease remain without a genetic diagnosis after clinical testing. Our research focuses on finding the causative genes in these unsolved patients and families. We have a focus on neuromuscular and neurodegenerative diseases. These diseases range from prenatal-onset conditions including fetal akinesias and arthrogryposis through to congenital myopathies, adult-onset muscular dystrophies and myopathies, neuropathies, dystonias, spastic paraplegias, and late-onset ataxias. We also work on patients with other rare diseases, where diagnostic testing options have been exhausted.
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For Australian patients and families, recruitment into research usually occurs if a patient remains without a diagnosis despite gold-standard clinical testing within the Neurogenetics Unit, Diagnostic Genomics – PathWest. This Unit is a national referral centre for the molecular diagnosis of neuromuscular diseases. We work on unsolved families from all states and territories across Australia. We also receive samples from undiagnosed families from around the world, and these are particularly for families that present with diseases for which our team are well known, for example myopathies.
We use a range of genomic technologies including short and long-read genome sequencing, Bionano optical genome mapping and RNA-sequencing. Using a range of advanced informatic tools and platforms we then curate the identified variants and work towards identifying the causative genes and variants. To confirm a novel human disease gene, we also perform a range of functional genomics assays including protein studies of patient biopsy material or cell lines, in vitro protein studies, cell-based assays to study protein localisation, aggregation and interactions, enzyme assays, and investigations using model organisms.
We also enter candidate genes and variants into Gene Matching platforms including GeneMatcher. This facilitates identification of additional cases and families with similar phenotypes and variants in the same candidate gene.
The causative variants we identify on a research basis are confirmed in an accredited diagnostic laboratory and reported clinically.
This research is highly collaborative, we work with leading research groups and clinical teams from across Australia and NZ, Japan, Europe, the UK and the USA.
To date, we have identified and characterised more than 30 novel human disease genes. Each of these discoveries results in an accurate molecular diagnosis for the families involved in our research but also represents another group of patients for which a molecular diagnosis can be made via routine diagnostic testing.
This work also sheds light onto the role of previously unknown genes and proteins, identifying new pathways involved in skeletal muscle development and functions.
Biobanking of patient cell lines and generating patient-derived induced pluripotent stem cells (iPSCs) are also an important area of activity for our group. These resources are incredibly important for exploring disease mechanisms and investigating potential therapies. We share these precious resources with the international research community.
