Infrastructure and expertise supported by Phenomics Australia are being used to address the gap in genetic disease diagnosis.
The challenge:
One-third of known disease genes, many impacting brain development, are not sufficiently expressed in clinically accessible tissues.
The solution:
Two new methods for RNA variant assessment in genes which are not expressed in clinically accessible tissues using skin cells from the affected individuals.
The future:
Use these new methods to help deliver diagnosis to countless individuals living with a genetically undiagnosed rare disease.
The challenge: One-third of known disease genes, many impacting brain development, are not sufficiently expressed in clinically accessible tissues.
While diagnostic DNA sequencing has revolutionised the ability to discover the genetic causes of human disease, it is accompanied by growing number of gene variants of uncertain pathology, which continue to accumulate and are challenging to resolve.
Approximately 50% of individuals assessed for a genetic disorder are found to have such a variant, with about 30% suspected to impact RNA processing, which can be resolved using a subsequent RNA sequencing based investigation to provide a diagnosis.
To enable such RNA testing, patient blood or skin samples/cell lines are used as a source of the variant gene RNA. However, approximately one-third of known disease genes, many impacting brain development, are not sufficiently expressed in these clinically accessible tissues, and therefore unable to be investigated and thus diagnosis cannot be obtained leading to many disadvantages.
The solution: Two new methods for RNA variant assessment in genes which are not expressed in clinically accessible tissues using skin cells from the affected individuals..
The Neurobiology Research Group at the University of Adelaide’s School of Biomedicine, led by Dr Lachlan Jolly and with the assistance of Phenomics Australia Functional Genomics South Australia node, developed two methods for RNA variant assessment in genes which are not expressed in clinically accessible tissues using skin cells from the affected individuals.
The first employs transdifferentiation which reprograms the skin cell into a neuron to access brain disorder gene RNA, and the second in transactivation which uses CRISPR technology to engineer skin cells to express any disease gene of choice.
These findings have been published in the American Journal of Human Genetics.
‘“What we’ve been able to do is activate the expression of brain disease genes in cells derived from a patient skin biopsy grown in the laboratory to obtain the genes RNA transcript; previously this would have only been possible through a sample of patient brain tissue, which is rarely available or advisable.” – Dr Lachlan Jolly, Robinson Research Institute, Head of the University of Adelaide’s School of Biomedicine’s Neurobiology Research Group
The future: Use these new methods to help deliver diagnosis to countless individuals living with a genetically undiagnosed rare disease.
The ability to activate disease genes in skin cells enables functional RNA based studies found in the non-expressed disease genes, which equates to 22.2% of all variants of uncertain pathology. This will help deliver diagnosis to the countless individuals living with a genetically undiagnosed rare disease.
“A genetic diagnosis is a prerequisite to appropriate care, therapies, clinical trials, family planning and importantly, a community of belonging and support.” says Dr Jolly. “Activating the disease genes in skin cells enables a functional RNA based study to resolve the pathology of the genetic variant. Such individuals would otherwise often never receive a genetic diagnosis because the genes RNA is unobtainable without highly invasive procedures”.
