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PERSYST Study Uses Skin Samples to Resolve Uncertain Genetic Variants

10 months ago2 min read

Key Insights

  • The PERSYST study, led by the University of Adelaide, is resolving variants of uncertain significance (VUS) using skin samples to extract RNA from disease-causing genes.

  • Innovative techniques like transactivation and transdifferentiation are used to activate silent genes in skin fibroblasts, enabling RNA sequencing and variant classification.

  • This approach aims to provide definitive diagnoses for patients with rare genetic diseases, opening access to clinical trials and precision therapies.

A pioneering study, known as PERSYST, is underway at the University of Adelaide's Neurobiology Research Group, aiming to transform genetic diagnostics by resolving variants of uncertain significance (VUS) through the analysis of skin samples. Led by Dr. Lachlan Jolly, the study addresses the challenge that many patients with VUS lack a definitive diagnosis because RNA from disease-causing genes often cannot be extracted from accessible tissues like blood or skin. This innovative research could significantly impact access to clinical trials and precision therapies for those with rare genetic diseases.

Overcoming Diagnostic Obstacles

The PERSYST study, short for Pathogenic Evaluation of Recalcitrant Variants by Systematic Transactivation, is a national program in Australia actively recruiting individuals living with a medical condition caused by VUSs within rare silent disease genes. Dr. Jolly's team employs innovative techniques—transactivation and transdifferentiation—to activate these "silent genes" in skin fibroblasts. This activation enables researchers to retrieve the necessary RNA for diagnosis, a crucial step in understanding and treating these conditions.

Enabling Access to Clinical Trials and Precision Therapies

This approach is particularly crucial for patients, as it opens access to clinical trials and precision therapies targeting rare genetic diseases. Approximately 13,000 clinical trials globally are focused on treatments for conditions tied to genetic mutations, but participation requires a solid genetic diagnosis. Jolly’s work aims to provide this diagnosis by unlocking RNA from hard-to-access genes, particularly those linked to brain disorders. The team has successfully activated over 230 silent genes, a major step in enabling RNA sequencing and variant classification.

Broader Implications and Future Directions

The PERSYST study is part of a broader effort to provide functional RNA-based evidence for VUSs, offering new hope to patients. With this research, individuals who previously faced diagnostic uncertainty could gain access to life-changing trials and treatments. This initiative not only enhances diagnostic capabilities but also paves the way for more targeted and effective therapeutic interventions for rare genetic disorders.
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