A history of successful diagnosis
CIRCA has completed numerous genomic studies, and successfully diagnosed many patients. We've identified a number of novel immunodeficiency genes, leading to treatments that would otherwise not have been considered.
Life-saving genomics: Stella's story
Collien thought her newborn, Stella, was just a colicky baby. But at only three weeks old, Stella started presenting with signs of what would later be diagnosed as a life-threatening immune disorder.
Through whole genome sequencing at Garvan, as part of the CIRCA program, it was discovered that Stella had a rare genetic variation in a molecule called DOCK8, which impairs the function of immune cells by preventing them from reaching and clearing pathogen infections in the skin.
DOCK8 immunodeficiency syndrome, only discovered in 2009, leads to recurrent bacterial, viral and fungal infections of the skin and respiratory system. Many patients with DOCK8 immunodeficiency syndrome have to undergo bone marrow transplants in order to survive, with many losing their lives. Stella is one of only five people in Australia to be diagnosed with the disorder.
Once gravely ill with an immune condition that was destroying his own cells, 7-year-old Alan is now an energetic boy who delights in Lego adventures and light-sabre duels. His medical saga is not yet over, but the improvement in his condition has been immense.
Alan is one of the first people in Australia to have received a diagnosis from whole genome sequencing that has changed his treatment – and, in Alan’s case, transformed his health.
Alan’s care, his diagnosis through WGS, his subsequent change in treatment and allied functional studies were overseen by CIRCA members and others, through Sydney Children’s Hospital, Randwick and the Garvan Institute.
- Learn more about Alan’s story in this in-depth web feature.
Discovering the unknown
At only 11 years old, Oscar suffered a stroke. He was placed in ICU after suffering three more. The doctors couldn’t understand why an otherwise healthy looking boy was having a stroke, but what they did know was that his body was battling something serious.
Oscar’s genome was sequenced at Garvan, where an underlying driver of Oscar’s previously undiagnosed condition was identified. Genome sequencing uncovered that Oscar has a variation in a gene called MAGT1 which results in a disease called X-linked Magnesium EBV neoplasia, or XMEN.
Solving rare disease mysteries
A genetic research discovery has helped diagnose a young boy’s severe, debilitating immune condition after years of inconclusive tests, which helped his younger sister avoid a potential future of devastating illness.
After suffering from severe symptoms related to the immune system from the age of 18 months, including a stroke after contracting chicken pox, the cause of a boy’s critical state of health was still a mystery. When he was nine years old, his doctors referred his case to CIRCA, a national Garvan-led collaboration of medical and scientific professionals that investigates the genetic causes of rare immune diseases.
Making sense of a new immune disease
AD-HIES (Autosomal Dominant Hyper IgE Syndrome) is a disease in which patients suffer from deficiencies in their immune system. An international team’s detective work signals new promise in the effort to demystify unexplained, perplexing diseases.
Through their functional studies, Prof Tangye and his team discovered that a faulty ZNF341 gene leads to a ‘hole’ in immune defences. Patients lack certain types of immune cells, which means they struggle to fight some infections and acquire immunity following vaccination. Also, they have an abundance of a different type of immune cell - which leads to severe allergy.
Other achievements of CIRCA members
- Several members (Stuart Tangye, Cindy Ma, Elissa Deenick) have played critical roles in discovering and characterising novel genetic variants underlying inborn errors of immunity (eg mutations in RHOH, OX40, TCF3, RORC, IRF4, TYK2, IL12RB2, IL23R, SPPL2A, ZIP7, GINS1, CD70, RLTPR, PIK3CD and CTLA4) on immune cell development and function in the setting of infectious disease and immune dysregulation.
- Elucidating disease pathogenesis in X-linked lymphoproliferative disease due to mutations in SH2D1A, autosomal dominant hyper-IgE syndrome (STAT3 deficiency), autosomal recessive hyper-IgE syndrome (DOCK8-deficiency), and conditions arising from mutations in TYK2 and RORC.