Our research

Patients with extraordinary immunological clinical presentations and strong family histories are encouraged to participate in CIRCA’s research.

How CIRCA works: a summary

Candidate families for sequencing are referred by their consulting immunologists and screened on strict criteria, including extensive phenotyping and sequencing of a panel of known genes.

  1. Patients with severe clinical symptoms (related to the immune system) and strong family histories are recruited to take part in CIRCA.
  2. Targeted sequencing or diagnostic whole genome sequencing is then performed through the Immunopathology lab at the Children's Hospital at Westmead and/or Genome.One.
  3. In some cases, the function of a patient’s immune cells is assessed by affiliated research groups with the capacity to develop mouse models of disease using the CRISPR/Cas9 platform.
  4. In many cases, disease-causing gene variants are identified from a known panel of genes. When such a variant is not identified, the patient’s whole genome is investigated further.

Next steps: defining new molecular pathologies

Following genetic analysis, consulting clinicians, geneticists and research scientists collaborate to identify candidate gene variations and perform functional studies. These include in vitro human cell assays and establishment of mouse models with the same variant, to test the functional consequences of the genetic variations observed.

This experimental work has the power to confirm which genetic variations are causative of disease, and through what mechanism.

Our research and diagnostic process

Background information

Every individual’s genome contains large numbers of genetic variations, so understanding which of a patient’s gene variants cause disease requires in-depth analysis in experimental systems.

An individual’s genome might also influence their response to immunotherapies in the context of cancer treatment or organ transplantation.

A key focus of CIRCA is “primary immunodeficiencies” (PIDs), which are a collection of rare, chronic disorders, in which important cells of the immune system either fail to develop or the immune system functions improperly. Individuals with a PID are susceptible to frequent and potentially fatal infections with a range of pathogens. PIDs are often also associated with autoinflammatory disease, as well as the development of cancer.

PIDs are commonly diagnosed in early childhood and arise because of genetic variation. PID-associated genetic variants have already been identified in nearly 300 different genes; however, the exact cause of disease in many PID cases is not yet known. Because PIDs arise from a range of different gene variants, the symptoms of the diseases may differ.

Because the genes involved in PIDs are generally critical regulators of the immune response, the study of PID-associated genes has led to a greatly increased understanding of immune function in general. This knowledge is also transferrable to other more common conditions.

An autoimmune disease occurs when a person's immune system mistakenly attacks their own body. Genetics are likely to be a major contributor when children develop autoimmune diseases in the first ten years of life. We are testing the hypothesis that many of these cases are caused by de novo mutations in DNA (harmful variants present in a child, but not their ancestors) that disrupt the mechanisms normally preventing the immune system from attacking the body.

CIRCA brings together pediatricians and clinical specialists in childhood-onset autoimmune disease with experts in the analysis of genes and cellular mechanisms for self-tolerance and autoimmunity. Two new technologies make testing these hypotheses possible: whole genome sequencing on the Illumina X-Ten platform, and testing of candidate variants by replicating them in mice using CRISPR-Cas9.

The genome sequence of patients and both their parents will be examined, in collaboration with endocrinologists and pediatricians. Genetic variations that are observed will be validated experimentally by replicating these variants in the mouse models. These mouse models are used to define exactly how the variants disrupt immune function, and to test pathway-specific therapeutics. The immune cells present in the patients blood are studied in order to develop laboratory tests for genetic lesions in specific pathways resulting in autoimmune disease.

People with rare, clinically extreme conditions of immune dysregulation may find it difficult to obtain a diagnosis through traditional clinical testing methods. For these patients, undergoing genetic testing or genome sequencing may make it possible to obtain a genetic diagnosis (an identification of the genetic variant that underpins their disease).

A genetic diagnosis makes it possible to tailor support or treatment specifically to the individual, and to anticipate future concerns. It can also bring to an end the ‘diagnostic odyssey’ of invasive, inconclusive testing.

For the broader community, the information gained from understanding the genetics of rare conditions can also reveal much about the workings of the immune system. This type of information has been immediately transferrable to more common immunological diseases. For example, the discoveries of disease-causing  genes in cases of severe immune dysfunction (TNF alpha receptor, IL-1 receptor antagonist and JAK3) have given rise to new therapeutic targets for rheumatoid arthritis.