Advancing the Genetic Diagnosis of Predominantly Antibody Deficiency through Development and Implementation of Functional Diagnostic Screening Assays.

Project summary

Predominantly Antibody Deficiency (PAD) is the most prevalent form of primary immunodeficiency (PID). Disease prognosis and treatment decisions are critically dependent on identification of an underlying DNA mutation (rare genetic variant). However, with current state-of-art technologies, in fewer than 30% of PAD patients a causative rare gene variant can be identified. Due to the high level of DNA variation in each individual, and the number of genes that potentially could be involved, identification of the rare variant causing disease can be like looking for a needle in a haystack.

For a variant to be confirmed as the cause of disease, proof of its ability to drive impaired immune function is required. Current strategies for assessing the effect of genetic variants on immune function are time consuming and rely on extensive knowledge of each gene.

With this in mind, we identified that the genes shown to cause PAD function within a limited number of biological pathways. We identified means to evaluate the function of each of these pathways quickly and efficiently in the laboratory. We will measure the activity of these pathways in undiagnosed patients. This functional information will be utilized to narrow down the search for variants within genes that function in the affected pathway. This pathway-focused approach will enable more rapid diagnosis and can direct targeted treatment of patients, with the aim of reducing the development of irreversible organ damage and improving patient quality of life.

Biographical Sketch

Emily Edwards completed her Bachelor of Science in Applied Biomedical Science at the University of Wales Institute Cardiff (Cardiff, UK) in 2007. She subsequently commenced her PhD studies at Cardiff University into killer T cell function in viral disease and cancer, which she completed in in 2011. From 2011 to 2013, she undertook a Postdoctoral position at the Queensland Institute of Medical Research (QIMR) Berghofer (Brisbane, Australia), studying immune recognition of the common herpes virus Cytomegalovirus (CMV). From 2014 to 2018, she worked at the Garvan Institute of Medical Research (Sydney, Australia), examining PID cases with impaired immune control of Epstein-Barr Virus (EBV), resulting in virus-induced disease including malignancies.

Since 2018, she is a Senior Postdoctoral Fellow leading the study of Predominantly Antibody Deficiency (PAD), the most common PID, working with Prof Menno van Zelm at Monash University (Melbourne, Australia). Monash University hosts the Jeffrey Modell Foundation Centre for Primary Immunodeficiencies in Melbourne, of which she is a member. Emily is current Vice President of AusPIPS Inc. (Australian Primary Immunodeficiency Patient Support) an Australian charity advocating for patients with PID.

Emily’s work has three main focuses:

1. Identifying new genetic variants (DNA mutations) driving PAD and its associated comorbidities.
2. Developing in vitro assays to evaluate functional impairments in the immune cell function of patients with PAD to subsequently guide genetic variant discovery and provide an evidence base for targeted treatment.
3. Examining the quantity and quality of SARS-CoV-2-specific antibodies after vaccination for COVID-19 in PID patients, dissecting the patient response and the contribution of Immunoglobulin (Ig) replacement therapy to immune protection from disease.