Clinical Genomics Research

Implementing a patient-centred care model to diagnosis of Maturity Onset Diabetes of the Young (MODY)

Clinical Genomics Interdisciplinary Research Program Implementing a patient-centred care model to diagnosis of Maturity Onset Diabetes of the Young (MODY) MODY is the most common genetic form of diabetes and is commonly misdiagnosed as type 1 or type 2 diabetes mellitus. The accurate diagnosis of MODY via molecular genetic testing is important as there are management implications including choice of treatment, prognosis and reproduction.

Funded by St Vincent’s Curran Foundation, this study is led by A/Prof Kathy Wu and aims to mainstream MODY genetic testing for non-genetics professionals and patients in the diabetes clinic and develop clinical guidelines for MODY genetic testing.  The goal is to reduce the number of clinic appointments for patients and improve patient outcomes via accurate MODY diagnosis.

St Vincent’s Hospital Human Research Ethics Committee: 2019/ETH00149

Australian New Zealand Clinical Trials Registry. ACTRN:12620001123932

Publications:

Moxham R, Greenfield J, Viardot A and Wu KHC.  Tip of the iceberg: are we missing undiagnosed patients with maturity onset diabetes of the young? Int Med J. 2022 DOI.org/10.1111/imj.15948

Collaborating departments & institutions:

Department of Endocrinology, St Vincent’s Hospital

Endocrine & Metabolic Unit, Royal Adelaide Hospital

South Australian Adult Genetics Unit

Student involvement:

Ms Devashree Balasingam, BSc(Med) Honours Research, UNSW, graduated with High Distinction in 2023

Status:

Completed recruitment and data analysis. Further manuscripts in preparation.  

Significant findings:

Our study demonstrated feasibility of integrating genetic testing into routine diabetes clinics. Our clinical criteria for guiding genetic testing yielded a diagnostic rate of 20.8%, showing potential for it to be used as a basis for future clinical guideline development. There was high patient satisfaction and 60% of surveyed endocrinologists reported changing their patient's management based on their mutation-positive results. These findings suggest that our mainstreaming genetic testing model of care if adopted systematically, can significantly improve patient outcomes in diabetes. The endocrinologist's comfort levels and readiness to integrate genetic testing into routine clinical care further support this approach, provided that clear guidelines, a streamlined referral process and cost-effective testing options are in place.

Next steps:

A working group is currently in place to develop clinical guidelines for MODY genetic testing in Australia and New Zealand.

Towards implementation of pharmacogenomics-guided therapy in patients with mental illness (ENACT)

Genetic contributions play an important role in determining how patients metabolise and respond to medications. Pharmacogenomics testing, which involves testing of these genetic factors via a simple cheek swab, would allow prescribers to tailor choice and dosing of medications to each patient, optimising therapeutic efficacy and minimising side effects.

This study, funded by St Vincent’s Inclusive Health Program Grant, is led by A/Prof Kathy Wu, and divided into Stages P, 1, 2, and 3.

Stage P & 1: We aim to understand the perspectives of patients who have had pharmacogenomics testing and those of the clinicians involved in their care with the goal to inform wider adoption of pharmacogenomics into routine clinical practice.

St Vincent’s Hospital Human Research Ethics Committee: 2019/ETH12892

Australian New Zealand Clinical Trials Registry. ACTRN12621000739819

Publications:

Moxham R, Tjokrowidjaja A, Devery S, Smyth R, McLean A, Roberts DM, Wu KHC. Clinical utilities and end-user experience of pharmacogenomics: 39 mo of clinical implementation experience in an Australian hospital setting. World J Med Genet 2023; 11(4): 39-50 DOI:https://dx.doi.org/10.5496/wjmg.v11.i4.39

Student involvement:

Mr Andrew Tjokrowidjara, BSc Honours Research, UNSW, graduated with Distinction in 2021

Status:

The Stages P and 1 are completed, with findings being used to inform the Stages 2 and 3 of the study. Significant findings: Patients are generally positive and willing to use pharmacogenomics compared with clinicians who identified barriers to its routine uptake as: cost, lack of knowledge, guidelines and evidence. Our findings suggest that the uptake of pharmacogenomics in Australia is likely to be driven by patients, and that clinicians need to be prepared to provide information and guidance to their patients.

Next steps:

We proposed an interdisciplinary model of care to integrate pharmacogenomics in psychiatric care, which is implemented in Stage 2 with outcomes measures being analysed in Stage 3 (as below). Stage 2 & 3: We aim to develop, implement and evaluate an innovative model of care to pharmacogenomics implementation, with a goal of integrating pharmacogenomics in routine care of patients with mental illness to improve clinical outcomes for this vulnerable population. St Vincent’s Hospital Human Research Ethics Committee: 2021/ETH00548 Australian New Zealand Clinical Trials Registry. ACTRN12621001368820

Status:

Recruitment open Study website: https://www.svhs.org.au/research-education/participating-in-research-trials/enact-trial

Collaborating departments & institutions:

Department of Psychiatry, St Vincent’s Hospital Centre for Economic Impacts of Genomic Medicine (GenIMPACT), Macquarie Business School, Macquarie University

Student/Trainee involvement:

Dr Alison McLean, Genetics Advanced Trainee St Vincent’s Hospital 2021/22, was awarded the Avant Early Career Research Program Scholarship in 2022 for her involvement in this study. She has presented the research findings at the Institute of Precision Medicine and Bioinformatics Annual Symposium 2023.

Australian trial of genotype-guided pharmacotherapy for depression (ALIGNED)

Depression is a common form of mental distress that affects 1 in 7 Australians in their lifetime. Finding the right medication and the right dose can be challenging, often requiring several trial-and-error attempts.

Approximately two thirds of people do not get better with the first medication they’re prescribed and one third of people do not recover even after four different medications are tried. Led by A/Prof Kathy Wu and informed by people with lived experience of depression, the ALIGNED study is a MRFF-funded nationwide, double-blinded randomised controlled trial that aims to evaluate clinical and economic data on DNA-guided treatment versus standard treatment for people living with Major Depressive Disorder.  

The goals are to develop a bedside prediction tool for antidepressant response through data integration and machine learning, and to gather economic data to inform MBS funding in the future.

St Vincent’s Hospital Human Research Ethics Committee: 2021/ETH00806 Australian New Zealand Clinical Trials Registry. ACTRN12621000926831

Collaborating universities, institutions and parties:

Department of psychiatry, St Vincent’s Hospital The George Institute for Global Health University of New South Wales University of Sydney University of Western Australia Australian National University Centre for Economic Impacts of Genomic Medicine (GenIMPACT), Macquarie Business School, Macquarie University Lived experience advisors

Status:

Recruitment open

Study website: www.alignedstudy.org.au

Survey of genetics patient journey through the Australian healthcare system (ENTRUST)

There is limited research into the journey of genetics patients within the Australian healthcare system. Led by A/Prof Kathy Wu, this is a multi-site study that aims to assess patient-reported experience, psychosocial and health outcomes of genetic consultations and/or testing.  We will audit genetics service provision including telehealth and multidisciplinary clinics to learn about the psychosocial impact of genetic testing with the goal to improve the overall genetic journey of Australian patients.

St Vincent’s Hospital Human Research Ethics Committee: 2020/ETH03268

Collaborating departments & institutions:

Genetic Medicine, Westmead Hospital

Medical Genomics, Royal Prince Alfred Hospital

Clinical Genetics, Nepean Hospital

Clinical Genetics, Liverpool Hospital

Clinical Genetics, Royal North Shore Hospital

Clinical Genetics, Hunter New England LHD

Student involvement:

Ms Mehrab Abdullah, BAdvSci (Hons), UNSW, graduated with Distinction in 2022

Status:

Completed Findings presented at International Congress of Genetics 2023 & Human Genetics Society of Australasia (HGSA) ASM 2023. Manuscript in preparation.

Significant findings:

Patient-reported outcomes measures showed genetic testing and consultations had a positive impact on both personal health and psychosocial domains. Genetics input assisted in patient’s reproductive decision-making, improved genetic risk perception, and facilitated changes in lifestyle. Lack of longer-term genetics support and follow-up, and long wait times to a genetics appointment were consistently identified as factors for patient dissatisfaction. Genetics clinics need more funding to continue to provide such impactful service in a timely and sustainable manner.

Characterising and tracking of patients with Inherited Neurodegenerative Disorders (INDD)

Study Inherited neurodegenerative disorders are collectively a heritable condition caused by progressive loss of neurons in the central and/or peripheral nervous system, causing impaired sensory, motor, autonomic, and/or cognitive functions.

This study is led by A/Prof Kathy Wu and aims to prospectively evaluate the longitudinal progression of patients with INDD to generate a comprehensive phenotypic profile of biological, behavioural, clinical, neurocognitive and neurophysiological markers; allowing phenotype-genotype correlation to enhance our understanding of these rare disorders. This work will provide more complete neurobiological descriptions, novel mechanistic insights, and clear recommendations regarding candidate biomarkers for diagnosis and treatment tracking. St Vincent’s Hospital Human Research Ethics Committee: 2023/ETH01375

Collaborating departments & institutions:

Dr Ian Harding, Department of Neuroscience & Monash Biomedical Imaging, Monash University

NHS RFC1 project Division Translational Genomics of Neurodegenerative Diseases, Center of Neurology & Hertie-Institute for Clinical Brain Research, University of Tübingen

Student involvement:

Ms Nicole Zwahlen, UNDA MD Research Project to be completed in 2024

Status:

Recruitment open

Monogenic Parkinson’s Disease Australia Initiative

Parkinson’s disease (PD) is a debilitating and progressive condition affecting millions of people worldwide.  Between 5 – 10% of PD cases result from inherited single gene mutations. These monogenic forms of PD are significantly underdiagnosed due to a lack of genetic testing and limited genetic diagnosis rates. To address this issue, this study aims to improve the genetic diagnosis of monogenic PD through the accurate identification of disease-causing variants in known genes and the discovery of novel genes.  This will impact our patients immediately by providing clinically accredited genetic testing results that inform their prognosis and treatment options.

Led by our Neurologist colleague, A/Prof Kishore Kumar, at the Garvan Institute, this MRFF-funded study will collaborate with Shake It Up Australia Foundation and Parkinson’s Australia to create a national patient registry of early onset and familial PD to rapidly identify and recruit genetically diagnosed/suspected monogenic PD patients for Australian and international clinical trials.

Collaborating universities and institutions:

University of NSW The Council of the Queensland Institute of Medical Research Murdoch University Griffith University University of Sydney Macquarie University Perron Institute Status: HREC application in progress

Functional Genomics

Functional genomics is a field of genomics that deals with understanding the gene function and interactions to be able to establish a relationship between a person’s genome (their complete set of DNA) and their phenotype (their observable physical differences and/or symptoms). The introduction of whole genome sequencing in recent years has accelerated the identification of causative gene variants in rare disorders (eg: familial cardiomyopathy, polycystic kidney disease).

However, the by-product of contemporary genomic testing is the identification of genetic variants of uncertain significance, leaving a significant proportion of patients without a molecular diagnosis. Led by Prof Jamie Vandenberg at the Victor Chang Cardiac Research Institute, this MRFF-funded study will develop accurate, clinically validated, high throughput functional genomics assays which can be utilised to dissect signalling cascades, improve diagnostic yield, and find new drug targets, with the ultimate goal of reducing morbidity and mortality, and improving patient outcomes.

Collaborating departments and institutions:

University of NSW

Illawarra Health and Medical Research Institute

University of Wollongong

The Sydney Children’s Hospital Network

Status:

In progress