This project seeks to perform whole genome sequence (WGS) and whole transcriptome sequence (WTS) analysis on 350 patients with suspected inherited bone marrow failure syndromes and related disorder (IBMFS-RD) in order to increase the genomic diagnostic rate in IBMFS.
IBMFS-RD are a heterogeneous group of rare diseases resulting in significant morbidity and early mortality. These syndromes are individually and collectively rare (affecting \<1 per 10,000 people) and a significant proportion are unexplained by mutations in known genes. Whilst rare, these familial conditions are also likely underdiagnosed due to their relatively recent description and also due to lack of accessible genomic testing. For patients with clinically suspected IBMFS-RD, receiving a genomic diagnosis is critical to: * Establish a precise and reliable diagnosis (including distinguishing a monogenic aetiology from more common acquired or autoimmune causes of bone marrow failure which have dramatically different treatments (e.g. immunosuppression) * Inform prognosis, clinical course, optimal treatment choice and screening for non-haematological organ dysfunction * Optimise allogeneic haematopoietic stem cell transplant (HSCT) chemotherapy conditioning and minimise regimen-related toxicity * Inform risk-benefit analysis of performing allogeneic HSCT to potentially prioritise other therapies (including novel gene therapy strategies) * Avoiding the catastrophe of HSCT donation from occult genetically affected relatives * Provide counselling (including stem cell donor counselling) and offer genetic testing for potentially affected family members * Provide accurate reproductive counselling and reproductive options to affected individuals This study aims to provide WGS and WTS to a national cohort of patients with IBMFS-RD to determine diagnostic rate, health economic impact, health implementation challenges and other exploratory endpoints.
Study Type
OBSERVATIONAL
Enrollment
350
To perform whole genome/transcriptome analysis of patients in a cohort of up to 350 Australian patients with IBMFS-RD
Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia
RECRUITINGDefinitive IBMFS-RD diagnosis
IBMFS-RD diagnosis - An initial analysis of a panel of \~100 genes of established relevance to IBMFS-RD phenotype will be performed on all patients. If no molecular diagnosis is made from the panel of genes, further analysis on the genomic data will be performed using the best practice analytical tools and techniques. All results will be communicated to patients.
Time frame: 3-12 months post baseline
Develop a whole transcriptome gene expression classifier
To develop a whole transcriptome gene expression classifier to aid diagnosis of IBMFS-RD.
Time frame: 4 years
Cost-effectiveness of genomic testing in patients with suspected IBMFS-RD
The cost-effectiveness of genomic testing is assessed by the differences in costs and quality of life associated with genomic testings compared with standard of care. Costs being considered include direct medical costs incurred within the health system arising from utilisation of hospital services and drug dispensing. Quality of life is assessed by EORTC-QLQ-C30 version 3 and CHU9D questionnaires for adult and paediatric patients respectively.
Time frame: 4 years
Budget-impact of genomic testing in patients with suspected IBMFS-RD
Evaluation of budget-impact of genomic testing includes examining the financial and operational sustainability as well as scalability of offering genomic testing beyond the trial period.
Time frame: 4 years
Health implementation analyses regarding the acceptability of genomic testing
The acceptability of comprehensive and centralised genomic testing in IBMFS-RD to patients is measured by a patient acceptability questionnaire which assesses patients' view and understanding of genomic testing.
Time frame: 4 years
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Populate Registry
To populate the Aplastic Anaemia and Other Bone Marrow Failure Syndromes Registry (AAR, Monash University) with consenting patients with IBMFS-RD to facilitate long-term follow up.
Time frame: 4 years