Diagnosis, Discovery and Novel Phenotype Characterisation Using Multimodal Genomics in Patients With Inherited Bone Marrow Failure and Related Disorders (IBMDx Study)
Trial Snapshot
- Phase
- Not Applicable
- Status
- Recruiting
- Sponsor
- Enrollment
- 350
- Locations
- 1
- Primary Endpoint
- Definitive IBMFS-RD diagnosis
Study Overview
Brief Summary
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.
Detailed Description
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 Design
- Study Type
- Observational
- Observational Model
- Other
- Time Perspective
- Prospective
Eligibility Criteria
- Ages
- 3 Months to — (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •age ≥ 3 months
- •able to give informed consent (or parent/guardian able to give informed consent)
- •a clinicopathological diagnosis (or differential diagnosis) of inherited bone marrow failure syndrome or related disorder (IBMFS-RD) as per the study team
Exclusion Criteria
- •A clinicopathological diagnosis of an acquired bone marrow failure syndrome (including acquired aplastic anaemia and hypoplastic myelodysplastic syndrome) as per the study team
- •Existing definitive genomic diagnosis for patient's haematological phenotype
Outcomes
Primary Outcomes
Definitive IBMFS-RD diagnosis
Time Frame: 3-12 months post baseline
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.
Secondary Outcomes
- Develop a whole transcriptome gene expression classifier(4 years)
- Cost-effectiveness of genomic testing in patients with suspected IBMFS-RD(4 years)
- Budget-impact of genomic testing in patients with suspected IBMFS-RD(4 years)
- Populate Registry(4 years)
- Health implementation analyses regarding the acceptability of genomic testing(4 years)