Diagnosis and Phenotype Characterisation Using Genomics in Patients With Inherited Bone Marrow Failure (IBMDx Study)

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.

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