Stem Cell & Myeloid Disorder

People Panel A_2x4_Rare DiseasesBackground

Inherited bone marrow (BM) failure syndromes are a rare group of genetic haematopoietic stem cell disorders characterised clinically by unexplained cytopenias with or without specific blood cell morphological abnormalities. These syndromes include bone marrow aplasias (eg Fanconi anaemia), familial myelodysplastic syndromes (MDS) and severe congenital (SCN). This project focuses on childhood syndromes as, in contrast to adults, the majority of cases are familial.

The estimated frequency of inherited BM failure syndromes is ~1 in 100,000 and varies from 1 in 200,000 for SCN to less than 1 per million for some of the rarest forms of inherited MDS and aplasia. The genetic basis for many types of SCN and for some types of familial MDS and bone marrow aplasia is known although for a significant proportion, particularly of the MDS, the causative genes remain to be identified.

Inherited BM failure syndromes have a wide spectrum of clinical severity varying from mild, asymptomatic cytopenia to progressive BM failure and/or acute leukaemia. Although it is usually straightforward to make a diagnosis of MDS or SCN or aplastic anaemia in a child, identification of the different sub-types is often difficult due to marked variability in clinical phenotype and the lack of a molecular genetic panels tailored to children. This has a significant impact on patient management as it can delay delivering curative treatment.

The immediate purpose of this study is to replace the large number of expensive, time-consuming tests currently used to diagnose the different individual BM failure syndromes by a single next generation sequencing (NGS)-based approach. Cases will be fully characterised using a ‘deep phenotyping’ approach and prescreened for known mutations on a targeted NGS platform.

The integration of molecular genetic and phenotypic characteristics in this project would be promptly translated into patient benefit through improved diagnosis and management of children with inherited BM failure syndromes and their families. Identification of novel genes also has wider implications by providing insight into the cellular and molecular mechanisms which underlie haematopoietic stem/progenitor cell dysfunction in MDS and bone marrow failure.

Inclusion and exclusion criteria

Inclusion criteria
BM failure syndrome of unknown molecular aetiology presenting in childhood
Isolated neutropenia or peripheral cytopenia affecting >1 lineage with either morphological abnormalities of >1 blood cell lineage or a hypocellular BM (thrombocytopenias are enrolled by BRIDGE-BPD)
BM failure presenting as part of a syndrome (eg neurodevelopmental, immunological, skeletal)
Any combination of the above.

Exclusion criteria
Known secondary causes of BM failure/pancytopenia, eg drugs
High suspicion of autoimmune aetiology.

Information to capture from medical records

Clinical presentation; signs and symptoms
Detailed physical examination
Secondary complications
Disease progression and treatments received
Detailed family history
All haematological, immunological and biochemical investigations performed
All results from previous genetic analysis performed
Neonatal blood spot screen
All imaging studies performed as clinically indicated.

Centres at which SMD is currently recruiting

Barts Health NHS Trust, London
Cambridge University Hospitals NHS Foundation Trust
Cardiff & Vale University UHB
Central Manchester University Hospital NHS Foundation Trust
Great Ormond Street Hospital for Children NHS Foundation Trust, London
Hull and East Yorkshire Hospitals NHS Foundation Trust
Leeds Childrens Hospital
NHS Greater Glasgow and Clyde
Oxford University NHS Trust