Project: The interplay between Inborn Error of Immunity and blood disorders: unravelling immune defects behind common haematological diseases

Acronym	IEI-Haem (Reference Number: EJPRD23-019)
Project Topic	The universe of Inborn errors of Immunity (IEI) is rapidly expanding: their clinical spectrum is not only characterised by infections but often includes haematological complications. Moreover, an increasing number of “IEI phenocopies” due to somatic mutations in specific cell types are progressively being unveiled and complicate the genetic plot of IEI, which are therefore not only caused by germline mutations. However, these aspects have never been studied by large prospective studies. This international project aims to fill this gap by prospectively recruiting patients <25 y/o with haematologic disorders that fall into one of the following 4 subgroups: autoimmune cytopenia (AICs), polyclonal lymphoproliferation (PL), monoclonal (malignant) lymphoproliferation (ML), bone marrow failure/myelodysplasia (BMF/MDS). Recruited subjects will undergo an extensive immunologic workup (extended immunophenotyping, cytokine and autoantibody dosage) together with genetic testing (NGS) to detect both germline and somatic variants. Bulk RNA sequencing will be performed either as functional validation of variants or to identify altered pathways in selected cases with inconclusive genetics. Patient advocacy organisations (PAOs) will be pivotal to assist patients’ needs throughout the project and to raise awareness of predictive and yet unknown signs of IEI. We expect to recruit a total of almost 700 children over a 3-year period. Considering recent studies on AICs and BMF/MDS, a global detection rate of 30% “hidden” IEI is expected, with higher rates in the AIC subgroup and lower ones for ML, given the complexity of lymphoma pathogenesis. We also expect to detect new IEI candidate genes or new examples of IEI phenocopies. The immunological workup should detect early disease biomarkers or currently unknown molecular signatures of specific disorders. These may increase the chance of identifying an IEI in a specific subgroup and promptly address the patient to a targeted treatment or to hematopoietic stem cell transplantation, avoiding late complications, increasing patients’ survival, and abating the economic burden of the disease on healthcare services. Finally, involvement of PAOs may foster patients’ knowledge about their condition, increasing their compliance to disease follow-up and treatment and ameliorating their quality of life.
Network	EJP RD
Call	5th EJP RD Joint Transnational Call for Rare Diseases Research Project (JTC 2023)

Project partner

Number	Name	Role	Country
1	IRCCS Anna Meyer Children Hospital	Coordinator	Italy
2	Institut Imagine	Partner	France
3	University of Rome Tor Vergata	Partner	Italy
4	CHU Sainte-Justine, University of Montreal	Partner	Canada
5	CHU Sainte-Justine, University of Montreal	Partner	Canada
6	Fundació Hospital Universitari Vall d’Hebron – Institut de Recerca (VHIR)	Partner	Spain
7	Karolinska Institutet	Partner	Sweden