Exploring germline variants in genes associated with inborn errors of immunity and inherited bone marrow failure syndromes in pediatric hematological malignancies

Inborn errors of immunity (IEI) and inherited bone marrow failure syndromes (IBMFS) are associated with an increased lifetime cancer risk. However, the role of most IEI/IBMFS in childhood cancer predisposition remains largely unexplored. This study investigated the potential contribution of germline variants in IEI/IBMFS-associated genes to pediatric hematological malignancy development.

We analyzed 151 children with leukemia or lymphoma for germline (likely) pathogenic variants in 541 IEI/IBMFS-associated genes. None had features indicative of IEI/IBMFS prior to their cancer diagnosis.

Six patients (4 %) had monoallelic (likely) pathogenic variants in autosomal dominant genes (TNFRSF13B, MPL, AIRE, NLRP12). Thus far, these genes have no proven association with childhood cancer predisposition. The carrier frequency of monoallelic (likely) pathogenic variants in recessive genes was 33 %, considered to align with general population data. Twelve patients (8 %) carried variants in genes involved in DNA repair or chromosomal stability, half of which had been identified in previous work by our group or were known before the cancer diagnosis.

This study assessed for the first time in an unbiased and comprehensive manner the role of IEI/IBMFS in childhood hematological malignancy predisposition. Although the overall yield of this exploratory study was limited, our findings support the importance of research on childhood cancer predisposition at the intersection of hematological malignancies and IEI/IBMFS. We identified several variants in both dominant and recessive genes of which it would be interesting to investigate their causality. However, for now, sequencing of IEI/IBMFS-associated genes should be restricted to research context or in case of clinical suspicion.