Prevalence of myeloid gene alterations in paediatric cutaneous and systemic mastocytosis

Paediatric mastocytosis is a heterogeneous disorder with different clinical subtypes and an often indolent disease course. The molecular landscape of genetic mutations, beyond KIT D816V, remains under exploration. We thus investigated the prevalence of myeloid genetic mutations in peripheral blood samples of 69 paediatric patients with cutaneous mastocytosis and systemic mastocytosis (SM) using next-generation sequencing. KIT D816V was exclusively found in those with SM, while other KIT mutations (D419del, A502_Y503dup, Y503_A507dup, G565V and N822H) were only detected in those with cutaneous disease. Although no other common non-KIT myeloid mutations were shared among patients, we identified 64 non-synonymous coding genetic mutations across 30 genes, including 15 classified as pathogenic/likely pathogenic, with none occurring in SRSF2 and ASXL1. Most of these pathogenic/likely pathogenic non-KIT mutations (86.7%) were found in paediatric patients with SM. In summary, we discovered a number of non-KIT myeloid alterations in paediatric mastocytosis and which were more common in children with systemic disease. Variant allele frequency of many of these gene alterations was about 50% or 100%, suggesting germline in nature. The long-term impact of these additional genetic alterations on disease course is uncertain at present and supports the need for assessment in long-term follow-up studies.