Sun Xiaoping, Wang Chen, Metcalfe Dean D, Carter Melody C, Maric Irina
Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institute of Health, Bethesda, Maryland, USA.
Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Br J Haematol. 2025 Jun 19. doi: 10.1111/bjh.20214.
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.
儿童肥大细胞增多症是一种具有不同临床亚型且病程通常进展缓慢的异质性疾病。除了KIT D816V之外，基因突变的分子格局仍在探索之中。因此，我们使用二代测序技术研究了69例皮肤肥大细胞增多症和系统性肥大细胞增多症（SM）患儿外周血样本中髓系基因突变的发生率。KIT D816V仅在SM患儿中发现，而其他KIT突变（D419del、A502_Y503dup、Y503_A507dup、G565V和N822H）仅在患有皮肤疾病的患儿中检测到。尽管患者之间未共享其他常见的非KIT髓系突变，但我们在30个基因中鉴定出64个非同义编码基因突变，其中15个被分类为致病性/可能致病性，且均未出现在SRSF2和ASXL1基因中。这些致病性/可能致病性非KIT突变中的大多数（86.7%）在患有SM的儿科患者中发现。总之，我们在儿童肥大细胞增多症中发现了一些非KIT髓系改变，这些改变在患有系统性疾病的儿童中更为常见。许多这些基因改变的变异等位基因频率约为50%或100%，表明其本质上是种系突变。目前，这些额外的基因改变对病程的长期影响尚不确定，这支持了在长期随访研究中进行评估的必要性。
