GATA2 deficiency is an autosomal dominant transcriptopathy disorder with high risk for myelodysplastic syndrome (MDS). To elucidate genotype-phenotype associations and identify new genetic risk factors for MDS, we analyzed 218 individuals with germline heterozygous GATA2 variants. We observed striking age-dependent incidence patterns in GATA2-related MDS (GATA2-MDS), with MDS being absent in infants, rare before age 6 years, and steeply increasing in older children. Among 108 distinct GATA2 variants (67 novel), null mutations conferred a 1.7-fold increased risk for MDS, had earlier MDS onset compared to other variants (12.2 vs. 14.6 years, p = 0.009) and were associated with lymphedema and deafness. In contrast, intron 4 variants exhibited reduced penetrance and lower risk for MDS development. Analysis of the somatic landscape revealed unique patterns of clonal hematopoiesis. SETBP1 mutations occurred exclusively in patients with monosomy 7 and their frequency decreased with age. Conversely, the frequency of STAG2 mutations and trisomy 8 increased with age and appeared protective against early development of advanced MDS. Overall, the majority (73.9%) of mutation-positive cases harbored monosomy 7, suggesting it serves as a major driver in malignant progression. Our findings provide evidence for age-appropriate surveillance, and a foundation for genotype-driven risk stratification in GATA2 deficiency.
GATA2缺乏症是一种常染色体显性转录病，具有发展为骨髓增生异常综合征（MDS）的高风险。为阐明基因型与表型之间的关联并识别MDS的新遗传风险因素，我们分析了218例种系杂合GATA2变异的个体。我们观察到GATA2相关MDS（GATA2-MDS）具有显著的年龄依赖性发病模式：婴儿期未见MDS发生，6岁前极为罕见，而在较大儿童中发病率急剧上升。在108种不同的GATA2变异（其中67种为新发现）中，功能缺失突变使MDS风险增加1.7倍，与其他变异相比更早发生MDS（12.2岁对比14.6岁，p=0.009），并与淋巴水肿和耳聋相关。相比之下，内含子4变异的外显率降低且MDS发展风险较低。对体细胞突变景观的分析揭示了独特的克隆造血模式：SETBP1突变仅出现在7号染色体单体患者中，且其频率随年龄增长而下降；相反，STAG2突变和8号染色体三体的频率随年龄增长而上升，并对晚期MDS的早期发展具有保护作用。总体而言，大多数（73.9%）突变阳性病例存在7号染色体单体，提示其是恶性进展的主要驱动因素。我们的研究结果为GATA2缺乏症提供了适龄监测依据，并为基因型驱动的风险分层奠定了基础。
Age-dependent phenotypic and molecular evolution of pediatric MDS arising from GATA2 deficiency
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