[A new form of familial platelet disorder caused by germline mutations in RUNX1 in a pedigree].

Objective: To investigate the clinical and biological characteristics of familial platelet disorder (FPD) with germline Runt-related transcription factor (RUNX) 1 mutations. Methods: Patients diagnosed with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with RUNX1 mutations from February 2016 to December 2021 in Wuhan No.1 Hospital underwent pedigree analysis and were screened for gene mutations (somatic and germline). Patients diagnosed with FPD with germline RUNX1 mutations were enrolled and evaluated in terms of clinical characteristics and biological evolution. Bioinformatics analysis was used to assess the pathogenicity of mutations and to analyze the effect of mutated genes on the function of the corresponding protein. Results: Germline RUNX1 mutations were detected in three out of 34 patients suffering from MDS/AML who had RUNX1 mutations. A pedigree of FPD with RUNX1 (RUNX1-FPD) c.562A>C and RUNX1 c.1415T>C mutations was diagnosed, and the mutations were of patrilineal origin. Bioinformatics analysis indicated that the locus at positions 188 and 472 in the AML-1G type of RUNX1 was highly conserved across different species, and that variations might influence functions of the proteins. The mutations were evaluated to be highly pathogenic. Of the nine cases with germline RUNX1 mutations: two patients died due AML progression; one case with AML survived without leukemia after transplantation of hemopoietic stem cells; four patients showed mild-to-moderate thrombocytopenia; two cases had no thrombocytopenia. During the disease course of the proband and her son, mutations in RUNX1, NRAS and/or CEBPA and KIT appeared in succession, and expression of cluster of differentiation-7 on tumor cells was enhanced gradually. None of the gene mutations correlated with the tumor were detected in the four cases not suffering from MDS/AML, and they survived until the end of follow-up. Conclusions: RUNX1-FPD was rare. The mutations c.562A>C and c.1415T>C of RUNX1 could be the disease-causing genes for the family with RUNX1-FPD, and these mutations could promote malignant transformation. Biological monitoring should be carried out regularly to aid early intervention for family members with RUNX1-FPD.目的： 探讨伴胚系来源Runt相关转录因子（RUNX）1突变的家族性血小板疾病（FPD）的临床及生物学特征。 方法： 对2016年2月至2021年12月在武汉市第一医院血液内科就诊的伴RUNX1突变的骨髓增生异常综合征（MDS）/急性髓系白血病（AML）患者临床资料进行回顾性分析，筛选伴胚系来源RUNX1突变的FPD患者，对其进行家系分析、体细胞基因检测和胚系基因验证，分析其临床表现、生物学演变等并应用生物信息学软件评估胚系突变位点的致病性，预测基因突变对蛋白功能的影响。 结果： 34例携带RUNX1突变的MDS/AML患者中，有3例患者携带胚系来源RUNX1突变。其中1个确诊的FPD家系携带RUNX1 c.562A>C和RUNX1 c.1415T>C突变。该基因变异为先证者父系来源，应用生物信息学软件分析显示，其2个突变位点分别引起变异型RUNX1基因（AML-1G型）上第188、472位氨基酸的改变，这2个位点在不同物种之间高度保守，可能导致蛋白结构不稳定，进而影响蛋白功能，评价为很可能具有致病性。携带父系来源RUNX1突变的9例成员中，2例进展至AML死亡；1例表现为AML，接受造血干细胞移植后无病存活；4例表现为轻中度血小板减少，2例无血小板减少。在先证者及其儿子的疾病发展过程中，先后出现RUNX1、NRAS和/或CEBPA、KIT等基因突变，肿瘤细胞在免疫表型上表现为CD7的表达逐渐增强；4例仅表现为血小板减少的成员未检测出肿瘤相关热点基因变异，至随访截止均存活。 结论： RUNX1相关FPD（RUNX1-FPD）临床罕见，RUNX1 c.562A>C和c.1415T>C突变可能是导致本家系发生RUNX1-FPD的致病基因，获得性突变可促使其发生恶性转化。对RUNX1-FPD家系成员需定期监测疾病生物学演变，必要时早期干预治疗。.