Functional classification of RUNX1 variants in familial platelet disorder with associated myeloid malignancies.
Functional classification of RUNX1 variants in familial platelet disorder with associated myeloid malignancies.
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DOI：
10.1038/s41375-021-01200-w
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发表时间：
2021-11
期刊：
影响因子：
11.4
通讯作者：
Ripperger T
中科院分区：
文献类型：
--
作者：
Decker M;Lammens T;Ferster A;Erlacher M;Yoshimi A;Niemeyer CM;Ernst MPT;Raaijmakers MHGP;Duployez N;Flaum A;Steinemann D;Schlegelberger B;Illig T;Ripperger T
RUNX1杂合性致病种系变异[1]可导致家族性血小板紊乱伴相关髓系恶性肿瘤(RUNX1-FPD、FPDMM、FPD/AML；OMIM 601399；Orpha 71290)[2]。RUNX1-FPD的特点是不完全外显和广泛的临床表型，即使在受影响的家族中也是如此[3，4]。临床表现包括血小板减少，最常见的是中度的功能性血小板缺陷，以及发展为血液系统恶性肿瘤的风险~44%[5]，主要是骨髓增生异常综合征和急性髓系白血病，但很少有T细胞急性白血病[6]。许多RUNX1变异体只在单个家族中报道[3]，因此它们以前没有与RUNX1-FPD相关，也没有可用的功能数据。在计算机预测工具中(例如，稀有外显子变异系综学习器(REVELL)[7])往往不令人信服，特别是对于高度保守和经常受到影响的Run同源结构域(RHD)中的变体(补充图1)。根据目前的分类规则[5]，RUNX1变体必须经常被归类为具有不确定意义(VU)的变体。最近，Clingen髓系恶性肿瘤变异型诊断专家小组(MM-VCEP)发布了调整后的ACMG/AMP RUNX1指南，其中包括如何在变异型分类中整合功能数据[5]。
Heterozygous, pathogenic germline variants of RUNX1 [1] are causative for familial platelet disorder with associated myeloid malignancies (RUNX1-FPD, FPDMM, FPD/AML; OMIM 601399; ORPHA 71290)[2]. RUNX1-FPD is characterized by incomplete penetrance and a broad spectrum of clinical phenotypes, even within affected families [3, 4]. The clinical presentation includes thrombocytopenia, most frequently moderate, functional platelet defects, and a risk of~ 44%[5] to develop a hematological malignancy, mainly myelodysplastic syndrome and acute myeloid leukemia, but rarely also T-cell acute leukemia [6]. Many RUNX1 variants are reported only in individual families [3], hence they have not been associated withRUNX1-FPD before and no functional data is available. In silico prediction tools (eg, rare exome variant ensemble learner (REVEL)[7]) are frequently not convincing, especially for variants in the highly conserved and frequently affected Runt homology domain (RHD)(Supplementary Fig. 1). According to present classification rules [5], RUNX1 variants must be frequently classified as variants of uncertain significance (VUS). Lately, the ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) has published adjusted ACMG/AMP guidelines for RUNX1 including recommendations how to integrate functional data in variant classification [5].
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DOI：
10.2741/3977
发表时间：
2012-01-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
--
作者：
Lam K;Zhang DE
通讯作者：
Zhang DE
影响因子：
3.6
作者：
Schlegelberger, Brigitte;Heller, Paula G.
通讯作者：
Heller, Paula G.
影响因子：
64.8
作者：
Findlay GM;Daza RM;Martin B;Zhang MD;Leith AP;Gasperini M;Janizek JD;Huang X;Starita LM;Shendure J
通讯作者：
Shendure J
影响因子：
12.3
作者：
Brnich, Sarah E.;Abou Tayoun, Ahmad N.;Topper, Scott
通讯作者：
Topper, Scott
影响因子：
7.5
作者：
Brown, Anna L.;Arts, Peer;Scott, Hamish S.
通讯作者：
Scott, Hamish S.