Validation and clinical application of transactivation assays for RUNX1 variant classification.
Validation and clinical application of transactivation assays for RUNX1 variant classification.
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DOI：
10.1182/bloodadvances.2021006161
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发表时间：
2022-06-14
期刊：
影响因子：
7.5
通讯作者：
Ripperger, Tim
中科院分区：
文献类型：
--
作者：
Decker, Melanie;Agarwal, Anupriya;Benneche, Andreas;Churpek, Jane;Duployez, Nicolas;Duvall, Adam;Ernst, Martijn P. T.;Foerster, Alisa;Hoberg-Vetti, Hildegunn;Hofmann, Inga;Nash, Michelle;Raaijmakers, Marc H. G. P.;Tvedt, Tor H. A.;Vlachos, Adrianna;Schlegelberger, Brigitte;Illig, Thomas;Ripperger, Tim
转激活试验适用于RUNX1- fpd中观察到的大多数RUNX1错义变异的功能表征。对功能未知的RUNX1变异体进行转激活检测，加速了它们向临床护理的转化。家族性血小板紊乱伴髓系恶性肿瘤（RUNX1-家族性血小板紊乱[RUNX1- fpd]）是由RUNX1的杂合致病性种系变异引起的。在本研究中，我们评估了转激活法在研究RUNX1蛋白不同区域变异中的适用性。我们研究了11种变体，以独立验证支持按照ClinGen髓系恶性肿瘤变体管理专家小组指南进行的变体分类的转激活分析。变异分类是翻译遗传发现的关键。我们发现需要开发新的检测方法来评估c端RUNX1变体。两个不确定意义变异（VUS）被重新分类为可能致病。此外，我们的分析支持（可能的）其他两种变异的致病分类。我们证明了4个VUS的功能，但重新分类（可能）为良性是具有挑战性的，并建议需要重新评估当前的分类指南。最后，在7个家庭的背景下说明了我们的检测的临床应用。我们的数据证实了RUNX1-FPD在3个具有RUNX1-FPD特异性家族史的家族中存在疑似RUNX1-FPD，而在RUNX1-FPD非特异性家族中发现的3个变异，没有检测到功能缺陷。应用功能分析来支持RUNX1变异分类对于充分照顾指数患者及其处于危险中的亲属至关重要。它有助于将基因数据转化为个性化医疗。
Transactivation assays are appropriate for functional characterization of the majority of RUNX1 missense variants observed in RUNX1-FPD. Implementation of transactivation assays for RUNX1 variants with unknown function accelerates their translation into clinical care. Familial platelet disorder with associated myeloid malignancies (RUNX1-familial platelet disorder [RUNX1-FPD]) is caused by heterozygous pathogenic germline variants of RUNX1. In the present study, we evaluate the applicability of transactivation assays to investigate RUNX1 variants in different regions of the protein. We studied 11 variants to independently validate transactivation assays supporting variant classification following the ClinGen Myeloid Malignancies Variant Curation Expert Panel guidelines. Variant classification is key for the translation of genetic findings. We showed that new assays need to be developed to assess C-terminal RUNX1 variants. Two variants of uncertain significance (VUS) were reclassified to likely pathogenic. Additionally, our analyses supported the (likely) pathogenic classification of 2 other variants. We demonstrated functionality of 4 VUS, but reclassification to (likely) benign was challenging and suggested the need for reevaluating current classification guidelines. Finally, clinical utility of our assays was illustrated in the context of 7 families. Our data confirmed RUNX1-FPD suspicion in 3 families with RUNX1-FPD-specific family history, whereas for 3 variants identified in RUNX1-FPD-nonspecific families, no functional defect was detected. Applying functional assays to support RUNX1 variant classification can be essential for adequate care of index patients and their relatives at risk. It facilitates translation of genetic data into personalized medicine.
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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：
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通讯作者：
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影响因子：
3.6
作者：
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影响因子：
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通讯作者：
Ripperger T
DOI：
10.1111/hae.13280
发表时间：
2017-09
期刊：
Haemophilia : the official journal of the World Federation of Hemophilia
影响因子：
--
作者：
Rao AK;Poncz M
通讯作者：
Poncz M
影响因子：
3.7
作者：
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通讯作者：
Favier R