A comprehensive targeted next-generation sequencing panel for genetic diagnosis of patients with suspected inherited thrombocytopenia.
A comprehensive targeted next-generation sequencing panel for genetic diagnosis of patients with suspected inherited thrombocytopenia.
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DOI：
10.1002/rth2.12151
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发表时间：
2018-10
影响因子：
4.6
通讯作者：
UK GAPP Study Group
中科院分区：
文献类型：
--
作者：
Johnson B;Doak R;Allsup D;Astwood E;Evans G;Grimley C;James B;Myers B;Stokley S;Thachil J;Wilde J;Williams M;Makris M;Lowe GC;Wallis Y;Daly ME;Morgan NV;UK GAPP Study Group
遗传性血小板减少症（ITs）是一种异质性的疾病，其特征是血小板计数低，往往不成比例的出血，目前涉及超过30个基因。此前，UK - GAPP使用全外显子组测序（WES）的研究在47例（40%）患者中发现了19例致病变异，其中71%的患者具有已知导致IT的基因变异。采用有针对性的下一代测序平台，以提高诊断测试的效率，降低总体成本。我们开发了一种IT特异性基因面板，作为患者在WES之前使用安捷伦SureSelectQXT转座子富集系统的预筛选。使用基于小组的测序分析了31例患者，其中；10%（3/31）被鉴定为分类致病变异，16%（5/31）被鉴定为可能致病变异，51%（16/31）被鉴定为意义不明的变异，23%（7/31）被鉴定为无变异或良性变异。虽然需要进一步澄清遗传变异的影响，但应用IT特异性下一代测序面板是在WES之前预先筛选已知IT致病基因变异的可行方法。将IT与特发性血小板减少性紫癜（ITP）区分开来的额外好处，以及识别已知易患血液系统恶性肿瘤的基因变异的潜力，可能成为改善患者临床管理的关键一步。
Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet counts and often disproportionate bleeding with over 30 genes currently implicated. Previously the UK‐GAPP study using whole exome sequencing (WES) identified a pathogenic variant in 19 of 47 (40%) patients of which 71% had variants in genes known to cause IT. To employ a targeted next‐generation sequencing platform to improve efficiency of diagnostic testing and reduce overall costs. We have developed an IT‐specific gene panel as a pre‐screen for patients prior to WES using the Agilent SureSelectQXT transposon‐based enrichment system. Thirty‐one patients were analyzed using the panel‐based sequencing, of which; 10% (3/31) were identified with a classified pathogenic variant, 16% (5/31) were identified with a likely pathogenic variant, 51% (16/31) were identified with variants of unknown significance, and 23% (7/31) were identified with either no variant or a benign variant. Although requiring further clarification of the impact of the genetic variations, the application of an IT‐specific next generation sequencing panel is an viable method of pre‐screening patients for variants in known IT‐causing genes prior to WES. With an added benefit of distinguishing IT from idiopathic thrombocytopenic purpura (ITP) and the potential to identify variants in genes known to have a predisposition to hematological malignancies, it could become a critical step in improving patient clinical management.
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