Use of next-generation sequencing and candidate gene analysis to identify underlying defects in patients with inherited platelet function disorders.
Use of next-generation sequencing and candidate gene analysis to identify underlying defects in patients with inherited platelet function disorders.
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DOI：
10.1111/jth.12836
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
UK GAPP Study Group
中科院分区：
文献类型：
--
作者：
Leo VC;Morgan NV;Bem D;Jones ML;Lowe GC;Lordkipanidzé M;Drake S;Simpson MA;Gissen P;Mumford A;Watson SP;Daly ME;UK GAPP Study Group
遗传性血小板功能障碍（PFDs）是异质性的，当仅基于患者的表型和临床特征时，很难识别潜在的遗传缺陷。分析329个调节血小板功能、数量和大小的基因，以确定PFDs患者的候选基因缺陷。在对18例不相关的PFD索引病例的外显子组DNA进行下一代测序后，对候选PFD基因进行了靶向分析，这些病例被招募到英国血小板基因分型和表型（GAPP）研究中，并被诊断为影响Gi信号传导（n = 12）或分泌（n = 6）的血小板异常。使用计算预测算法评估候选基因缺陷的潜在致病性。对329个候选PFD基因的分析在具有Gi信号传导异常的指示病例中鉴定出63个候选缺陷，影响40个基因，而在具有分泌异常的患者中鉴定出49个基因中的53个缺陷。纯合子基因缺陷更常见与分泌异常。功能注释分析确定了两个患者亚组中不同的基因簇。13个基因与显着的注释富集的“细胞内信号传导”窝藏16个候选基因缺陷中确定的9个索引情况下，Gi信号异常。四个基因簇，代表14个基因，与显着相关的基因本体论注释中的分泌异常的情况下，确定了最显着的关联是与“建立蛋白质定位。”我们的研究结果证明了PFDs的遗传复杂性，并突出了血小板分泌和Gi信号异常患者的靶向分析的可能候选基因。
Inherited platelet function disorders (PFDs) are heterogeneous, and identification of the underlying genetic defects is difficult when based solely on phenotypic and clinical features of the patient. To analyze 329 genes regulating platelet function, number, and size in order to identify candidate gene defects in patients with PFDs. Targeted analysis of candidate PFD genes was undertaken after next‐generation sequencing of exomic DNA from 18 unrelated index cases with PFDs who were recruited into the UK Genotyping and Phenotyping of Platelets (GAPP) study and diagnosed with platelet abnormalities affecting either Gi signaling (n = 12) or secretion (n = 6). The potential pathogenicity of candidate gene defects was assessed using computational predictive algorithms. Analysis of the 329 candidate PFD genes identified 63 candidate defects, affecting 40 genes, among index cases with Gi signaling abnormalities, while 53 defects, within 49 genes, were identified among patients with secretion abnormalities. Homozygous gene defects were more commonly associated with secretion abnormalities. Functional annotation analysis identified distinct gene clusters in the two patient subgroups. Thirteen genes with significant annotation enrichment for ‘intracellular signaling’ harbored 16 of the candidate gene defects identified in nine index cases with Gi signaling abnormalities. Four gene clusters, representing 14 genes, with significantly associated gene ontology annotations were identified among the cases with secretion abnormalities, the most significant association being with ‘establishment of protein localization.’ Our findings demonstrate the genetic complexity of PFDs and highlight plausible candidate genes for targeted analysis in patients with platelet secretion and Gi signaling abnormalities.
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DOI：
10.1093/bioinformatics/btq033
发表时间：
2010-03-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Quinlan AR;Hall IM
通讯作者：
Hall IM
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
10.4
作者：
Patel, Y. M.;Lordkipanidze, M.;Mundell, S. J.
通讯作者：
Mundell, S. J.
影响因子：
10.4
作者：
Stevenson, W. S.;Morel-Kopp, M. -C.;Ward, C. M.
通讯作者：
Ward, C. M.
影响因子：
10.4
作者：
Lowe, G. C.;Lordkipanidze, M.;Watson, S. P.
通讯作者：
Watson, S. P.