Title

Diagnostichigh-throughputsequencingof2,patientswithbleeding,thromboticandplateletdisorders

Abstract

Atargetedhigh-throughputsequencing(HTS)paneltestforclinicaldiagnosticsrequirescarefulconsiderationoftheinclusionofappropriatediagnostic-gradegenes,theabilitytodetectmultipletypesofgenomicvariationwithhighlevelsofanalyticsensitivityandreproducibility,andvariantinterpretationbyamulti-disciplinaryteam(MDT)inthecontextoftheclinicalphenotype.Wehavesequenced2,indexpatientsusingtheThromboGenomicsHTSpaneltestofdiagnostic-gradegenesknowntoharbourvariantsassociatedwithrarebleeding,thromboticorplateletdisorders(BTPD).Themoleculardiagnosticratewasdeterminedbytheclinicalphenotype,withanoverallrateof49.2%forallthrombotic,coagulation,plateletcountandfunctiondisorderpatientsandarateof3.2%forpatientswithunexplainedbleedingdisorderscharacterizedbynormalhemostasistestresults.TheMDTclassifieduniquevariants,includingcopynumberandintronicvariants,asPathogenic,LikelyPathogenicorVariantsofUncertainSignificance.Half(50.9%)ofthesevariantsarenoveland41uniquevariantswereidentifiedin7genesrecentlyfoundtobeimplicatedinBTPD.Inspectionofcanonicalhemostasispathwaysidentified29patientswithevidenceofoligogenicinheritance.AmoleculardiagnosishasbeenreportedforindexpatientsprovidingevidencethatintroducinganHTSgenetictestisavaluableadditiontolaboratorydiagnosticsinpatientswithahighlikelihoodofhavinganinheritedBTPD.

ReadbyChristineLi

摘要

针对临床诊断的靶向高通量测序（HTS）面板检测需要仔细考虑是否包含适当的诊断级基因，能够检测多种类型的基因组变异，具有高水平的分析灵敏度和重现性的能力，以及来自具有临床背景下的多学科团队（MDT）对变异的解释。我们使用ThromboGenomicsHTS面板检测对2名患者进行了序列分析，该实验含有与罕见出血、血栓性或血小板疾病(BTPD)相关变异的诊断级基因。根据临床表型明确分子诊断率，所有血栓、凝血、血小板计数和功能异常患者的总诊断率为49.2%，特征是止血试验结果正常的不明原因出血紊乱的患者的诊断率为3.2%。一个多学科团队（MDT）将个独特变异（包括拷贝数变异和内含子变异）分为致病型、可能致病型和意义不明确型。这些变异中有一半（50.9%）是新发突变，在最近发现与BTPD相关的7个基因中发现41个独特的变异。对典型凝血通路的分析发现29例患者有寡基因遗传的证据。已有的名患者的分子诊断报告证明，引入HTS基因检测对高遗传可能性的BTPD患者的实验室诊断是有价值的补充检测。

译自：刘畅

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万康源（天津）基因科技有限公司

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