Allison L Cirino, Neal K Lakdawala, Barbara McDonough, Lauren Conner, Dale Adler, Mark Weinfeld, Patrick O'Gara, Heidi L Rehm, Kalotina Machini, Matthew Lebo, Carrie Blout, Robert C Green, Calum A MacRae, Christine E Seidman, Carolyn Y Ho
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Results from panel genetic testing and WGS were compared. In 20 of 41 participants, panel genetic testing identified variants classified as pathogenic, likely pathogenic, or uncertain significance. WGS identified 19 of these 20 variants, but the variant detection algorithm missed a pathogenic 18 bp duplication in myosin binding protein C (<i>MYBPC3</i>) because of low coverage. In 3 individuals, WGS identified variants in genes implicated in cardiomyopathy but not included in prior panel testing: a pathogenic protein tyrosine phosphatase, non-receptor type 11 (<i>PTPN11</i>) variant and variants of uncertain significance in integrin-linked kinase (<i>ILK</i>) and filamin-C (<i>FLNC</i>). WGS also identified 84 secondary findings (mean=2 per person, range=0-6), which mostly defined carrier status for recessive conditions.</p><p><strong>Conclusions: </strong>WGS detected nearly all variants identified on panel testing, provided 1 new diagnostic finding, and allowed interrogation of posited disease genes. Several variants of uncertain clinical use and numerous secondary genetic findings were also identified. Whereas panel testing and WGS provided similar diagnostic yield, WGS offers the advantage of reanalysis over time to incorporate advances in knowledge, but requires expertise in genomic interpretation to appropriately incorporate WGS into clinical care.</p><p><strong>Clinical trial registration: </strong>URL: https://clinicaltrials.gov. 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引用次数: 70
摘要
背景:随着DNA测序成本的下降，基因检测的选择已经扩大。全外显子组测序和全基因组测序(WGS)正在进入临床应用，与作为基因检测基石的疾病特异性多基因面板相比，它们的增量价值提出了问题。方法和结果:41例肥厚性心肌病患者接受了靶向肥厚性心肌病基因检测(多基因面板或家族变异检测)，纳入MedSeq项目，这是WGS的一项临床试验。面板基因检测结果与WGS结果比较。在41名参与者中的20名中，小组基因检测确定了被分类为致病性、可能致病性或不确定意义的变异。WGS鉴定了这20个变异中的19个，但由于覆盖率低，变异检测算法遗漏了myosin binding protein C (MYBPC3)中致病的18 bp重复。在3个个体中，WGS发现了与心肌病相关的基因变异，但未包括在先前的小组检测中:致病性蛋白酪氨酸磷酸酶，非受体11型(PTPN11)变异以及整合素连接激酶(ILK)和丝蛋白- c (FLNC)中不确定意义的变异。WGS还确定了84个次要发现(平均每人2个，范围=0-6)，这些次要发现大多定义了隐性疾病的携带者状态。结论:WGS检测到几乎所有在小组测试中发现的变异，提供了1个新的诊断发现，并允许对假定的疾病基因进行询问。几个不确定的临床应用变异和许多继发遗传发现也被确定。虽然小组检测和WGS提供了相似的诊断结果，但WGS提供了随着时间的推移重新分析的优势，以纳入知识的进步，但需要基因组解释方面的专业知识来适当地将WGS纳入临床护理。临床试验注册:网址:https://clinicaltrials.gov。唯一标识符:NCT01736566。
A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients.
Background: As DNA sequencing costs decline, genetic testing options have expanded. Whole exome sequencing and whole genome sequencing (WGS) are entering clinical use, posing questions about their incremental value compared with disease-specific multigene panels that have been the cornerstone of genetic testing.
Methods and results: Forty-one patients with hypertrophic cardiomyopathy who had undergone targeted hypertrophic cardiomyopathy genetic testing (either multigene panel or familial variant test) were recruited into the MedSeq Project, a clinical trial of WGS. Results from panel genetic testing and WGS were compared. In 20 of 41 participants, panel genetic testing identified variants classified as pathogenic, likely pathogenic, or uncertain significance. WGS identified 19 of these 20 variants, but the variant detection algorithm missed a pathogenic 18 bp duplication in myosin binding protein C (MYBPC3) because of low coverage. In 3 individuals, WGS identified variants in genes implicated in cardiomyopathy but not included in prior panel testing: a pathogenic protein tyrosine phosphatase, non-receptor type 11 (PTPN11) variant and variants of uncertain significance in integrin-linked kinase (ILK) and filamin-C (FLNC). WGS also identified 84 secondary findings (mean=2 per person, range=0-6), which mostly defined carrier status for recessive conditions.
Conclusions: WGS detected nearly all variants identified on panel testing, provided 1 new diagnostic finding, and allowed interrogation of posited disease genes. Several variants of uncertain clinical use and numerous secondary genetic findings were also identified. Whereas panel testing and WGS provided similar diagnostic yield, WGS offers the advantage of reanalysis over time to incorporate advances in knowledge, but requires expertise in genomic interpretation to appropriately incorporate WGS into clinical care.
期刊介绍：
Circulation: Genomic and Precision Medicine considers all types of original research articles, including studies conducted in human subjects, laboratory animals, in vitro, and in silico. Articles may include investigations of: clinical genetics as applied to the diagnosis and management of monogenic or oligogenic cardiovascular disorders; the molecular basis of complex cardiovascular disorders, including genome-wide association studies, exome and genome sequencing-based association studies, coding variant association studies, genetic linkage studies, epigenomics, transcriptomics, proteomics, metabolomics, and metagenomics; integration of electronic health record data or patient-generated data with any of the aforementioned approaches, including phenome-wide association studies, or with environmental or lifestyle factors; pharmacogenomics; regulation of gene expression; gene therapy and therapeutic genomic editing; systems biology approaches to the diagnosis and management of cardiovascular disorders; novel methods to perform any of the aforementioned studies; and novel applications of precision medicine. Above all, we seek studies with relevance to human cardiovascular biology and disease.
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