Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults.
Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults.
复制标题
全外显子组测序在成人遗传性心血管疾病临床诊断和治疗中的应用。
DOI：
10.1161/circgenetics.116.001573
复制
发表时间：
2017-02
期刊：
影响因子：
--
通讯作者：
Mani A
中科院分区：
文献类型：
--
作者：
Seidelmann SB;Smith E;Subrahmanyan L;Dykas D;Abou Ziki MD;Azari B;Hannah-Shmouni F;Jiang Y;Akar JG;Marieb M;Jacoby D;Bale AE;Lifton RP;Mani A
随着高通量测序技术的出现，心血管疾病(CVD)的遗传病因识别已经成为医学诊断和管理中不可或缺的一部分，并处于该领域个性化医学的前沿。完整外显子组测序(WES)在遗传性脑血管病的临床诊断、风险分层和管理中的应用尚未得到评估。我们分析了在耶鲁大学心血管遗传学项目接受基因测试的前200名成年遗传性心血管疾病患者的WES结果。达到并报告了基因诊断，成功率为26.5%(200例患者中有53例)。相比之下，使用商业遗传仪表板诊断的比例为18%(36/200)(p=0.04)。WES对心源性猝死(SCD)流产患者的临床诊断特别有用，在SCD患者中，心功能受抑和QT延长的原发损害尚不清楚。使用基因组注释和疾病分离对其余病例进行分析后，在另外14%的病例中发现了新的候选基因。WES是一种特别有价值的筛查工具，因为它有能力建立遗传性心血管疾病的临床诊断，特别是对于定义不明确的SCD病例。通过提出新的候选基因及其潜在的疾病关联，我们也为这种遗传工具在鉴定新的心血管疾病基因方面的应用提供了证据。跨护理中心的外显子组数据库的创建和共享应有助于发现未知的心血管疾病基因。
With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The utility of whole exome sequencing (WES) for clinical diagnosis, risk stratification and management of inherited CVD has not been previously evaluated. We analyzed the results of WES in first two hundred adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels (p=0.04). WES was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death (SCD), in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to discovery of novel candidate genes in another 14% of the cases. WES is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited cardiovascular diseases, particularly for poorly defined cases of SCD. By presenting novel candidate genes and their potential disease associations we also provide evidence for the utility of this genetic tool for identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown cardiovascular disease genes.