Cirino Allison L, Lakdawala Neal K, McDonough Barbara, Conner Lauren, Adler Dale, Weinfeld Mark, O'Gara Patrick, Rehm Heidi L, Machini Kalotina, Lebo Matthew, Blout Carrie, Green Robert C, MacRae Calum A, Seidman Christine E, Ho Carolyn Y
From the Cardiovascular Division (A.L.C., N.K.L., B.M., D.A., M.W., P.O., C.A.M., C.E.S., C.Y.H.), Department of Pathology (H.L.R.), and Division of Genetics (C.B., R.C.G., C.A.M.), Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA (N.K.L., B.M., D.A., M.W., P.O., H.L.R., R.C.G., C.A.M., C.E.S., C.Y.H.); Albany Medical College, NY (L.C.); Broad Institute of Harvard and MIT, Cambridge, MA (H.L.R., R.C.G., C.A.M.); Laboratory for Molecular Medicine (H.L.R., K.M., M.L.), Leadership Team (R.C.G.), Partners HealthCare Personalized Medicine, Cambridge, MA; and Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.).
Circ Cardiovasc Genet. 2017 Oct;10(5). doi: 10.1161/CIRCGENETICS.117.001768.
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.
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 () 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 () variant and variants of uncertain significance in integrin-linked kinase () and filamin-C (). WGS also identified 84 secondary findings (mean=2 per person, range=0-6), which mostly defined carrier status for recessive conditions.
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.
URL: https://clinicaltrials.gov. Unique identifier: NCT01736566.
随着DNA测序成本的下降，基因检测的选择范围不断扩大。全外显子组测序和全基因组测序（WGS）正在进入临床应用，这引发了关于它们与作为基因检测基石的疾病特异性多基因检测相比所具有的增量价值的问题。
41例肥厚型心肌病患者接受了肥厚型心肌病靶向基因检测（多基因检测或家族性变异检测），被纳入MedSeq项目，这是一项WGS的临床试验。对多基因检测和WGS的结果进行了比较。在41名参与者中的20名中，多基因检测鉴定出被分类为致病、可能致病或意义不确定的变异。WGS鉴定出了这20个变异中的19个，但由于覆盖度低，变异检测算法遗漏了肌球蛋白结合蛋白C（）中的一个致病的18bp重复。在3名个体中，WGS鉴定出了心肌病相关基因中的变异，但这些基因未包括在先前的多基因检测中：一个致病的蛋白酪氨酸磷酸酶，非受体11型（）变异以及整合素连接激酶（）和细丝蛋白-C（）中意义不确定的变异。WGS还鉴定出了84个次要发现（平均每人2个，范围为0 - 6个），这些大多确定了隐性疾病的携带者状态。
WGS检测出了多基因检测鉴定出的几乎所有变异，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。还鉴定出了几个临床用途不确定的变异和众多次要基因发现。虽然多基因检测和WGS提供了相似的诊断率，但WGS具有随着时间推移进行重新分析以纳入知识进展的优势，但需要基因组解读方面的专业知识才能将WGS适当地纳入临床护理。
