New Approaches to Molecular Diagnosis
New Approaches to Molecular Diagnosis
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DOI：
10.1001/jama.2013.3239
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发表时间：
2013-04-10
影响因子：
120.7
通讯作者：
Rehm, Heidi L.
中科院分区：
文献类型：
--
作者：
Korf, Bruce R.;Rehm, Heidi L.
在了解罕见和常见疾病的分子基础以及DNA分析技术方面的进展正在迅速改变分子遗传学和基因组检测的格局。高分辨率分子细胞遗传学分析现在可以检测几十万个核苷酸的DNA缺失或重复，远低于光学显微镜的分辨率。“单基因”疾病的诊断测试可以通过针对特定突变的靶向分析，通过对特定基因进行测序以扫描突变，或通过分析突变可能导致相似表型的多个基因来完成。大规模并行下一代测序的出现促进了对多个基因的分析，并且现在被用于对基因组（外显子组）的编码区进行测序以用于临床测试。外显子组测序需要对鉴定的数千种变体进行生物信息学分析，以找到导致病理的变体;还可能偶然鉴定其他医学上重要的变体，这可能会使遗传咨询复杂化。DNA测试也可用于识别影响药物代谢或药物与其细胞靶点相互作用的变体，允许定制药物和剂量的选择。外显子组和基因组测序正被应用于识别癌细胞中的特定基因变化，以指导治疗，识别遗传性癌症风险，并估计预后。基因组检测可用于确定常见疾病的风险因素，尽管这种检测的临床效用尚不清楚。基因和基因组检测可能会引发新的伦理、法律的和社会问题，其中一些问题可以通过现有的遗传非歧视立法来解决，但也必须在遗传咨询过程中解决。这篇文章的目的是帮助医生认识到新的方法，基因和基因组检测可能会应用于临床，并在正在了解的原则，解释测试结果。美国医学会杂志2013;309（14）：1511-1521 www.jama.com
Advances in understanding the molecular basis of rare and common disorders, as well as in the technology of DNA analysis, are rapidly changing the landscape of molecular genetic and genomic testing. High-resolution molecular cytogenetic analysis can now detect deletions or duplications of DNA of a few hundred thousand nucleotides, well below the resolution of the light microscope. Diagnostic testing for "single-gene" disorders can be done by targeted analysis for specific mutations, by sequencing a specific gene to scan for mutations, or by analyzing multiple genes in which mutation may lead to a similar phenotype. The advent of massively parallel next-generation sequencing facilitates the analysis of multiple genes and now is being used to sequence the coding regions of the genome (the exome) for clinical testing. Exome sequencing requires bioinformatic analysis of the thousands of variants that are identified to find one that is contributing to the pathology; there is also a possibility of incidental identification of other medically significant variants, which may complicate genetic counseling. DNA testing can also be used to identify variants that influence drug metabolism or interaction of a drug with its cellular target, allowing customization of choice of drug and dosage. Exome and genome sequencing are being applied to identify specific gene changes in cancer cells to guide therapy, to identify inherited cancer risk, and to estimate prognosis. Genomic testing may be used to identify risk factors for common disorders, although the clinical utility of such testing is unclear. Genetic and genomic tests may raise new ethical, legal, and social issues, some of which may be addressed by existing genetic nondiscrimination legislation, but which also must be addressed in the course of genetic counseling. The purpose of this article is to assist physicians in recognizing where new approaches to genetic and genomic testing may be applied clinically and in being aware of the principles of interpretation of test results. JAMA. 2013;309(14):1511-1521 www.jama.com