Although the thought may not have occurred to many practicing internists, knowing the billions of letters of DNA code in your own genomic anatomy is as introspective as you can get in the genetics realm. Thus far, this level of introspection has been achieved in perhaps 100 or so individuals. Included among those with publicly reported whole-genome analysis are James Watson and Craig Venter, both PhD scientists with a front-row seat on the evolving science. Other anonymous individuals have had their data publicly reported (Nature 2008;456:60-5), and it is presumed that still others have been sequenced and not yet reported or sequenced privately by commercial entities such as Knome.

The New England Journal of Medicine has published a report that shifts the application of this genome-sequencing phenomena in at least two ways. First, the full sequence was obtained in an individual with the goal of making a specific genetic diagnosis. Second, the sequenced individual was not a PhD scientist or an anonymous individual, but a physician.

The article reports the use of sequencing to diagnose the cause of an autosomal recessive form of Charcot-Marie-Tooth (CMT) disease (N. Engl. J. Med. 2010;362:1181-91). Interestingly, the patient had previously been screened for the currently testable genetic forms of this inherited form of peripheral neuropathy and that testing had been nondiagnostic. As the paper details, the analysis of the proband also resulted in a genetic explanation for his sibling’s disease as well as an explanation for susceptibility to carpal tunnel syndrome in some of the “unaffected” members of the family (those without CMT disease).

The skeptic will rightfully ask, “What value did the genetic diagnosis yield for clinical care?” The short answer is that because there are no immediate management or prognostic implications for the patient, this information is likely to be most useful as the basis for further research. On the other hand, the finding that being a carrier for the CMT mutation appears to predispose to carpal tunnel syndrome is a potentially actionable piece of clinical information and could lead to advice on how to avoid this neuropathy. However, this predisposition to carpel tunnel syndrome may not be broadly applicable outside of this family.

The application of this powerful technology is currently limited by cost, though that is likely to change. The cost of sequencing in this case was about $50,000. That number can be contrasted with the cost of generating the first human genome through the Human Genome Project (1991-2003), which is estimated to have cost about $2.7 billion. Although the $2.7 billion number may not be an “apples vs. apples” comparison, it is widely expected that today’s $50,000 cost will drop to $5,000 in the next 3-5 years.

So when the cost reaches $5,000, or $1,000, or $500, the question will occur, “Physician, should you examine yourself?” The answer will of course be driven by many factors in addition to cost. The hope of many of us is that we will soon be able to use this information to effectively diagnose, manage, and prevent disease. However, when you begin to seriously ponder the notion of getting your genome sequenced or advising a patient to do so, remember that the information obtained will also reveal things, good or bad, about relatives; much of the information is simply uninterpretable at this time (and will be for some time to come); and of the interpretable information, there may be some susceptibility information that you cannot “unknow” it once it has been revealed.

As genome sequencing gradually becomes more widespread and affordable, our understanding of the potential value of the information it provides also will grow. However, unless you are planning to retire soon, expect that you will be seriously confronted with the question of whether to obtain full genomic sequencing on a patient in the not-too-distant future.

Dr. Murray is the Clinical Chief of Genetics at Brigham and Women’s Hospital and an instructor at Harvard Medical School, Boston. He contributes to the “Genetics in Your Practice” column, which regularly appears in Internal Medicine News, an Elsevier publication.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

尽管许多执业内科医生们可能从未有过这一念头，但了解构成自身基因组DNA的数十亿个字母编码是你在遗传领域中所能进行的最高水平检测。迄今为止，可能已有大约100人完成了这一层面的自我检测。这其中包括公开报告了全基因组分析结果的James Watson和Craig Venter，这两位拥有博士学位的科学家均是科学发展的领军人物。另外一些匿名个体也公开报告了自身的基因组数据(Nature 2008;456:60-5)，据推测，还有一些个体已进行了测序但并未公开报告其结果或通过商业机构(譬如Knome)私下进行了测序。

 

《新英格兰医学杂志》(The New England Journal of Medicine)上发表的一项报告对基因组测序应用中存在的这一现象带来了至少2方面的改变。首先，对个人进行全基因组测序的目的是做出具体的遗传学诊断。其次，进行测序的个体并非拥有博士学位的科学家或任何匿名个人，而是一位内科医生。

 

该文章报告了应用测序对一种常染色体隐性形式的腓骨肌萎缩症(CMT)进行诊断(N. Engl. J. Med. 2010;362:1181-91)。有趣的是，先前曾对该患者的这一遗传性周围神经病进行过现阶段可检测的遗传学分型筛查，但那些检测未能做出诊断。在该文章的正文中，研究者通过对该家系的先证者进行分析，从而对他兄弟姐妹的疾病做出了遗传学解释，其还对该家系“未受累的”成员(那些未患CMT病的个体)易患腕管综合征的原因做出了解释。

 

怀疑论者理所当然会质疑道：“这种遗传学诊断为临床治疗带来了什么价值呢？”简短的回答是因为其并未给患者带来任何直接治疗效应或预后方面的影响，该信息的最大用途可能是为未来的研究奠定了基础。另一方面，作为一位CMT变异基因的携带者似乎更易罹患腕管综合征的这一发现为医生提供了可据此采取行动的潜在临床信息，这使得医生得以就如何避免这一神经病对患者给出建议。然而，通过这一方法判断患者对腕管综合征存在易感倾向在不属于此家系的其他患者中似乎无法得以普遍应用。

 

这一强大技术目前在应用方面还受限于其成本因素，虽然这可能发生改变。对这例患者进行测序的花费约为50,000美元。可以将这一数目与通过人类基因组计划测序的首个人类基因组的花费进行对比，后者的花费据估计大约为27亿美元。尽管与27亿美元的这一数目所进行得对比不具可比性，人们普遍预计，在未来3~5年中，测序成本将会从目前的50,000美元下降至5,000美元。

 

所以当成本降至5,000美元、1,000美元或500美元时，将会产生如下问题：“内科医生，你会对自己进行检查吗？”毫无疑问，除了成本因素外还有许多因素会参与决定这一答案。我们中的许多人希望，在不久之后，我们就能将该信息用于对疾病进行有效诊断、治疗和预防。然而，当你就测序自己的基因组或建议患者也进行此项检查的想法进行严肃思考时，请记住，从该项检查中所获取的信息还会反映患者亲属的相关信息(无论好或坏)；该信息中有许多成分在现阶段确实无法解释(在未来的某个时间会得到解释)；且在那些可以解释的信息中，还可能存在某些一旦发现就无法“视而不见”的易感性信息。

 

随着测序变得更为普遍和廉价，我们对该检测所产生信息潜在价值的理解也将随之增进。然而，除非你正计划在不久之后退休，否则，预计在不远的将来你就确实会面临这一问题了，即你是否会对某例患者进行全基因组测序呢？

 

Murray博士是布里格姆妇女医院遗传学临床主任，也是哈佛医学院的讲师。他的“实践中的遗传学”专栏会定期出现于爱思唯尔的“内科学新闻”上。

 

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