我是个懒人， 专业人士请阅读原文，我挑了自己觉得比较重要的几点说一下。我认为最重要的一点，那就是疑似遗传病患者做测序的时间，测序多大程度上能确诊， 确诊多大程度上能够帮助修正治疗方案。下面先摘录这篇原文。

Timely diagnoses can alter medical management, provide accurate information about recurrence risk for family planning, and may result in health care savings by ending diagnostic odysseys. In a study involving 44 children who were selected by clinical geneticists, a diagnosis was achieved in 23 (52%) by proband-only exome sequencing. Clinical management was altered in 25%. The mean time to diagnosis was 6 years, with the incurring of costs that would have been saved had exome sequencing been carried out earlier.

44个小孩在平均6岁的时候做全外显子测序，52%的小孩找出病因， 25% 的小孩修正了治疗方案。

我的批注：不是说做了全外显子测序就100%能找出病因，这还是在美国有专业遗传分析师的情况下， 国内的病人不要期望太高。另外很多遗传病药物国内没有， 所以找出病因后能修正治疗方案的患者在国内比例会大大低于25%。

In another study, exome sequencing in 63 critically ill infants yielded a diagnostic rate of 51% at a mean age of 33.1 days of life and had an effect on medical management in 72%. In the same study, 39 of 81 deceased infants received a diagnosis by exome sequencing.

63个婴儿在平均33天的时候做全外显子测序，51%找出病因， 72%的患者治疗方案受益于测序结果。

我的批注：疑似遗传病应该尽早测序， 满月就可以去测序了，不要拖到太晚。

第二点，传统遗传检测手段的局限性，比如说国内某大公司的无创产前诊断：

A study in which genome sequencing was compared with a standard battery of genetic tests in 42 patients showed diagnostic yields of 43% and 10%, respectively。

一项研究显示，传统的遗传病检测检出率是10%， 全基因组测序检出率是43%。

我的批注：非测序的传统遗传诊断手段非常有限， 尽量去做测序。

第三点， 父母测序非常有必要

An improvement in diagnostic rates, in one example by 16 percentage points, has been reported when sequencing in the affected person (proband) is performed concurrently with sequencing in the biologic parents (trio testing).

一项研究表明患者的父母也做测序能够提升患者诊断率16%。

我的批注：今年暑假我就为这个事在国内发过飙，我跟医生说了需要让父母也测序，结果挂了电话医生还是只给婴儿测了序，最后结果出来无法完全确诊，害我花了一周时间去做手动遗传分析。这次是个特例， 以后我不会再做第二次了。

第四点，分析测序结果并出具结论充满挑战

Next-generation sequencing generates thousands of sequence variants that must be filtered and prioritized for clinical interpretation, which results in the reporting of a limited number of variants per report. This process may differ slightly among individual laboratories, but it generally includes annotation of variants, application of frequency filters and database searches to enrich for rare variants and eliminate common variants, and prediction of functional effect. Clinical evaluation of a DNA sequence variant includes an assessment of potential effects on the function of one or more genes and an assessment of the evidence supporting attribution of the illness at presentation to the affected gene or genes. Both assessments benefit from strong association information (e.g., variant to disease and absence of variant to absence of disease). However, such evidence may be difficult to obtain for rare variants or diseases.

测序会检测到上千的突变碱基，各公司因为使用不同的分析软件平台而会给出不同的结果。对于罕见病或罕见突变，公司出具的报告很难做出定论。

我的批注：根据我接手的国内案例，情况确实如此， 很少会给出确诊的结论，大多数都是“该突变可能致病，建议遗传咨询”。我做的最久一个案例花了我7天近50个小时的工作时间，这个特殊情况是因为患者家属是我的朋友而且是我在回国度假的情况下，如果是平时在美国上班，我根本不可能拿出这么多时间来处理一个陌生人的个案。

当然，因为我是遗传学博士，知乎上还是会有人会以为我只需要一分钟就能回答一个遗传咨询的问题的，这种情况我就只好呵呵了。

科普一下基因的结构(外显子和内含子)以及测序报告里面常见的桑格测序原始数据图， 见下图：

重点疾病多基因测序， 全外显子测序，全基因组这三种常用测序诊断的示意图如下：

这篇文章里面还有不少有用的信息，时间有限，我就不一一列举出来了，医生和遗传咨询领域的专业人士应该好好阅读一下，毕竟新英格兰医学杂志的综述对临床还是很有指导意义的。

来源：知乎 www.zhihu.com

作者：杀生丸

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