新英格蘭醫學雜誌關於遺傳病測序診斷的最新綜述

我是個懶人， 專業人士請閱讀原文，我挑了自己覺得比較重要的幾點說一下。我認為最重要的一點，那就是疑似遺傳病患者做測序的時間，測序多大程度上能確診， 確診多大程度上能夠幫助修正治療方案。下面先摘錄這篇原文。

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個小孩在平均6歲的時候做全外顯子測序，52%的小孩找出病因， 25% 的小孩修正了治療方案。

我的批註：不是說做了全外顯子測序就100%能找出病因，這還是在美國有專業遺傳分析師的情況下， 國內的病人不要期望太高。另外很多遺傳病藥物國內沒有， 所以找出病因後能修正治療方案的患者在國內比例會大大低於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個嬰兒在平均33天的時候做全外顯子測序，51%找出病因， 72%的患者治療方案受益於測序結果。

我的批註：疑似遺傳病應該儘早測序， 滿月就可以去測序了，不要拖到太晚。

第二點，傳統遺傳檢測手段的局限性，比如說國內某大公司的無創產前診斷：

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。

一項研究顯示，傳統的遺傳病檢測檢出率是10%， 全基因組測序檢出率是43%。

我的批註：非測序的傳統遺傳診斷手段非常有限， 盡量去做測序。

第三點， 父母測序非常有必要

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).

一項研究表明患者的父母也做測序能夠提升患者診斷率16%。

我的批註：今年暑假我就為這個事在國內發過飆，我跟醫生說了需要讓父母也測序，結果掛了電話醫生還是只給嬰兒測了序，最後結果出來無法完全確診，害我花了一周時間去做手動遺傳分析。這次是個特例， 以後我不會再做第二次了。

第四點，分析測序結果並出具結論充滿挑戰

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.

測序會檢測到上千的突變鹼基，各公司因為使用不同的分析軟體平台而會給出不同的結果。對於罕見病或罕見突變，公司出具的報告很難做出定論。

我的批註：根據我接手的國內案例，情況確實如此， 很少會給出確診的結論，大多數都是「該突變可能致病，建議遺傳諮詢」。我做的最久一個案例花了我7天近50個小時的工作時間，這個特殊情況是因為患者家屬是我的朋友而且是我在回國度假的情況下，如果是平時在美國上班，我根本不可能拿出這麼多時間來處理一個陌生人的個案。

當然，因為我是遺傳學博士，知乎上還是會有人會以為我只需要一分鐘就能回答一個遺傳諮詢的問題的，這種情況我就只好呵呵了。

科普一下基因的結構(外顯子和內含子)以及測序報告裡面常見的桑格測序原始數據圖， 見下圖：

重點疾病多基因測序， 全外顯子測序，全基因組這三種常用測序診斷的示意圖如下：

這篇文章裡面還有不少有用的信息，時間有限，我就不一一列舉出來了，醫生和遺傳諮詢領域的專業人士應該好好閱讀一下，畢竟新英格蘭醫學雜誌的綜述對臨床還是很有指導意義的。