Full-genome screening for newborn babies is now on the cards

對新生兒進行全基因組篩查已成為可能

Genetic disease

基因疾病

【背景】新生兒全基因組檢測通過篩查和診斷新生兒遺傳病，可在其癥狀或早期干預，“早發(fā)現、早干預” ，有效避免或減少疾病對兒童及家庭的影響。 新生兒全基因組檢測包括150多種遺傳性疾病和兒童安全用藥相關藥物的基因組分析，實現對遺傳性耳聾、地中海貧血、苯丙酮尿癥、葡萄糖-6-磷酸脫氫酶缺乏癥、杜氏肌營養(yǎng)不良、脊髓性肌萎縮等常見疾病的一站式篩查。通過篩查和遺傳咨詢，可以評估疾病復發(fā)的風險，為家庭生育提供指導。根據新生兒安全用藥檢測結果，指導新生兒生長發(fā)育期間合理安全用藥，有效降低藥物不良反應的影響。

Over the years, doctors have described more than 7,000 rare diseases, generally defined as those affecting fewer than one in 2,000 people. So, though individually unusual, such illnesses are collectively a serious problem—a long-tail of need which is hard to treat because patients are few in number and their symptoms often picked up too late. Three-quarters of rare diseases are genetic, and Global Genes, an American advocacy group, reckons 400m people around the world are affected by them. For medicine to do better, people with them need to be noticed earlier, preferably in the first days of their lives.

多年來，醫(yī)生們描述了7000多種罕見疾病，這些疾病通常被定義為發(fā)病率低于兩千分之一的疾病。因此，盡管這些疾病在個體中不常見，但總體而言這是一個嚴重的問題——需求的長尾效應很難治療，因為患者數量很少，而且他們的癥狀往往發(fā)現得太晚。四分之三的罕見疾病是遺傳性的，美國的一個倡導組織Global Genes估計全世界有4億人受其影響。為了使藥物發(fā)揮更好的作用，患者需要盡早發(fā)現這些疾病，最好是在他們出生后的前幾天。

To that end, doctors in many places want to sequence and screen babies’ entire genomes at birth. In America there are projects to do just that at Boston Children’s Hospital, Columbia University and Rady Children’s Hospital in San Diego. A pioneering group at Harvard, known as BabySeq, has recently received money to expand its small-scale work to include 1,000 babies. In Europe, a five-year project called Screen4Care is starting. And efforts are also under way in Australia, China and Qatar. But the project to watch is in Britain. There, a government-owned company called Genomics England, originally set up to run a study called the 100,000 Genomes Project, which investigated genetic diseases and cancer in adults, will soon start a pilot project intended to sequence the genomes of 200,000 babies. That could presage a national programme.

【1】pioneering 有開拓精神的; 開拓性的?

【2】presage 預示

為此，許多地方的醫(yī)生希望對嬰兒出生時的全基因組進行測序和篩查。在美國，波士頓兒童醫(yī)院、哥倫比亞大學和圣地亞哥的瑞迪兒童醫(yī)院都有這樣的項目。哈佛大學的一個名為BabySeq的開創(chuàng)性團隊最近獲得了一筆資金，將其小規(guī)模工作擴大到包括1000名嬰兒在內。在歐洲，一個名為Screen4Care的五年項目正在啟動。澳大利亞、中國和卡塔爾也在進行中。但值得關注的項目在英國。在那里，有一家名為Genomics England的政府部門所有的公司，其成立之初是為了開展一項名為“10萬人基因組計劃”的研究，該研究主要研究成人的遺傳疾病以及癌癥。該公司不久將啟動一個試點項目，旨在對20萬名嬰兒的基因組進行測序。這可能預示著一項全國性的計劃。

Screen saverScreening babies for genetic diseases is not a novel idea. Across North America, Europe and the Middle East, in particular, newborns are often checked at birth for a handful of common heritable illnesses, such as sickle-cell anaemia, thalassaemia and cystic fibrosis. But a whole-genome sequence offers the prospect of spotting thousands of disorders rather than the few which are currently searched for.

對嬰兒進行遺傳病篩查并不是一個新奇的想法。特別是在北美、歐洲和中東地區(qū)，在新生兒出生時經常需要檢查是否患有一些常見的遺傳性疾病，如鐮狀細胞性貧血、地中海貧血和囊性纖維化。不過，全基因組測序有望發(fā)現數千種疾病，而不是目前正在篩查的少數疾病。

Early diagnosis means earlier treatment. This, in turn, means that children’s lives will be improved and even saved. But the power of the technology also means it is possible, in theory, to screen for conditions that would occur later in life, or even to help parents avoid having other children with the same genetic mutation.

早診斷意味著早治療。這反過來又意味著兒童的生活將得到改善，甚至得到拯救。但這項技術的力量也意味著，從理論上講，它有可能篩查出今后可能出現的情況，甚至可以幫助父母避免生下其他有同樣基因突變的孩子。

Just how many risk-associated variants it is appropriate to screen for is an open question. BabySeq, which was the first project of its kind, tested for about 1,000. It found that 11% of the 159 infants it looked at harboured at least one variant associated with a child-onset disorder.

究竟有多少與風險相關的變異適合篩查是一個懸而未決的問題。BabySeq是第一個此類項目，其測試了大約1000人。研究發(fā)現159名嬰兒中有11%至少有一種與兒童期疾病相關的變異。

While techno-utopians might think it a good idea to test for everything, parents of newborns are more cautious. On May 4th, at a meeting held in London by Genomics England, Rick Scott, the organisation’s chief medical officer, said discussions with parents and doctors had led his team to conclude that people want any genomic-screening programme for newborns to look for a far narrower set of conditions than BabySeq sought. The most appealing tests were for variants associated with a high probability of childhood illness, and which would benefit from early treatment.

雖然技術烏托邦主義者可能認為對一切都進行檢測是個好主意，但新生兒的父母則更加謹慎。5月4日，由Genomics England在倫敦舉辦的一次會議中，該組織的首席醫(yī)療官里克?斯科特表示，與父母和醫(yī)生的討論讓他的團隊得出結論，人們希望任何新生兒基因組測序計劃可以涵蓋的疾病范圍遠比BabySeq尋找的要少得多。最吸引人的測試是與兒童疾病高概率相關的變異，這將受益于早期治療。

The set of variants Genomics England will seek is therefore being decided “cautiously”, says Dr Scott. At the moment, the proposed list has several hundred items on it. If implemented in toto, this would result in about one baby in 200 receiving a diagnosis of a rare genetic disorder. That list would be likely to grow as understanding improves and new treatments arrive.

因此，斯科特博士說，Genomics England將尋找的一組變異是“謹慎”決定的。目前，提議的清單上有幾百項。如果全面實施，這將導致大約每200個嬰兒中就會有一名會診斷患有一種罕見的遺傳疾病。隨著理解的提高和新的治療方法的出現，這個清單可能會增加。

This public consultation has shown that some parents want to know everything possible about their child while others very definitely do not. One particular finding, according to David Bick, a clinical geneticist who advises Genomics England, is that parents want certainty. They feel it is no use being told that a child is “fairly likely” to have a condition. Rather, they want a pretty clear “yes” or “no”.

這次公眾咨詢表明，一些家長想要盡可能了解關于孩子的一切，而另一些家長顯然不想。據Genomics England的臨床遺傳學家大衛(wèi)·比克說，一個特別的發(fā)現是，父母想要的是確定性。他們認為，告訴一個孩子“相當有可能”患有某種疾病是沒有用的。相反，他們想要一個非常明確的“有”或“沒有”。

Many also do not want to know of adult-onset illnesses that their children may one day suffer. This means rejecting tests which might indicate a newborn’s risk, later in life, of contracting cancer, diabetes or Alzheimer’s disease. That information would bring with it the burden of deciding what to tell their child, and when. Rather, these parents feel, it should be up to the children themselves, if they so wish, to seek that information when they are older—which would be easy if their genomes were already on file.

許多人也不想知道他們的孩子有一天可能會患上成年發(fā)病的疾病。這意味著拒絕那些可能表明新生兒在以后的生活中有患癌癥、糖尿病或阿爾茨海默病風險的檢測。這些信息會帶來負擔，需要決定告訴孩子什么，什么時候告訴他們。相反，這些父母認為，應該由孩子自己來決定，如果他們愿意的話，在他們長大后找出這些信息——如果他們的基因組已經被存檔，這將是很容易的。

There are, however, still some conundrums. For example, Pompe’s disease is a disorder in which a carbohydrate called glycogen builds up in the body's cells. The infant-onset form of this illness must be treated straight away. The adult-onset form can be left until those with it are in their 30s. The current genetic test cannot distinguish between these forms. The cost of prompt treatment for youngsters is therefore that some parents must carry the knowledge that their offspring will suffer eventually, though not immediately.

【1】conundrum 復雜難解的問題

?【背景：龐貝氏病】由于溶酶體內缺乏酸性α-葡萄糖苷酶（acidalpha-glucosidase, GAA），使糖原及麥芽糖不能轉化為葡萄糖而被利用，以致體內大量糖原在骨骼肌、心肌和平滑肌等組織細胞內聚積而致病。 龐貝氏病是累及全身的系統(tǒng)性疾病，臨床變異較大，但主要以肌病表現為主。有個別報道中樞神經系統(tǒng)和腎小管受累。 根據起病年齡癥狀嚴重程度和進展速度不同可分為三種類型：?嬰兒型，癥狀比較嚴重，一般在出生1個月或3～4個月后發(fā)病。首發(fā)癥狀為進食后發(fā)紺，呼吸困難。全身肌肉無力，呈弛緩性癱瘓，且病情進展較快，常在1歲之內因心肺功能衰竭而死亡。檢查可見巨舌，心臟擴大，少數病兒肝臟腫大，心律失常。 兒童型，病情進展較慢，除肌無力外，其他器官受累不一；常以動作發(fā)育遲滯或步態(tài)不穩(wěn)為初起癥狀，繼而肌力減退，吞咽困難，呼吸肌麻痹，可伴腓腸肌肥大；常因肺部感染致呼吸衰竭而死亡。但部分患者可生存20年以上。 成人型，因殘留GAA酶活性較高，癥狀比較輕微，僅表現骨骼肌無力，緩慢進展性的四肢肌肉萎縮，近端較遠端重；以軀干肌、骨盆帶肌明顯，半數以上病人影響呼吸肌。常被誤診為多發(fā)性肌炎或肌營養(yǎng)不良癥。

?然而，仍然存在一些難題。例如，龐貝氏病是一種由一種叫做糖原的碳水化合物在身體細胞中積聚而成的疾病。這種疾病的嬰兒發(fā)病型必須立即治療。成人發(fā)病型可以保留到30多歲。目前的基因測試無法區(qū)分這些形式。因此，對青少年進行及時治療的代價是，一些父母必須知道，他們的后代最終會遭受痛苦，盡管不是馬上。

Tay-Sachs disease, an illness fatal in childhood, causes another dilemma. Some parents absolutely do not want to know about it, because that would spoil their experience of the early years they have with their child. Others feel knowledge is power, and so do wish to know.?

【背景】泰-薩克斯病是由于HEXA基因突變所致。基因突變意味著構成基因的DNA序列永久改變，進而導致身體內一個或多個程序出錯。突變的HEXA基因導致人體不能合成己糖脫氨酶A（Hex-A），從而引起一種叫做GM2神經節(jié)苷脂的脂肪物質積聚在大腦和神經細胞，阻止大腦和神經正常工作，最終使其喪失功能。?

泰-薩克斯病，一種兒童時期的致命疾病，導致了另一個困境。有些父母決然不想知道這件事，因為這會破壞他們與孩子相處的早年經歷。有些人認為知識就是力量，他們也希望知道。

One of the trickiest questions of all concerns Duchenne muscular dystrophy, a degenerative illness that starts in childhood. Screening for this would find it in six of every 100,000 children tested. But only a small number of these have forms of the disease that can currently be treated, and the drugs needed are not widely available. However, learning that one’s child has this disease could also allow children to join trials of new drugs.?

【背景】杜氏肌肉營養(yǎng)不良癥會導致肌纖維無力、萎縮。主要是進行性的肌肉無力和萎縮。多數是在4歲以前發(fā)病，比如開始發(fā)現男孩走路搖搖擺擺，之后就發(fā)現他上臺階特別費勁，他起身也很困難，如果要是想起來，需要蹭著身起來。主要是肌肉無力，少部分還會連累心臟，還有的病人會影響智力，包括落后和低下。?

最棘手的問題之一與杜氏肌營養(yǎng)不良癥有關，這是一種始于兒童時期的退化性疾病。對這種疾病進行篩查發(fā)現，每10萬名接受檢測的兒童中就有6名患有此病。但其中只有一小部分具有目前可以治療的疾病形式，而且所需的藥物也不是廣泛可用。然而，知道自己的孩子患有這種疾病也可以讓孩子參加新藥的試驗。

Over the coming year Genomics England, along with doctors, patients and the wider public, will wrangle with such questions, armed with a set of principles (which are themselves up for discussion) about what tests should be done. These principles include the idea that screening should lead to improved outcomes in those it is applied to; that this should not involve many invasive follow-up tests; and that there is strong evidence the genetic variant being tested for does indeed cause the condition in question.

在接下來的一年里，Genomics England將與醫(yī)生、患者和更廣泛的公眾一道，圍繞這些問題展開爭論，并制定一套關于應該做哪些檢測的原則(這些原則本身也有待討論)。這些原則包括：篩查應能改善其應用對象的結果；這不應該包括很多有創(chuàng)的后續(xù)檢查；而且，有強有力的證據表明，正在測試的基因變異確實導致了上述情況。

And there is one other thing. This is the tricky question of how to ensure that the data are kept safe for a lifetime. Properly informed consent for all the various uses such data might be put to is central to the British plan. Other places may not be so scrupulous. Moreover, things change. The temptation to crack open genetic databases for police investigations might prove irresistible. Insurance firms would surely be delighted to snoop as well, if they were allowed to.

還有一件事。這是一個棘手的問題，即如何確保數據終身安全。在英國的計劃中，對這些數據可能用于的各種用途的適當知情同意是核心。其他地方可能不會這么謹慎。此外，事情會發(fā)生變化。為警方調查而“開放”基因數據庫的誘惑可能無法抗拒。如果被允許，保險公司肯定也會樂于窺探。

Most important, such data are a veritable Aladdin’s cave for medical researchers—a cave to which only some parents will be prepared to add their children’s sequences. (Informed consent means data should not be used in this way unless parents have explicitly agreed to it.)

【1】Aladdin's cave 收藏珍奇物品之處；寶庫

最重要的是，這些數據對醫(yī)學研究人員來說是一個名副其實的阿拉丁寶庫——一個只有一些父母準備把他們孩子的測序數據添加進去的寶庫。(知情同意意味著，除非父母明確同意，否則不應以這種方式使用數據。)

Combining the fruits of future scientific advances with people’s full dna sequences, collected at birth, could bring huge medical benefits. But it might also be a double-edged sword. Current knowledge of how genomes work is primitive. There is also a lot of so-called dark genetic matter in them, which does things currently unknown. Genomes may conceal secrets of, say, potential mental illness, or of behavioural predispositions that a genome’s owner would rather stayed private. Current rules say that they should. But for those who have opened the door to doctors and scientists to look at their data, the question of whether those data will remain secure for a lifetime may be a gamble.?

【1】predisposition 易受感染的體質；傾向

將未來科學進步的成果與人類出生時收集的完整DNA序列相結合，可能會帶來巨大的醫(yī)療效益。但這也可能是一把雙刃劍。目前關于基因組如何工作的知識還很原始。其中也有很多所謂的“暗遺傳物質”，它們的作用目前未知?；蚪M可能會隱藏一些秘密，比如潛在的精神疾病或基因組所有者寧愿保密的行為傾向。目前的規(guī)則表明他們應該這么做。但對于那些向醫(yī)生和科學家敞開大門，讓他們查看自己的數據的人來說，這些數據是否會終身安全的問題可能是一場冒險。