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DNA测序能诊断智力残疾

来源:福布斯中文网 2012-10-11 10:50

10月3日,研究人员在发表于主要科学期刊的两篇论文中建议,应推动DNA测序更多地应用于日常门诊,而不仅仅是作为一种研究工具。

来自荷兰的研究人员建议用DNA测序取代旧有的基因测试以诊断重度智力残疾的病因,这也是一天之中第二次有研究人员推动这种新兴技术成为重症诊断测试的首选办法。上述研究结果发表在《新英格兰医学期刊》(New England Journal of Medicine)。

“这是智力残疾的新诊断方法,这一点毫无疑问。”来自拉德伯德大学内梅亨医学中心(Radboud University Nijmegen Medical Center)的韩·布伦纳(Han Brunner)说道,他也是上述研究报告的作者之一,“对那些患有复杂病症、不容易通过传统方法进行诊断的病人来说,这是朝向基因组医学的范式转变。”

不久前,一篇发表于《科学转化医学》杂志(Science Translational Medicine)的研究报告提议,可以将DNA测序作为新生儿重症监护病房诊断新生儿病因的标准首选方法,因为由新软件和硬件组合而成的测序系统可以让医生在短短50小时内得到结果,从而在时间紧迫的情况下更加快速地找出致病原因。

“我们的研究结论是,如今已经可以做到在两天内对整个基因组进行测序并将中期结果反馈给医生。”斯蒂芬·金斯莫尔(Stephen Kingsmore)在周二举行的电话会议上对记者说道。他是堪萨斯儿童福利医院儿科基因组医学中心(Center for Pediatric Genomic Medicine at Children’s Mercy Hospitals)的主任,同时也是上述研究报告的主要作者。“我们认为,通过让新生儿科医生在行医问诊时将基因组考虑在内,这将改变新生儿医学的面貌。”

布伦纳和他的同事使用的技术名为“外显子组测序”(exome sequencing),这种技术只从全基因组中提取已知的人类基因进行测序,它可以降低测序成本。这些荷兰研究人员对100名智商低于50的病患以及他们智力正常的父母进行了测序,结果发现有16例智力残疾是由已知的基因突变造成,另外22例的罪魁祸首似乎是功能未知的基因。这种测序技术至少可以跟目前用于检测这些重度智力残疾患者的基因技术比肩。

在2个病例中,诊断结果改变了医生治疗患者的方式:其一,改变饮食习惯可能被证明是有帮助的;其二,基因诊断结果将直接关系到患者将收到哪种类型的癫痫药物。

但这种诊断技术还有其他一些好处。家长们往往会拼命寻求诊断结果,只是因为他们想知道哪里出了错。如果他们决定再要一个孩子的话,他们还经常对将要发生的事情感到害怕。而这种测试可以检测出家长身上是否携带有导致新生儿缺陷的基因。

在上述研究涉及的绝大多数病例中,子代从亲代那里遗传到缺陷基因并不是什么大问题。令人惊讶的是,造成这些病例的大多数基因突变是新出现的——它们并不存在于亲代的基因组中。有3例智力残疾的缺陷基因是通过X染色体遗传自母亲,由于男性只有一条X染色体而女性有两条X染色体,因此X染色体上的基因缺陷对男性子代很不利。

一般而言,每个新生儿都带有一种全新的基因突变,这些突变大多数都无关紧要。但布伦纳说,有些基因出现突变就会造成精神残疾,这样的基因有1,000个。因此,一些不幸的孩子之所以受苦只是因为本底突变概率在作祟。

布伦纳称,外显子组测序的花费约为每人2,400美元,这没有将数据分析的费用算进去。不过,有一部分费用有可能会降下来。上述研究所进行的测序工作是通过生命技术公司(Life Technologies)制造的SOLiD系统完成的,如果使用该公司即将推出的Proton系统或DNA测序市场领导厂商Illumina公司制造的更加流行的HiSeq系统,那么测序费用还能进一步降低。

“外显子组测序已经进入临床诊断领域。”希瑟·芒福德(Heather Memford)如是说。她是华盛顿大学(University of Washington)的儿科医生和遗传学家,她在《新英格兰医学期刊》上就研究结果发表了一篇评论文章,“作为临床医生,我们面临的问题是,我们是现在就使用这种方法诊断病患还是等到以后?”

在《科学转化医学》杂志发表论文的研究人员跟Illumina公司直接进行了合作,他们一开始研发出一种诊断测试方法,这种方法可以对600个有可能造成缺陷的基因进行检测。Illumina公司将该方法打包出售,一些从政府获得从事基因测试资质认证的商业实验室可能会采纳这套方案。不过,后来研究人员又对2个已经死亡的新生儿以及5个仍然活着但无法诊断病因的新生儿进行了全基因组测序,除了1个病例以外,他们找到了造成(或很可能造成)新生儿疾病的缺陷基因。每组测试的花费——包括数据分析的花费在内——是13,500美元。这听起来好像很多,但新生儿重症监护病房每天的费用就达到8,000美元。

最大的问题仍然是,这样的测试方法多快能够从一种研究工具转变成一种被商业实验室采纳、由保险公司支付费用的临床诊断方法?有一些人认为这种转变已经开始发生,但芒福德称,她进行的所有DNA测序工作用的都是研究基金而非保险金。金斯莫尔表示,他不确定这种测试方法如何能够在病患间普及,但他认为自己所在的堪萨斯儿童福利医院最终可能将它变成面向其他医院的一种服务。(生物谷 Bioon.com)

Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability

Joep de Ligt, M.Sc., Marjolein H. Willemsen, M.D., Bregje W.M. van Bon, M.D., Ph.D., Tjitske Kleefstra, M.D., Ph.D., Helger G. Yntema, Ph.D., Thessa Kroes, B.Sc., Anneke T. Vulto-van Silfhout, M.D., David A. Koolen, M.D., Ph.D., Petra de Vries, B.Sc., Christian Gilissen, Ph.D., Marisol del Rosario, B.Sc., Alexander Hoischen, Ph.D., Hans Scheffer, Ph.D., Bert B.A. de Vries, M.D., Ph.D., Han G. Brunner, M.D., Ph.D., Joris A. Veltman, Ph.D., and Lisenka E.L.M. Vissers, Ph.D.

Background

The causes of intellectual disability remain largely unknown because of extensive clinical and genetic heterogeneity.

Methods

We evaluated patients with intellectual disability to exclude known causes of the disorder. We then sequenced the coding regions of more than 21,000 genes obtained from 100 patients with an IQ below 50 and their unaffected parents. A data-analysis procedure was developed to identify and classify de novo, autosomal recessive, and X-linked mutations. In addition, we used high-throughput resequencing to confirm new candidate genes in 765 persons with intellectual disability (a confirmation series). All mutations were evaluated by molecular geneticists and clinicians in the context of the patients' clinical presentation.

Results

We identified 79 de novo mutations in 53 of 100 patients. A total of 10 de novo mutations and 3 X-linked (maternally inherited) mutations that had been previously predicted to compromise the function of known intellectual-disability genes were found in 13 patients. Potentially causative de novo mutations in novel candidate genes were detected in 22 patients. Additional de novo mutations in 3 of these candidate genes were identified in patients with similar phenotypes in the confirmation series, providing support for mutations in these genes as the cause of intellectual disability. We detected no causative autosomal recessive inherited mutations in the discovery series. Thus, the total diagnostic yield was 16%, mostly involving de novo mutations.

Conclusions

De novo mutations represent an important cause of intellectual disability; exome sequencing was used as an effective diagnostic strategy for their detection. (Funded by the European Union and others.)

Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units.

Carol Jean Saunders, Neil Andrew Miller, Sarah Elizabeth Soden, Darrell Lee Dinwiddie, Aaron Noll, Noor Abu Alnadi, Nevene Andraws, Melanie LeAnn Patterson, Lisa Ann Krivohlavek, Joel Fellis, Sean Humphray, Peter Saffrey, Zoya Kingsbury, Jacqueline Claire Weir, Jason Betley, Russell James Grocock, Elliott Harrison Margulies, Emily Gwendolyn Farrow, Michael Artman, Nicole Pauline Safina, Joshua Erin Petrikin, Kevin Peter Hall, and Stephen Francis Kingsmore

Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. Hence, an immense unmet need exists for improved molecular diagnosis in infants. Because disease progression is extremely rapid, albeit heterogeneous, in newborns, molecular diagnoses must occur quickly to be relevant for clinical decision-making. We describe 50-hour differential diagnosis of genetic disorders by whole-genome sequencing (WGS) that features automated bioinformatic analysis and is intended to be a prototype for use in neonatal intensive care units. Retrospective 50-hour WGS identified known molecular diagnoses in two children. Prospective WGS disclosed potential molecular diagnosis of a severe GJB2-related skin disease in one neonate; BRAT1-related lethal neonatal rigidity and multifocal seizure syndrome in another infant; identified BCL9L as a novel, recessive visceral heterotaxy gene (HTX6) in a pedigree; and ruled out known candidate genes in one infant. Sequencing of parents or affected siblings expedited the identification of disease genes in prospective cases. Thus, rapid WGS can potentially broaden and foreshorten differential diagnosis, resulting in fewer empirical treatments and faster progression to genetic and prognostic counseling.

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