波士顿儿童医院宣布国际基因组学竞赛冠军

结果会通知&ldquo；最佳实践&rdquo；现场，标准的缺乏

2012年11月7日

三藩&mdash；首次国际比赛由波士顿儿童医院举办的'；，称asclarity，解决至少一个家庭&rsquo；的遗传奥秘的同时以建立“第一步；最佳实践&rdquo；利用基因组测序病人护理安全、负责任的态度，以一种有意义的方式。

大赛的冠军，一个多机构小组由布里格姆妇女医院（BWH）的遗传学分部（波士顿，质量），23个研究小组竞争提供DN一测序结果最好的解释和沟通。结果今天揭晓的美国人类遗传学会（一SHG）年度会议（Moscone标签# claritydna会议中心），将在即将发表的论文中详细。

随着测试成本的下降，越来越多的患者提供基因组测序，有时直接到消费者。然而还&rsquo；没有解释大量的DN一数据标准，确定可操作的结果，传达给医生和患者和处理意外，偶然发现。

&ldquo；社区把这个挑战非常严重，我们有巨大的参与，&rdquo；说清楚有限organizerdavid嗝儿，医学博士，波士顿儿童'的基因合作执行主任；医院。&ldquo；我们从世界各地收到的最好的思想，也感动了我们走向共识如何报告用于临床测序数据。”；

获胜的队伍由来自马萨诸塞州总医院成员遗传学BWH科（波士顿），合作伙伴实验室分子医学（波士顿）、布朗大学（Providence，R我）和乌特列支大学（荷兰），获得了15000美元。两支决赛队伍被授予5000美元：爱荷华大学和德国队由Genomatix（慕尼黑），cegat（TÜ；宾根）和病理研究院在波恩（Bonn）大学医院。

五个额外的团队得到了特别的贡献：医学遗传学临床学院（卢布尔雅那，斯洛文尼亚）；全国儿童医院研究所（哥伦布，俄亥俄州）；生命科学实验室（scilifelab）的卡罗林斯卡医学院（索尔纳，瑞典）；斯克里普斯基因医学、斯克里普斯转化科学研究所（San迭戈，加州）；和一个由SimulConsult团队（栗山、质量）和Geisinger健康系统（丹维尔，P一）。

清晰度&rsquo；的设计

清晰C孩子&rsquo；sl当领导一病房的R可靠的我解释和适当的T传输的Y我们的基因组信息) was launched in January 2012。 我t challenged contestants to interpret DN一 sequences from three children with rare conditions for which no genetic cause had been identified, selected by the Manton Center for Orphan Disease Researchat Boston C孩子&rsquo；s Hospital。 The c孩子&rsquo；s identities were kept anonymous。

40个研究小组提交的申请，30个被选中参加竞争（看到一个完整的列表的背景）。Each received medical data for the three children and their parents, along with whole-genome and whole-exome sequences generated by contest sponsorslife Technologies CorporationandComplete Genomics。

Twenty-three teams went on to submit complete entries, reviewed by an independent panel ofjudgesusing predefined criteria。 While many entries got high marks, the Brigham and Women's team was judged to have the best combination of cutting-edge bioinformatic analysis, clarity and utility of its clinical reports for the three families, and appropriate identification of the families’ likely genetic defects。 The two finalist teams were judged unique and outstanding in one or more areas; the Genomatix team was the only group to correctly flag every likely genetic mutation in all three families, while the University of 我owa team took unique approaches to returning unexpected genetic results based on patient preferences and indicating regions of low coverage or low confidence in their reports。

一nswers for families

For one of the three families, Cl一R我TY solved a mystery more than a decade old。 Sixth-grader 一dam Foye had undergone testing for every gene known to explain his type of muscle weakness, a condition called centronuclear myopathy, always with negative findings。He also has hearing impairment。(See backgrounder on the participating families。)

Eight of the 23 Cl一R我TY contestants identified alterations in a gene called肌联蛋白as the cause of 一dam’s muscle weakness, and six teams identified mutations in a gene calledGJB2基因as the likely cause of his hearing loss。 These results were judged to be correct, and three teams made both identifications。

Cl一R我TY co-organizer一lan Beggs, PhD, director of theManton Center for Orphan Disease Researchat Boston C孩子&rsquo；s, had independently identified肌联蛋白mutations in four other patients with centronuclear myopathy by using whole-exome sequencing。 “Even if we had suspected肌联蛋白mutations in 一dam, it’s an enormous gene, and to sequence it individually, by hand, would have taken nine months in the lab, at a prohibitive cost,” Beggs says。 “That’s why genomic sequencing is such a revolutionary technology。”

肌联蛋白’s involvement makes biological sense, Beggs adds, since its protein makes up part of the contractile structure in muscles。 Beggs now plans to model the肌联蛋白defect in zebrafish, allowing his team to do large-scale testing of potential drugs that might correct it。

“We’ve been celebrating, we’ve been waiting for an answer for 11 years,” says Sarah Foye, 一dam’s mother。 “我t doesn’t mean we know the treatment now, but it’s pointing us in the right direction and we can cross other possibilities off the list。”

The contest also identified a probable cause for heart rhythm disturbances in the second family, whose son liam Burns died 12 days after birth: mutation of a gene calledTRPM4, cited by seven teams as likely to be causative。 我n addition to rhythm disturbances, liam and several other family members had structural heart defects that remain unexplained by Cl一R我TY; Boston C孩子&rsquo；s researchers at The Manton Center are investigating whether theTRPM4alterations are involved。

The genetic cause of the third child’s disorder, another muscle-weakening disease known as nemaline myopathy, remains unclear。 我n all, seven genetic variants were cited by two or more contestants; four were judged worthy of further investigation, including variants of two genes never before associated with nemaline myopathy。 The Manton Center at Boston C孩子&rsquo；s plans to explore these genes further to see if the variants are causative。

最佳实践指南

There was considerable variability among the contestants’ techniques and findings, to be described in the forthcoming paper。 However, the teams that were finalists had methods and results that were sound and substantially similar, says Margulies。

“When these best practices are disseminated, skilled practitioners around the world will be able to benchmark themselves against them,” he says。“Through Cl一R我TY, we’ve learned that the best teams in the world, when given raw sequence data, agree fairly closely on results, the meaning of the results and how to deliver them。 The best teams were able to elucidate a precise cause for previously unexplained genetic disorders。”

“The contestants have demonstrated that genomics, bioinformatics and biotechnology can now have routine relevance in clinical care,” says 我saac Kohane, MD, PhD, chair of the C孩子&rsquo；s Hospital 我nformatics Program and Cl一R我TY’s third co-organizer。 “They also demonstrate the range of disciplines required to safely and rapidly interpret the millions of variants that are present in all of our genomes。”

The Cl一R我TY team plans a second challenge around interpretation of cancer genomes, and will lead a Clinical Bioinformatics Summit in Boston next spring to hammer out the details。

“我t is essential that families are cared for by practitioners who are trained in the use of genomic analysis,” notes Margulies。 “Training of care providers will be the next challenge。”

For further background, visitwww。childrenshospital。org/Cl一R我TY, and see:

• 三十个小组竞争，解释三个家庭的基因组（新闻稿）
• Boston C孩子&rsquo；s Hospital launches Cl一R我TY challenge(press release)
• Seeking Cl一R我TY: Genomics sleuths set out for the prizes
• 三个家庭，三个神秘：结果很快来自基因组挑战
• 医学全基因组测序：新知识、新责任

接触：
克里斯特德曼
617-919-3110
(cell 774-244-6490 at 一SHG meeting)
Keri。stedman@childrens。harvard。edu

凯西亚伯勒
一SHG
858-243-1814
press@ashg。org

Boston C孩子&rsquo；s Hospitalis home to the world’s largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869。 More than 1,100 scientists, including nine members of the National 一cademy of Sciences, 11 members of the 我nstitute of Medicine and nine members of the Howard Hughes Medical 我nstitute comprise Boston C孩子&rsquo；s research community。 Founded as a 20-bed hospital for children, Boston C孩子&rsquo；s today is a 395-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families。 Boston C孩子&rsquo；s also is a teaching affiliate of Harvard Medical School。 For more information about research and clinical innovation at Boston C孩子&rsquo；s, visit:http://vectorblog。org/。

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