FORGE Canada Consortium: Outcomes of a 2-Year National Rare-Disease Gene-Discovery Project
FORGE Canada Consortium: Outcomes of a 2-Year National Rare-Disease Gene-Discovery Project
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DOI：
10.1016/j.ajhg.2014.05.003
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发表时间：
2014-06-05
影响因子：
9.8
通讯作者：
Boycott, Kym M.
中科院分区：
文献类型：
--
作者：
Beaulieu, Chandree L.;Majewski, Jacek;Boycott, Kym M.
遗传性单基因疾病对儿童及其家庭的福祉产生巨大影响。超过一半的患有这些疾病的儿童没有分子诊断，因为这种疾病的罕见性，显著的临床异质性，以及有数千种罕见疾病的致病突变尚未确定的现实。正是在这种背景下，2010年成立了一个加拿大联盟，通过使用全外显子组测序快速鉴定导致广泛的儿科发病罕见疾病的突变。FORGE（寻找罕见疾病基因）加拿大联盟汇集了来自加拿大21个遗传学中心和3个科技创新中心的临床医生和科学家。从全国范围的提案请求中，从提交的371种疾病中选择了264种疾病进行研究;在2年的时间内，确定了146种疾病的致病变异（包括以前与人类疾病无关的67个基因;其中41个基因已被遗传或功能验证，26个目前正在研究中）。在这里，我们提出了我们的经验与四种策略用于基因发现和讨论FORGE的影响，在一些领域，从临床诊断扩大许多疾病的表型谱的生物学洞察力获得疾病状态和正常的人类发展。最后，在此经验的基础上，我们讨论了在加拿大和国际上罕见疾病遗传发现的前进方向。
Inherited monogenic disease has an enormous impact on the well-being of children and their families. Over half of the children living with one of these conditions are without a molecular diagnosis because of the rarity of the disease, the marked clinical heterogeneity, and the reality that there are thousands of rare diseases for which causative mutations have yet to be identified. It is in this context that in 2010 a Canadian consortium was formed to rapidly identify mutations causing a wide spectrum of pediatric-onset rare diseases by using whole-exome sequencing. The FORGE (Finding of Rare Disease Genes) Canada Consortium brought together clinicians and scientists from 21 genetics centers and three science and technology innovation centers from across Canada. From nation-wide requests for proposals, 264 disorders were selected for study from the 371 submitted; disease-causing variants (including in 67 genes not previously associated with human disease; 41 of these have been genetically or functionally validated, and 26 are currently under study) were identified for 146 disorders over a 2-year period. Here, we present our experience with four strategies employed for gene discovery and discuss FORGE's impact in a number of realms, from clinical diagnostics to the broadening of the phenotypic spectrum of many diseases to the biological insight gained into both disease states and normal human development. Lastly, on the basis of this experience, we discuss the way forward for rare-disease genetic discovery both in Canada and internationally.