Large-scale discovery of novel genetic causes of developmental disorders.
Large-scale discovery of novel genetic causes of developmental disorders.
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DOI：
10.1038/nature14135
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发表时间：
2015-03-12
期刊：
影响因子：
64.8
通讯作者：
Deciphering Developmental Disorders Study
中科院分区：
文献类型：
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作者：
Deciphering Developmental Disorders Study
尽管三十年来成功地发现了单基因疾病的遗传原因，但高达一半的可能遗传起源的严重发育障碍儿童仍然没有遗传诊断。特别具有挑战性的是那些罕见到足以避免被识别为离散临床实体的疾病，那些具有高度可变的临床表现的疾病，以及那些难以与其他非常相似的疾病区分开的疾病。在这里，我们展示了使用无偏见的基因型驱动的方法来确定类似疾病的患者子集的力量。通过研究1，133名患有严重未确诊发育障碍的儿童及其父母，使用外显子组测序，，和基于阵列的染色体重排检测相结合，我们发现了12个与发育障碍相关的新基因。这些新的相关基因增加了10%（从28%到31%），可以诊断的儿童比例。在这些新涉及的基因中的六个中的错义突变的聚类表明正常发育被激活或显性负性机制扰乱。我们的研究结果表明，在全基因组和全国范围内采取综合策略来阐明罕见遗传疾病的根本原因是有价值的。
Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing,,,,,,,,and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.
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影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
影响因子：
4.8
作者：
Kumagai, Keigo;Kawano, Miyuki;Hanada, Kentaro
通讯作者：
Hanada, Kentaro
影响因子：
4.5
作者：
Boumil, Rebecca M.;Letts, Verity A.;Frankel, Wayne N.
通讯作者：
Frankel, Wayne N.
影响因子：
7.7
作者：
Smith, Blair H.;Campbell, Archie;Morris, Andrew D.
通讯作者：
Morris, Andrew D.
影响因子：
64.8
作者：
通讯作者：
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