Nature. 2015 Mar 12;519(7542):223-8. doi: 10.1038/nature14135. Epub 2014 Dec 24.
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.
尽管在过去三十年里，主要基于表型成功发现了单基因疾病的遗传病因，但仍有高达一半可能由遗传因素导致严重发育障碍的儿童未得到基因诊断。特别具有挑战性的是那些极为罕见以至于尚未被确认为独立临床实体的疾病、临床表现高度可变的疾病，以及难以与其他非常相似的疾病区分开来的疾病。在此，我们展示了使用无偏差的基因型驱动方法来识别患有相似疾病的患者亚组的能力。通过对1133名患有严重未确诊发育障碍的儿童及其父母进行研究，结合外显子组测序和基于阵列的染色体重排检测，我们发现了12个与发育障碍相关的新基因。这些新涉及的基因使能够得到诊断的儿童比例提高了10%（从28%提高到31%）。其中六个新涉及基因中的错义突变聚类表明，正常发育正因激活或显性负性机制而受到干扰。我们的研究结果证明了在全基因组范围和全国范围内采用综合策略来阐明罕见遗传疾病根本原因的价值。
