Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules
Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules
复制标题
DOI：
10.1016/j.ajhg.2015.11.024
复制
发表时间：
2016-01-07
影响因子：
9.8
通讯作者：
Schenck, Annette
中科院分区：
文献类型：
--
作者：
Kochinke, Korinna;Zweier, Christiane;Schenck, Annette
智力残疾（ID）障碍在遗传和表型上是极其异质的。这种复杂性能否被全面地描述为促进对ID疾病及其潜在生物学的理解的一种手段？我们提供了一个包含746个目前已知基因的数据库，这些基因的突变导致ID（ID相关基因[ID-AGs]），根据ID表现和相关临床特征进行分类。使用这种综合资源，我们表明ID-AGs基本上富含共表达，蛋白质-蛋白质相互作用和特定的生物学功能。高度丰富的功能主题和表型的系统鉴定揭示了典型的表型组合特征的过程定义的ID疾病组，如染色质相关的疾病和DNA修复的缺陷。引人注目的是，表型分类有效地将ID-AG分解为具有显著提高的生物一致性和预测能力的子集。定制的功能果蝇数据集揭示了ID-AG和特定临床类别之间的进一步特征表型。我们的研究和资源为ID疾病的分子和临床景观提供了系统的见解，代表了克服ID研究当前局限性的重要一步，并证明了系统的人类和跨物种表型组学分析在高度异质性遗传疾病中的实用性。
Intellectual disability (ID) disorders are genetically and phenotypically extremely heterogeneous. Can this complexity be depicted in a comprehensive way as a means of facilitating the understanding of ID disorders and their underlying biology? We provide a curated database of 746 currently known genes, mutations in which cause ID (ID-associated genes [ID-AGs]), classified according to ID manifestation and associated clinical features. Using this integrated resource, we show that ID-AGs are substantially enriched with co-expression, protein-protein interactions, and specific biological functions. Systematic identification of highly enriched functional themes and phenotypes revealed typical phenotype combinations characterizing process-defined groups of ID disorders, such as chromatin-related disorders and deficiencies in DNA repair. Strikingly, phenotype classification efficiently breaks down ID-AGs into subsets with significantly elevated biological coherence and predictive power. Custom-made functional Drosophila datasets revealed further characteristic phenotypes among ID-AGs and specific clinical classes. Our study and resource provide systematic insights into the molecular and clinical landscape of ID disorders, represent a significant step toward overcoming current limitations in ID research, and prove the utility of systematic human and cross-species phenomics analyses in highly heterogeneous genetic disorders.