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Am J Hum Genet. 2016 Jan 7;98(1):149-64. doi: 10.1016/j.ajhg.2015.11.024.

Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules.

Author information

1
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, 6525 GA Nijmegen, the Netherlands.
2
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
3
Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, 6525 GA Nijmegen, the Netherlands.
4
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, UK.
5
Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, 6525 GA Nijmegen, the Netherlands. Electronic address: martijn.huijnen@radboudumc.nl.
6
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, 6525 GA Nijmegen, the Netherlands. Electronic address: annette.schenck@radboudumc.nl.

Abstract

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.

PMID:
26748517
PMCID:
PMC4716705
DOI:
10.1016/j.ajhg.2015.11.024
[Indexed for MEDLINE]
Free PMC Article

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