title: Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules.
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.
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Korinna
authors.initials: K
authors.lastname: Kochinke
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Nijhof
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fenckova
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Pavel
authors.initials: P
authors.lastname: Cizek
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Honti
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Keerthikumar
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Merel A W
authors.initials: MA
authors.lastname: Oortveld
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Kramer
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, UK.
authors.forename: Caleb
authors.initials: C
authors.lastname: Webber
authors.affiliation: 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.
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Huynen
authors.affiliation: 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.
authors.forename: Annette
authors.initials: A
authors.lastname: Schenck
mesh_terms: D000818:Animals; D004330:Drosophila / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D009154:Mutation; D010641:Phenotype