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

• Published in: American journal of human genetics Vol. 98; no. 1; pp. 149 - 164
• Main Authors: Kochinke, Korinna, Zweier, Christiane, Nijhof, Bonnie, Fenckova, Michaela, Cizek, Pavel, Honti, Frank, Keerthikumar, Shivakumar, Oortveld, Merel A.W., Kleefstra, Tjitske, Kramer, Jamie M., Webber, Caleb, Huynen, Martijn A., Schenck, Annette
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.01.2016; Cell Press; Elsevier
• Subjects: Animals; DNA repair; Drosophila - genetics; Genes; Genetic disorders; Genotype & phenotype; Humans; Intellectual Disability - genetics; Learning disabilities; Mutation; Phenotype
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2015.11.024

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.