Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect

Abstract

Purpose: Mediator is a multiprotein complex that allows the transfer ofgenetic information from DNA binding proteins to the RNA polymerase II duringtranscription initiation. MED12L is a subunit of the kinase module, which is oneof the four subcomplexes of the mediator complex. Other subunits of the kinasemodule have been already implicated in intellectual disability, namely MED12,MED13L, MED13, and CDK19. Methods: We describe an international cohort of seven affected individualsharboring variants involving MED12Lidentified by array CGH, exome or genome sequencing. Results: All affected individuals presented with intellectual disabilityand/or developmental delay, including speech impairment. Other features includedautism spectrum disorder, aggressive behavior, corpus callosum abnormality, andmild facial morphological features. Three individuals had a MED12L deletion or duplication. The other fourindividuals harbored single-nucleotide variants (one nonsense, one frameshift,and two splicing variants). Functional analysis confirmed a moderate andsignificant alteration of RNA synthesis in two individuals. Conclusion: Overall data suggest that MED12L haploinsufficiency is responsiblefor intellectual disability and transcriptional defect. Our findings confirmthat the integrity of this kinase module is a critical factor for neurologicaldevelopment.