Mediator is a multiprotein complex that allows the transfer of genetic information from DNA binding proteins to the RNA polymerase II during transcription initiation. MED12L is a subunit of the kinase module, which is one of the four subcomplexes of the mediator complex. Other subunits of the kinase module have been already implicated in intellectual disability, namely MED12, MED13L, MED13, and CDK19.
We describe an international cohort of seven affected individuals harboring variants involving MED12L identified by array CGH, exome or genome sequencing.
All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment. Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features. Three individuals had a MED12L deletion or duplication. The other four individuals harbored single-nucleotide variants (one nonsense, one frameshift, and two splicing variants). Functional analysis confirmed a moderate and significant alteration of RNA synthesis in two individuals.
Overall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect. Our findings confirm that the integrity of this kinase module is a critical factor for neurological development.
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We thank the patients and their families for participating in this study. The study was supported by a grant from the National Human Genome Research Institute (NHGRI) UM1HG007301 (SMH, MLT).
The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics. M.T.C. and K.M. are employees of GeneDx, Inc., a wholly owned subsidiary of OPKO Health, Inc. The other authors declare no conflicts of interest.
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Nizon, M., Laugel, V., Flanigan, K.M. et al. Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect. Genet Med 21, 2713–2722 (2019) doi:10.1038/s41436-019-0557-3
- intellectual disability
- mediator complex
- transcriptional defect
- corpus callosum