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

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  • A Correction to this article was published on 03 July 2019

Abstract

Purpose

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.

Methods

We describe an international cohort of seven affected individuals harboring variants involving MED12L identified by array CGH, exome or genome sequencing.

Results

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.

Conclusion

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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Change history

  • 03 July 2019

    In the Acknowledgements section of the paper the authors neglected to mention that the study was supported by a grant from the National Human Genome Research Institute (NHGRI) UM1HG007301 (SMH, MLT). In addition, the award of MD was associated with the authors Michelle Thompson and Susan Hiatt instead of PhD. The PDF and HTML versions of the Article have been modified accordingly.

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Acknowledgements

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).

Author information

Correspondence to Mathilde Nizon MD.

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Disclosure

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

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Keywords

  • MED12L
  • intellectual disability
  • mediator complex
  • transcriptional defect
  • corpus callosum

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