De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder

Snijders Blok, L. et al. (2018) De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder. Human Genetics, 137(5), pp. 375-388. (doi: 10.1007/s00439-018-1887-y) (PMID:29740699) (PMCID:PMC5973976)

Abstract

Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes.

• Item Type: Articles
• Additional Information: This work was supported by the Max Planck Society (S.E.F.), a grant from the US National Human Genome Research Institute (NHGRI; UM1HG007301) (S.M.H., K.M.B., J.N.C., K.L.E., E.M.B., G.M.C.), and the Netherlands Organisation for Scientific Research (NWO) Gravitation Grant 24.001.006 to the Language in Interaction Consortium (L.S.B., H.G.B., S.E.F.). Patient L was part of the DDD study cohort (DECIPHER ID: DDD263479). The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute [grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome Trust.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Zuberi, Dr Sameer
• Authors: Snijders Blok, L., Hiatt, S. M., Bowling, K. M., Prokop, J. W., Engel, K. L., Cochran, J. N., Bebin, E. M., Bijlsma, E. K., Ruivenkamp, C. A. L., Terhal, P., Simon, M. E. H., Smith, R., Hurst, J. A., McLaughlin, H., Person, R., Crunk, A., Wangler, M. F., Streff, H., Symonds, J. D., Zuberi, S. M., Elliott, K. S., Sanders, V. R., Masunga, A., Hopkin, R. J., Dubbs, H. A., Ortiz-Gonzalez, X. R., Pfundt, R., Brunner, H. G., Fisher, S. E., Kleefstra, T., and Cooper, G. M.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Human Genetics
• Publisher: Springer Verlag
• ISSN: 0340-6717
• ISSN (Online): 1432-1203
• Published Online: 08 May 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Human Genetics 137(5):375--388
• Publisher Policy: Reproduced under a Creative Commons License