2. Academic Validation
  3. De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder

De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder

  • Am J Hum Genet. 2019 Apr 4;104(4):709-720. doi: 10.1016/j.ajhg.2019.02.006.
Eduardo Calpena 1,  Alexia Hervieu 2,  Teresa Kaserer 2,  Sigrid M A Swagemakers 3,  Jacqueline A C Goos 4,  Olajumoke Popoola 2,  Maria Jesus Ortiz-Ruiz 2,  Tina Barbaro-Dieber 5,  Lucy Bownass 6,  Eva H Brilstra 7,  Elise Brimble 8,  Nicola Foulds 9,  Theresa A Grebe 10,  Aster V E Harder 7,  Melissa M Lees 11,  Kristin G Monaghan 12,  Ruth A Newbury-Ecob 6,  Kai-Ren Ong 13,  Deborah Osio 13,  Francis Jeshira Reynoso Santos 14,  Maura R Z Ruzhnikov 8,  Aida Telegrafi 12,  Ellen van Binsbergen 7,  Marieke F van Dooren 15,  Deciphering Developmental Disorders Study 16,  Peter J van der Spek 3,  Julian Blagg 2,  Stephen R F Twigg 1,  Irene M J Mathijssen 4,  Paul A Clarke 17,  Andrew O M Wilkie 18
Affiliations

Affiliations

  • 1 Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • 2 Cancer Research UK Cancer Therapeutics Unit, the Institute of Cancer Research, London SM2 5NG, UK.
  • 3 Department of Pathology and Department of Bioinformatics, Erasmus University Medical Center, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
  • 4 Department of Plastic and Reconstructive Surgery, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
  • 5 Genetics Division, Cook Children's Medical Center, Fort Worth, TX 76102, USA.
  • 6 Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, St. Michael's Hospital, Bristol BS2 8EG, UK.
  • 7 Department of Genetics, University Medical Center Utrecht, Utrecht University, 3508 AB Utrecht, the Netherlands.
  • 8 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 9 Wessex Clinical Genetics Services, University Hospital Southampton, Southampton SO16 5YA, UK.
  • 10 Department of Child Health, University of Arizona College of Medicine, Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
  • 11 North Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3EH, UK.
  • 12 GeneDx, Gaithersburg, MD 20877, USA.
  • 13 Department of Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UK.
  • 14 Genetics Division, Joe DiMaggio Children's Hospital, Hollywood, FL 33021, USA; Charles E. Schmidt College of Medicine, Florida Atlantic University, Hollywood, FL 33021, USA.
  • 15 Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
  • 16 Deciphering Developmental Disorders Study, Wellcome Sanger Institute, Cambridge CB10 1SA, UK.
  • 17 Cancer Research UK Cancer Therapeutics Unit, the Institute of Cancer Research, London SM2 5NG, UK. Electronic address: paul.clarke@icr.ac.uk.
  • 18 Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. Electronic address: andrew.wilkie@imm.ox.ac.uk.
PMID: 30905399 DOI: 10.1016/j.ajhg.2019.02.006
Abstract

The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder. Using whole-exome or whole-genome Sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects; a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals. All predicted substitutions localize to the ATP-binding pocket of the kinase domain. Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism. Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing or visual impairments. To evaluate the functional impact of the mutations, we measured phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfected with wild-type (WT) or mutant CDK8 constructs. These experiments demonstrated a reduction in STAT1 phosphorylation by all mutants, in most cases to a similar extent as in a kinase-dead control. We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic similarity to syndromes associated with mutations in other subunits of the Mediator kinase module, indicating probable overlap in pathogenic mechanisms.

Keywords

CDK8; Mediator complex; Mediator kinase modulopathy; behavioral disorder; congenital heart disease; de novo mutation; dominant negative; hypotonia; intellectual disability; kinase.

Figures