Journal article

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia

Hanneke A Haijes, Maria JE Koster, Holger Rehmann, Dong Li, Hakon Hakonarson, Gerarda Cappuccio, Miroslava Hancarova, Daphne Lehalle, Willie Reardon, G Bradley Schaefer, Anna Lehman, Ingrid MBH van de Laar, Coranne D Tesselaar, Clesson Turner, Alice Goldenberg, Sophie Patrier, Julien Thevenon, Michele Pinelli, Nicola Brunetti-Pierri, Darina Prchalova Show all

The American Journal of Human Genetics | CELL PRESS | Published : 2019


The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequence..

View full abstract

University of Melbourne Researchers


Awarded by Czech Ministry of Health

Awarded by Oxford NIHR (National Institute for Health Research) Biomedical Research Centre

Awarded by Telethon Foundation Telethon Undiagnosed Diseases Program

Awarded by Deutsche Forschungsgesellschaft (DFG)

Awarded by "Proteins at Work" program of the Netherlands Organization for Scientific Research (NWO)

Funding Acknowledgements

We thank all included individuals and their families for their cooperation. We thank Ton A.J. van Essen, who unfortunately passed away during the completion of this manuscript. We are indebted to Craig Kaplan for providing yeast strains, plasmids, and insightful discussions. The human RPB1 cDNA was kindly provided by P. Cook. The study was supported by the following: grant 17-29423A from the Czech Ministry of Health for individuals with the p.Pro371Leu and p.Met769Thr variants; grant R6-388/WT100127 from the Oxford NIHR (National Institute for Health Research) Biomedical Research Centre and the Health Innovation Challenge Fund (a parallel funding partnership between the Wellcome Trust and the Department of Health) for the individual with the p.Gln735* variant; funding from the Duke Genome Sequencing Clinic, supported by the Duke University Health System, for the individual with the p.Ile848Thr variant; grant GSP15001 from the Telethon Foundation Telethon Undiagnosed Diseases Program for the individual with the p.Tyr1109His variant; and funding from Mining for Miracles (BC Children's Hospital Foundation) and Genome British Columbia through the CAUSES (Clinical Assessment of the Utility of Sequencing as a Service) study for the individual with the p.Lys1125del variant. The investigators include Shelin Adam, Christele du Souich, Alison M. Elliott, Anna Lehman, Jill Mwenifumbo, Tanya N. Nelson, Clara van Karnebeek, and Jan M. Friedman, and bioinformatics support was provided by the lab of Wyeth Wasserman. The work of H.T.M.T. is supported by the SFB850 and SFB992 programs of the Deutsche Forschungsgesellschaft (DFG). The mass spectrometry analysis was supported by the "Proteins at Work" program of the Netherlands Organization for Scientific Research (NWO, 184.032.201). The work of H.A. Haijes is supported by the personal Alexandre Suerman Stipend of the University Medical Centre Utrecht.