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

Hanneke A. Haijes, Maria J. E. Koster, Holger Rehmann, Dong Li, Hakon Hakonarson, Gerarda Cappuccio, Miroslava Hancarova, Daphne Lehalle, Willie Reardon, G. Bradley Schaefer, Anna Lehman, Ingrid M. B. H. van de Laar, Coranne D. Tesselaar, Clesson Turner, Alice Goldenberg, Sophie Patrier, Julien Thevenon, Michele Pinelli, Nicola Brunetti-Pierri, Darina PrchalovaMarketa Havlovicova, Marketa Vlckova, Zdenek Sedlacek, Elena Lopez, Vassilis Ragoussis, Alistair T. Pagnamenta, Usha Kini, Harmjan R. Vos, Robert M. van Es, Richard F. M. A. van Schaik, Ton A. J. van Essen, Maria Kibaek, Jenny C. Taylor, Jennifer Sullivan, Vandana Shashi, Slave Petrovski, Christina Fagerberg, Donna M. Martin, Koen L. van Gassen, Rolph Pfundt, Marni J. Falk, Elizabeth M. McCormick, H. T. Marc Timmers, Peter M. van Hasselt*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    7 Citations (Scopus)


    The RNA polymerase II complex (pol II) is responsible for transcription of all similar to 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 consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.

    Original languageEnglish
    Pages (from-to)283-301
    Number of pages19
    JournalAmerican Journal of Human Genetics
    Issue number2
    Publication statusPublished - 1-Aug-2019



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