De novo heterozygous variants in POLR2A cause a neurodevelopmental syndrome with infantile-onset hypotonia

ABSTRACT POLR2A encodes RPB1, the largest subunit of the RNA polymerase II (pol II) complex, which is responsible for transcription of all ~21,000 protein-encoding genes. Here we describe the first fifteen patients harboring de novo heterozygous variants in POLR2A. The majority presents with profound infantile onset hypotonia and developmental delay. Missense variants that were expected to exert only mild structural effects, lead to malfunctioning RPB1, thereby inducing a dominant negative effect on pol II function. Intriguingly, these patients presented with a severe clinical phenotype. Conversely, variants expected to result in loss-of-function, leading to reduced availability of RPB1 were better tolerated: these patients exhibited the mildest phenotypes.