Thrombocytopenia Microcephaly Syndrome - a novel phenotype associated with ACTB mutations

The human genome encodes six actin isoforms, produced in a time- and tissue-specific manner during development. Until now mutations in ACTB, encoding beta-cytoplasmic actin (lower case Greek beta-CYA), were exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF), a complex developmental disorder 1,2. Here, we report 6 patients with de novo heterozygous variants in ACTB, without BWCFF features, who presented with mild microcephaly and thrombocytopenia. Patient primary fibroblasts, utilized to assess the cell-based consequences of these mutations as well as any compensatory effects, show aberrant behavior consistent with a contractile phenotype. A discrete actin filament population, comprising force generating and transmitting actin binding proteins (ABP) that have already been associated with thrombocytopenia, is altered in patient cells. Our results describe a new clinical phenotype associated with ACTB mutations, and identify a cytoskeletal protein interaction network crucial for thrombopoiesis.