Genomic and biological panoramas of non-muscle actinopathies

Background Cytoskeletal non-muscle actin isoforms are the most abundant intracellular proteins and extensively interact with other molecules. Biological consequences and genotype-phenotype correlations of the variants in genes encoding these isoforms, ACTB and ACTG1, are not delineated. Methods Clinical data analysis from 290 individuals with pathogenic ACTB/ACTG1 variants; characterization of patient cells, mutant proteins, patient-derived iPSC-based models and mutant mice. Results We show that ACTB and ACTG1 variants have distinct clinical profiles. ACTB nonsense, frameshift and missense variants that lead to rapid protein degradation result in milder phenotypes. Heterozygous Actb knockout causes altered neuronal cell morphology and abnormal expression of actin-related genes in newborn mouse brains. Truncating ACTG1 variants are likely to be non-pathogenic, but chromosomal deletions encompassing ACTG1 and flanking genes may result in susceptibility to neurodevelopmental phenotypes. Subsets of disease-causing ACTB missense variants (MVs) result in more severe Type 1 Baraitser-Winter Cerebrofrontofacial (BWCFF1) or Deafness Dystonia syndromes. Pathogenic ACTG1 MVs cause BWCFF2 or isolated hearing loss. These amino acid substitutions are associated with dramatically dysregulated actin polymerization and depolymerization dynamics and, in induced pluripotent stem cells (iPSC) derived models, lead to neuronal migration defects. A significant subset of MVs result in disorders that cannot yet be classified into recognizable groups. Conclusions ACTB or ACTG1 variants and result in minimum eight mechanistically diverse non-muscle actinopathies. These results will improve their diagnosis and management, and pave the way for new treatment strategies. This study reflects the scale of collaborative clinical studies and multi-modal mechanistic studies required to dissect rare allelic disorders.