The identification of PRUNE1 mutations in the sizeable and diverse patient cohorts described here, together with confirmatory functional assays demonstrating a deleterious effect of gene mutation on PRUNE function, have enabled us to determine the core clinical phenotype associated with Prune syndrome and implicate altered tubulin dynamics as a credible mechanism by which loss of PRUNE function may result in the microcephaly, additional cortical and subcortical abnormalities and the neurological phenotype observed. This evidence concerns the gene PRUNE1 and microcephaly.