Heterozygous loss-of function variants in DOCK4 cause neurodevelopmental delay and microcephaly

Neurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 ( DOCK4 ) through the activation of RAC1 . Here, we clinically describe 8 individuals (7 males and one female) with variants in DOCK4 and overlapping phenotype of mild to severe global developmental delay. Additional symptoms include coordination or gait abnormalities, microcephaly, unspecific brain malformations, hypotonia and seizures. Five individuals carry missense variants (four of them detected de novo ) and three individuals carry null variants (two of them maternally inherited). Molecular modelling of the heterozygous missense variants suggests that the majority of them affect the globular structure of DOCK4. In vitro functional expression studies in transfected Neuro-2A cells showed that all missense variants impaired neurite outgrowth. Furthermore, Dock4-knock-out Neuro-2A cells also exhibited defects in promoting neurite outgrowth. Furthermore, a sex-specific expressivity is possible, as the only female of the cohort was comparatively mildly affected. Our results, including clinical, molecular and functional data, suggest that loss-of-function variants in DOCK4 cause a variable spectrum of a novel neurodevelopmental disorder with microcephaly.