Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation

Mid- hindbrainmalformations can occur during embryogenesis through a disturbance of transient and localized gene expression patterns within these distinct brain structures. Rho guanine nucleotide exchange factor(ARHGEF) family members are key for controlling the spatiotemporal activation of Rho GTPase, to modulate cytoskeleton dynamics, cell division, and cell migration. We identified, by means of whole exome sequencing, a homozygous frameshift mutationin the ARHGEF2 as a cause of intellectual disability, a midbrain- hindbrainmalformation, and mild microcephalyin a consanguineouspedigree of Kurdish-Turkish descent. We show that loss of ARHGEF2 perturbs progenitor cell differentiation and that this is associated with a shift of mitotic spindle plane orientation, putatively favoring more symmetric divisions. The ARHGEF2 mutation leads to reduction in the activation of the RhoA/ROCK/MLC pathway crucial for cell migration. We demonstrate that the human brainmalformation is recapitulated in Arhgef2 mutant mice and identify an aberrant migration of distinct components of the precerebellar system as a pathomechanism underlying the midbrain- hindbrainphenotype. Our results highlight the crucial function of ARHGEF2 in human braindevelopment and identify a mutation in ARHGEF2 as novel cause of a neurodevelopmental disorder.