A recurrent, de novo pathogenic variant in ARPC4 disrupts actin filament formation and causes a neurodevelopmental disorder with microcephaly and speech delay

SUMMARY We report seven affected individuals from six families with a recurrent, de novo variant in the ARPC4 gene (NM_005718.4:c.472C>T; p.R158C). Core features in affected individuals include microcephaly, mild motor delays, and significant speech impairment. ARPC4 is a core subunit of the actin-related protein (ARP2/3) complex which catalyzes the formation of F-actin networks. We show that the recurrent ARPC4 missense change is associated with a decreased amount of F-actin in cells from two affected individuals. Taken together, our results implicate heterozygous ARPC4 missense variants as a cause of neurodevelopmental disorders and microcephaly.