Key result
A recurrent de novo missense variant in ARPC4 (p.Arg158Cys) causes a neurodevelopmental disorder characterized by microcephaly and speech delay, and is associated with a 43% decrease in F-actin abundance in patient fibroblasts.
Case Report (n=7)
A recurrent de novo missense variant in ARPC4 disrupts actin filament formation and is implicated as a cause of a neurodevelopmental disorder characterized by microcephaly and speech delay.
Hypothesis-generating for ARPC4-related neurodevelopmental disorders; leaves open replication and clinical utility.
We report seven affected individuals from six families with a recurrent, de novo variant in the ARPC4 gene (c.472C>T [p.Arg158Cys (GenBank: NM_005718.4)]). 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.
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Cintrón et al. (2021) conducted a case report in Microcephaly and neurodevelopmental disorder (n=7). ARPC4 c.472C>T (p.Arg158Cys) variant vs. Unaffected controls was evaluated on F-actin abundance in fibroblasts (43% decrease, p=<0.0001). A recurrent de novo missense variant in ARPC4 (p.Arg158Cys) causes a neurodevelopmental disorder characterized by microcephaly and speech delay, and is associated with a 43% decrease in F-actin abundance in patient fibroblasts.
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