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

• Published in: HGG advances 2022-01, Vol.3 (1), p.100072-100072, Article 100072
• Main Authors: Laboy Cintron, Dianne, Muir, Alison M., Scott, Abbey, McDonald, Marie, Monaghan, Kristin G., Santiago-Sim, Teresa, Wentzensen, Ingrid M., De Luca, Chiara, Brancati, Francesco, Harris, David J., Goueli, Cecilia, Stottmann, Rolf, Prada, Carlos E., Biderman Waberski, Marta, Mefford, Heather C.
• Format: Article
• Language: English
• Subjects: actin; ARPC4; de novo; developmental delay; genetic; microcephaly
• ISSN: 2666-2477; 2666-2477
• DOI: 10.1016/j.xhgg.2021.100072

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. We report a neurodevelopmental disorder with microcephaly in seven affected individuals with the same de novo variant in the ARPC4 gene. The recurrent variant in ARPC4, a subunit of the complex that catalyzes F-actin network formation, is associated with decreased F-actin in cells from affected individuals.