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

Dianne Laboy Cintron; Alison M Muir; Abbey Scott; Marie McDonald; Kristin G Monaghan; Teresa Santiago-Sim; Ingrid M Wentzensen; Chiara De Luca; Italian Undiagnosed Diseases Network; Francesco Brancati; David J Harris; Cecilia Goueli; Rolf Stottmann; Carlos E Prada; Marta Biderman Waberski; Heather C Mefford

doi:10.1016/j.xhgg.2021.100072

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

HGG Adv. 2021 Nov 25;3(1):100072. doi: 10.1016/j.xhgg.2021.100072. eCollection 2022 Jan 13.

Authors

Dianne Laboy Cintron¹, Alison M Muir¹, Abbey Scott², Marie McDonald³, Kristin G Monaghan⁴, Teresa Santiago-Sim⁴, Ingrid M Wentzensen⁴, Chiara De Luca⁵; Italian Undiagnosed Diseases Network; Francesco Brancati^{5

6}, David J Harris⁷, Cecilia Goueli⁸, Rolf Stottmann⁹, Carlos E Prada^{8

10

11}, Marta Biderman Waberski¹², Heather C Mefford^{1

2}

Affiliations

¹ Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.
² Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, USA.
³ Department of Pediatrics, Duke University, Durham, NC, USA.
⁴ GeneDx, Inc, 207 Perry Parkway, Gaithersburg, MD, USA.
⁵ Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
⁶ IRCCS San Raffaele Roma, 00163 Roma, Italy.
⁷ Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH, USA.
⁹ Nationwide Children's Hospital, Columbus, OH, USA.
¹⁰ Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
¹¹ Department of Pediatrics, Feinberg School of Medicine of Northwestern University, Chicago, IL 60611, USA.
¹² Department of Pediatrics, Virginia Commonwealth University, Fairfax, VA, USA.

Abstract

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.

Keywords: ARPC4; actin; de novo; developmental delay; genetic; microcephaly.