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,
Francesco Brancati,
David J. Harris,
Cecilia Goueli,
Rolf Stottmann,
Carlos E. Prada,
Marta Biderman Waberski,
Heather C. Mefford
Affiliations
Dianne Laboy Cintron
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA
Alison M. Muir
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA
Abbey Scott
Division of Genetic Medicine, Seattle Children’s Hospital, Seattle, WA, USA
Marie McDonald
Department of Pediatrics, Duke University, Durham, NC, USA
Kristin G. Monaghan
GeneDx, Inc, 207 Perry Parkway, Gaithersburg, MD, USA
Teresa Santiago-Sim
GeneDx, Inc, 207 Perry Parkway, Gaithersburg, MD, USA
Ingrid M. Wentzensen
GeneDx, Inc, 207 Perry Parkway, Gaithersburg, MD, USA
Chiara De Luca
Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
Francesco Brancati
Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; IRCCS San Raffaele Roma, 00163 Roma, Italy
David J. Harris
Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Cecilia Goueli
Department of Pediatrics, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Rolf Stottmann
Nationwide Children’s Hospital, Columbus, OH, USA
Carlos E. Prada
Department of Pediatrics, Cincinnati Children’s Hospital, Cincinnati, OH, USA; Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA; Department of Pediatrics, Feinberg School of Medicine of Northwestern University, Chicago, IL 60611, USA
Marta Biderman Waberski
Department of Pediatrics, Virginia Commonwealth University, Fairfax, VA, USA
Heather C. Mefford
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA; Division of Genetic Medicine, Seattle Children’s Hospital, Seattle, WA, USA; Corresponding author
Summary: 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.
