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

HGG Advances (Jan 2022)

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

Journal volume & issue: Vol. 3, no. 1
p. 100072

Abstract

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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.

Published in HGG Advances

ISSN: 2666-2477 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics
Website: https://www.cell.com/hgg-advances/home

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