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A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority. We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC. Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts. Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.


Anaïs Begemann, Heinrich Sticht, Amber Begtrup, Antonio Vitobello, Laurence Faivre, Siddharth Banka, Bader Alhaddad, Reza Asadollahi, Jessica Becker, Tatjana Bierhals, Kathleen E Brown, Ange-Line Bruel, Theresa Brunet, Maryline Carneiro, Kirsten Cremer, Robert Day, Anne-Sophie Denommé-Pichon, Dave A Dyment, Hartmut Engels, Rachel Fisher, Elaine S Goh, M J Hajianpour, Lucia Ribeiro Machado Haertel, Nadine Hauer, Maja Hempel, Theresia Herget, Jessika Johannsen, Cornelia Kraus, Gwenaël Le Guyader, Gaetan Lesca, Frédéric Tran Mau-Them, John Henry McDermott, Kirsty McWalter, Pierre Meyer, Katrin Õunap, Bernt Popp, Tiia Reimand, Korbinian M Riedhammer, Martina Russo, Lynette G Sadleir, Margarita Saenz, Manuel Schiff, Elisabeth Schuler, Steffen Syrbe, Amelie Theresa Van der Ven, Alain Verloes, Marjolaine Willems, Christiane Zweier, Katharina Steindl, Markus Zweier, Anita Rauch. New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics. Genetics in medicine : official journal of the American College of Medical Genetics. 2021 Mar;23(3):543-554

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PMID: 33149277

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