Begemann, Anaïs; Sticht, Heinrich; Begtrup, Amber; Vitobello, Antonio; Faivre, Laurence; Banka, Siddharth; Alhaddad, Bader; Asadollahi, Reza; Becker, Jessica; Bierhals, Tatjana; Brown, Kathleen E; Bruel, Ange-Line; Brunet, Theresa; Carneiro, Maryline; Cremer, Kirsten; Day, Robert; Denommé-Pichon, Anne-Sophie; Dyment, Dave A; Engels, Hartmut; Fisher, Rachel; Goh, Elaine S; Hajianpour, M J; Haertel, Lucia Ribeiro Machado; Hauer, Nadine; Hempel, Maja; Herget, Theresia; Johannsen, Jessika; Kraus, Cornelia; Le Guyader, Gwenaël; Lesca, Gaetan; Mau-Them, Frédéric Tran; McDermott, John Henry; McWalter, Kirsty; Meyer, Pierre; Õunap, Katrin; Popp, Bernt; Reimand, Tiia; Riedhammer, Korbinian M; Russo, Martina; Sadleir, Lynette G; Saenz, Margarita; Schiff, Manuel; Schuler, Elisabeth; Syrbe, Steffen; Van der Ven, Amelie Theresa; Verloes, Alain; Willems, Marjolaine; Zweier, Christiane; Steindl, Katharina; Zweier, Markus; Rauch, Anita     «

Begemann, Anaïs; Sticht, Heinrich; Begtrup, Amber; Vitobello, Antonio; Faivre, Laurence; Banka, Siddharth; Alhaddad, Bader; Asadollahi, Reza; Becker, Jessica; Bierhals, Tatjana; Brown, Kathleen E; Bruel, Ange-Line; Brunet, Theresa; Carneiro, Maryline; Cremer, Kirsten; Day, Robert; Denommé-Pichon, Anne-Sophie; Dyment, Dave A; Engels, Hartmut; Fisher, Rachel; Goh, Elaine S; Hajianpour, M J; Haertel, Lucia Ribeiro Machado; Hauer, Nadine; Hempel, Maja; Herget, Theresia; Johannsen, Jessika; Kraus, Co...     »

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.      «

PURPOSE: 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. METHODS: 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 pa...     »