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New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics

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New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics. / 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.

in: GENET MED, Jahrgang 23, Nr. 3, 03.2021, S. 543-554.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Begemann, A, Sticht, H, Begtrup, A, Vitobello, A, Faivre, L, Banka, S, Alhaddad, B, Asadollahi, R, Becker, J, Bierhals, T, Brown, KE, Bruel, A-L, Brunet, T, Carneiro, M, Cremer, K, Day, R, Denommé-Pichon, A-S, Dyment, DA, Engels, H, Fisher, R, Goh, ES, Hajianpour, MJ, Haertel, LRM, Hauer, N, Hempel, M, Herget, T, Johannsen, J, Kraus, C, Le Guyader, G, Lesca, G, Mau-Them, FT, McDermott, JH, McWalter, K, Meyer, P, Õunap, K, Popp, B, Reimand, T, Riedhammer, KM, Russo, M, Sadleir, LG, Saenz, M, Schiff, M, Schuler, E, Syrbe, S, Van der Ven, AT, Verloes, A, Willems, M, Zweier, C, Steindl, K, Zweier, M & Rauch, A 2021, 'New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics', GENET MED, Jg. 23, Nr. 3, S. 543-554. https://doi.org/10.1038/s41436-020-01011-x

APA

Begemann, A., Sticht, H., Begtrup, A., Vitobello, A., Faivre, L., Banka, S., Alhaddad, B., Asadollahi, R., Becker, J., Bierhals, T., Brown, K. E., Bruel, A-L., Brunet, T., Carneiro, M., Cremer, K., Day, R., Denommé-Pichon, A-S., Dyment, D. A., Engels, H., ... Rauch, A. (2021). New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics. GENET MED, 23(3), 543-554. https://doi.org/10.1038/s41436-020-01011-x

Vancouver

Begemann A, Sticht H, Begtrup A, Vitobello A, Faivre L, Banka S et al. New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics. GENET MED. 2021 Mär;23(3):543-554. https://doi.org/10.1038/s41436-020-01011-x

Bibtex

@article{213a1d081a8c43c1b00ed843b738a345,
title = "New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics",
abstract = "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.",
author = "Ana{\"i}s Begemann and Heinrich Sticht and Amber Begtrup and Antonio Vitobello and Laurence Faivre and Siddharth Banka and Bader Alhaddad and Reza Asadollahi and Jessica Becker and Tatjana Bierhals and Brown, {Kathleen E} and Ange-Line Bruel and Theresa Brunet and Maryline Carneiro and Kirsten Cremer and Robert Day and Anne-Sophie Denomm{\'e}-Pichon and Dyment, {Dave A} and Hartmut Engels and Rachel Fisher and Goh, {Elaine S} and Hajianpour, {M J} and Haertel, {Lucia Ribeiro Machado} and Nadine Hauer and Maja Hempel and Theresia Herget and Jessika Johannsen and Cornelia Kraus and {Le Guyader}, Gwena{\"e}l and Gaetan Lesca and Mau-Them, {Fr{\'e}d{\'e}ric Tran} and McDermott, {John Henry} and Kirsty McWalter and Pierre Meyer and Katrin {\~O}unap and Bernt Popp and Tiia Reimand and Riedhammer, {Korbinian M} and Martina Russo and Sadleir, {Lynette G} and Margarita Saenz and Manuel Schiff and Elisabeth Schuler and Steffen Syrbe and {Van der Ven}, {Amelie Theresa} and Alain Verloes and Marjolaine Willems and Christiane Zweier and Katharina Steindl and Markus Zweier and Anita Rauch",
year = "2021",
month = mar,
doi = "10.1038/s41436-020-01011-x",
language = "English",
volume = "23",
pages = "543--554",
journal = "GENET MED",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

RIS

TY - JOUR

T1 - New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics

AU - Begemann, Anaïs

AU - Sticht, Heinrich

AU - Begtrup, Amber

AU - Vitobello, Antonio

AU - Faivre, Laurence

AU - Banka, Siddharth

AU - Alhaddad, Bader

AU - Asadollahi, Reza

AU - Becker, Jessica

AU - Bierhals, Tatjana

AU - Brown, Kathleen E

AU - Bruel, Ange-Line

AU - Brunet, Theresa

AU - Carneiro, Maryline

AU - Cremer, Kirsten

AU - Day, Robert

AU - Denommé-Pichon, Anne-Sophie

AU - Dyment, Dave A

AU - Engels, Hartmut

AU - Fisher, Rachel

AU - Goh, Elaine S

AU - Hajianpour, M J

AU - Haertel, Lucia Ribeiro Machado

AU - Hauer, Nadine

AU - Hempel, Maja

AU - Herget, Theresia

AU - Johannsen, Jessika

AU - Kraus, Cornelia

AU - Le Guyader, Gwenaël

AU - Lesca, Gaetan

AU - Mau-Them, Frédéric Tran

AU - McDermott, John Henry

AU - McWalter, Kirsty

AU - Meyer, Pierre

AU - Õunap, Katrin

AU - Popp, Bernt

AU - Reimand, Tiia

AU - Riedhammer, Korbinian M

AU - Russo, Martina

AU - Sadleir, Lynette G

AU - Saenz, Margarita

AU - Schiff, Manuel

AU - Schuler, Elisabeth

AU - Syrbe, Steffen

AU - Van der Ven, Amelie Theresa

AU - Verloes, Alain

AU - Willems, Marjolaine

AU - Zweier, Christiane

AU - Steindl, Katharina

AU - Zweier, Markus

AU - Rauch, Anita

PY - 2021/3

Y1 - 2021/3

N2 - 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.

AB - 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.

U2 - 10.1038/s41436-020-01011-x

DO - 10.1038/s41436-020-01011-x

M3 - SCORING: Journal article

C2 - 33149277

VL - 23

SP - 543

EP - 554

JO - GENET MED

JF - GENET MED

SN - 1098-3600

IS - 3

ER -