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

  • 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


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.

Bibliografische Daten

StatusVeröffentlicht - 03.2021
PubMed 33149277