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

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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
Genetics in Medicine ( IF 8.8 ) Pub Date : 2020-11-05 , DOI: 10.1038/s41436-020-01011-x
Anaïs Begemann ₁ , Heinrich Sticht ₂ , Amber Begtrup ₃ , Antonio Vitobello _{4,

5} , Laurence Faivre _{4,

6} , Siddharth Banka _{7,

8} , Bader Alhaddad ₉ , Reza Asadollahi ₁ , Jessica Becker ₁₀ , Tatjana Bierhals ₁₁ , Kathleen E Brown ₁₂ , Ange-Line Bruel _{4,

5} , Theresa Brunet ₉ , Maryline Carneiro ₁₃ , Kirsten Cremer ₁₀ , Robert Day ₁₄ , Anne-Sophie Denommé-Pichon _{4,

5} , Dave A Dyment _{15,

16} , Hartmut Engels ₁₀ , Rachel Fisher ₁₇ , Elaine S Goh ₁₈ , M J Hajianpour ₁₉ , Lucia Ribeiro Machado Haertel ₂₀ , Nadine Hauer ₂₁ , Maja Hempel ₁₁ , Theresia Herget ₁₁ , Jessika Johannsen ₂₂ , Cornelia Kraus ₂₁ , Gwenaël Le Guyader ₂₃ , Gaetan Lesca _{24,

25} , Frédéric Tran Mau-Them _{4,

5} , John Henry McDermott _{7,

8} , Kirsty McWalter ₃ , Pierre Meyer ₂₆ , Katrin Õunap _{27,

28} , Bernt Popp _{21,

29} , Tiia Reimand _{27,

28,

30} , Korbinian M Riedhammer _{9,

31} , Martina Russo ₁ , Lynette G Sadleir ₃₂ , Margarita Saenz ₁₂ , Manuel Schiff _{33,

34} , Elisabeth Schuler ₃₅ , Steffen Syrbe ₃₅ , Amelie Theresa Van der Ven ₁₁ , Alain Verloes _{36,

37} , Marjolaine Willems ₃₈ , Christiane Zweier ₂₁ , Katharina Steindl ₁ , Markus Zweier ₁ , Anita Rauch _{1,

39,

40}

Affiliation

Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
Institute of Biochemistry, Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
GeneDx, Gaithersburg, MD, USA.
INSERM UMR 1231 Equipe GAD, Université de Bourgogne, Dijon, France.
Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
Centre de Référence Maladies Rares «Anomalies du développement et syndromes malformatifs», centre de génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
Institute of Human Genetics, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO, USA.
Department of Neuropediatrics, Lyon University Hospital, Lyon, France.
Cancer Research Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, University of Michigan, Arbor, MI, USA.
Laboratory Medicine and Genetics and Institute for Better Health, Trillium Health Partners, Mississauga, ON, Canada.
Department of Pediatrics, Medical Genetics, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
Hospital Santa Catarina de Blumenau, Blumenau, Brazil.
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Department of Pediatrics, University medical center Hamburg-Eppendorf, Hamburg, Germany.
CHU de Poitiers, Poitiers, France.
Department of Medical Genetics, Lyon University Hospital, Lyon, France.
CNRS UMR 5292, INSERM U1028, Claude Bernard Lyon 1 University, Lyon, France.
Department of Pediatric Neurology, CHU Montpellier, PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
Reference center for Inborn Errors of Metabolism, Necker University Hospital, APHP, Université de Paris, Faculté de médecine Paris-Descartes, Paris, France.
Institut Imagine, Inserm UMRS_1163, Paris, France.
Department of Pediatrics, University Hospital Heidelberg, Heidelberg, Germany.
UMR1141 INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Genetics Department, AP-HP, Robert-Debré University Hospital, Paris, France.
Département Génétique Médicale, CHRU de Montpellier, Montpellier, France.
Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.

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.

中文翻译：

对新型 CYFIP2 相关神经发育障碍和 WRC 介导的肌动蛋白动力学损害的临床和分子谱的新见解

目的

细胞质 FMRP 相互作用蛋白 2 ( CYFIP2 ) 基因中的一些从头错义变体最近被描述为 18 人严重智力残疾、癫痫发作和肌张力减退的新原因，其中大多数是 p.Arg87 取代。

方法

我们收集了来自 19 名新发现的和所有 18 名先前发表的具有CYFIP2变体的个体的数据。通过对六种患者成纤维细胞系中 WAVE 调节复合物 (WRC) 介导的肌动蛋白聚合的结构建模和研究，我们评估了CYFIP2变体对 WRC 的影响。

结果

19 人中有 16 人携带两种先前描述的和 11 种新的（可能的）疾病相关的错义变体。我们将 p.Asp724 报告为第二个突变热点（4/19 例）。基因型 - 表型相关性证实了 p.Arg87 患者的一致严重表型，但 p.Asp724 和其他替代的表型变化更大。三名具有较轻表型的个体携带假定的功能丧失变异体，其致病性仍不清楚。结构建模预测错义变异会干扰 WRC 内的相互作用或损害 CYFIP2 的稳定性。与其在 WRC 介导的肌动蛋白聚合中的作用一致，我们证实了患者成纤维细胞中肌动蛋白细胞骨架的异常调节。