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Eur J Hum Genet. 2019 May;27(5):747-759. doi: 10.1038/s41431-018-0331-z. Epub 2019 Jan 21.

Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures.

Author information

1
Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
2
Radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Zurich, Switzerland.
3
GeneDx, Gaithersburg, MD, USA.
4
Division of Child Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
5
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
6
Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
7
Department of Pediatrics, Klinikum Nuremberg, Nuremberg, Germany.
8
Department of Neuropediatrics, Klinikum Weiden, Kliniken Nordoberpfalz AG, Weiden, Germany.
9
Le Bonheur Children's Hospital, Memphis, TN, USA.
10
Division of Medical Genetics, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.
11
Department of Neuropediatrics, Lyon University Hospital, Lyon, France.
12
University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
13
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
14
Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 3BZ, UK.
15
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
16
Department of Medical Genetics, Lyon University Hospital, Lyon, France.
17
CNRS UMR 5292, INSERM U1028, Claude Bernard Lyon 1 University, Lyon, France.
18
Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
19
Children's National Health System, Washington, DC, USA.
20
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
21
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
22
Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria.
23
Ambry Genetics, Aliso Viejo, CA, USA.
24
Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
25
Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
26
Department of Pediatrics, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
27
Department of Clinical Genomics, Mayo Clinic Florida, Jacksonville, FL, USA.
28
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
29
Victor Babes National Institute of Pathology, Bucharest, Romania.
30
Institute of Biochemistry, Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
31
Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland. anita.rauch@medgen.uzh.ch.
32
Radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Zurich, Switzerland. anita.rauch@medgen.uzh.ch.
33
Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. anita.rauch@medgen.uzh.ch.
34
Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland. anita.rauch@medgen.uzh.ch.

Abstract

CYFIP2, encoding the evolutionary highly conserved cytoplasmic FMRP interacting protein 2, has previously been proposed as a candidate gene for intellectual disability and autism because of its important role linking FMRP-dependent transcription regulation and actin polymerization via the WAVE regulatory complex (WRC). Recently, de novo variants affecting the amino acid p.Arg87 of CYFIP2 were reported in four individuals with epileptic encephalopathy. We here report 12 independent patients harboring a variety of de novo variants in CYFIP2 broadening the molecular and clinical spectrum of a novel CYFIP2-related neurodevelopmental disorder. Using trio whole-exome or -genome sequencing, we identified 12 independent patients carrying a total of eight distinct de novo variants in CYFIP2 with a shared phenotype of intellectual disability, seizures, and muscular hypotonia. We detected seven different missense variants, of which two occurred recurrently (p.(Arg87Cys) and p.(Ile664Met)), and a splice donor variant in the last intron for which we showed exon skipping in the transcript. The latter is expected to escape nonsense-mediated mRNA decay resulting in a truncated protein. Despite the large spacing in the primary structure, the variants spatially cluster in the tertiary structure and are all predicted to weaken the interaction with WAVE1 or NCKAP1 of the actin polymerization regulating WRC-complex. Preliminary genotype-phenotype correlation indicates a profound phenotype in p.Arg87 substitutions and a more variable phenotype in other alterations. This study evidenced a variety of de novo variants in CYFIP2 as a novel cause of mostly severe intellectual disability with seizures and muscular hypotonia.

PMID:
30664714
PMCID:
PMC6461771
[Available on 2020-05-01]
DOI:
10.1038/s41431-018-0331-z

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