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.
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The authors are grateful to the participating individuals and their families. We thank Christian Söldner and Michel Albert for their support with preparation of figures. AR, LA, and BP were supported by the University of Zurich research priority program radiz (rare disease initiative Zurich). AR was further supported by the Swiss National Science Foundation (SNSF) grant 320030_179547. The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. Support also provided by NIH T32 GM007748 (M.H.W.). The DDD Study (Cambridge South REC approval 10/H0305/83 and the Republic of Ireland REC GEN/284/12) presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome. The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome or the Department of Health. AB was supported by the Forschungskredit UZH and the Josef Huwyler Ruth Bernet-Engeli Stiftung.
Conflict of interest
Kirsty McWalter, Megan T. Cho, Maria J. Guillen Sacoto, and Kristin G. Monaghan are employees of GeneDx, Inc., a wholly owned subsidiary of OPKO Health, Inc. The remaining authors declare that they have no conflict of interest.
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