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

TitleSpatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures.
Publication TypeJournal Article
Year of Publication2019
AuthorsZweier, M, Begemann, A, McWalter, K, Cho, MT, Abela, L, Banka, S, Behring, B, Berger, A, Brown, CW, Carneiro, M, Chen, J, Cooper, GM, Finnila, CR, Sacoto, MJGuillen, Henderson, A, Hüffmeier, U, Joset, P, Kerr, B, Lesca, G, Leszinski, GS, McDermott, JHenry, Meltzer, MR, Monaghan, KG, Mostafavi, R, Õunap, K, Plecko, B, Powis, Z, Purcarin, G, Reimand, T, Riedhammer, KM, Schreiber, JM, Sirsi, D, Wierenga, KJ, Wojcik, MH, Papuc, SM, Steindl, K, Sticht, H, Rauch, A
Corporate AuthorsDeciphering Developmental Disorders (DDD) Study
JournalEur J Hum Genet
Date Published2019 May

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.

Alternate JournalEur. J. Hum. Genet.
PubMed ID30664714
PubMed Central IDPMC6461771
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
radiz / / Universität Zürich (University of Zurich) /
320030_179547 / / Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation) /
/ / Wellcome Trust / United Kingdom
T32 GM007748 / GM / NIGMS NIH HHS / United States