@article {594,
	title = {Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures.},
	journal = {Eur J Hum Genet},
	volume = {27},
	year = {2019},
	month = {2019 May},
	pages = {747-759},
	abstract = {<p>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.</p>},
	issn = {1476-5438},
	doi = {10.1038/s41431-018-0331-z},
	author = {Zweier, Markus and Begemann, Ana{\"\i}s and McWalter, Kirsty and Cho, Megan T and Abela, Lucia and Banka, Siddharth and Behring, Bettina and Berger, Andrea and Brown, Chester W and Carneiro, Maryline and Chen, Jiani and Cooper, Gregory M and Finnila, Candice R and Guillen Sacoto, Maria J and Henderson, Alex and H{\"u}ffmeier, Ulrike and Joset, Pascal and Kerr, Bronwyn and Lesca, Gaetan and Leszinski, Gloria S and McDermott, John Henry and Meltzer, Meira R and Monaghan, Kristin G and Mostafavi, Roya and {\~O}unap, Katrin and Plecko, Barbara and Powis, Z{\"o}e and Purcarin, Gabriela and Reimand, Tiia and Riedhammer, Korbinian M and Schreiber, John M and Sirsi, Deepa and Wierenga, Klaas J and Wojcik, Monica H and Papuc, Sorina M and Steindl, Katharina and Sticht, Heinrich and Rauch, Anita}
}
