Corbett, Mark A.van Eyk, Clare L.Webber, Dani L.Bent, Stephen J.Newman, MorganHarper, KellyBerry, Jesia G.Azmanov, Dimitar N.Woodward, Karen J.Gardner, Alison E.Slee, JenniePérez Jurado, Luis AlbertoMacLennan, Alastair H.Gecz, Jozef2019-06-202019-06-202018Corbett MA, van Eyk CL, Webber DL, Bent SJ, Newman M, Harper K et al. Pathogenic copy number variants that affect gene expression contribute to genomic burden in cerebral palsy. NPJ Genom Med. 2018 Dec 14;3:33. DOI: 10.1038/s41525-018-0073-42056-7944http://hdl.handle.net/10230/41847Cerebral palsy (CP) is the most frequent movement disorder of childhood affecting 1 in 500 live births in developed countries. We previously identified likely pathogenic de novo or inherited single nucleotide variants (SNV) in 14% (14/98) of trios by exome sequencing and a further 5% (9/182) from evidence of outlier gene expression using RNA sequencing. Here, we detected copy number variants (CNV) from exomes of 186 unrelated individuals with CP (including our original 98 trios) using the CoNIFER algorithm. CNV were validated with Illumina 850 K SNP arrays and compared with RNA-Seq outlier gene expression analysis from lymphoblastoid cell lines (LCL). Gene expression was highly correlated with gene dosage effect. We resolved an additional 3.7% (7/186) of this cohort with pathogenic or likely pathogenic CNV while a further 7.7% (14/186) had CNV of uncertain significance. We identified recurrent genomic rearrangements previously associated with CP due to 2p25.3 deletion, 22q11.2 deletions and duplications and Xp monosomy. We also discovered a deletion of a single gene, PDCD6IP, and performed additional zebrafish model studies to support its single allele loss in CP aetiology. Combined SNV and CNV analysis revealed pathogenic and likely pathogenic variants in 22.7% of unselected individuals with CP.application/pdfengCopyright © The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Cervell -- Malalties -- Aspectes genèticsinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41525-018-0073-4info:eu-repo/semantics/openAccess