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Pathogenic copy number variants that affect gene expression contribute to genomic burden in cerebral palsy

2018; Nature Portfolio; Volume: 3; Issue: 1 Linguagem: Inglês

10.1038/s41525-018-0073-4

2056-7944

Mark Corbett, Clare L. van Eyk, Dani L. Webber, Stephen J. Bent, Morgan Newman, Kelly Harper, Jesia G. Berry, Dimitar N. Azmanov, Karen Woodward, Alison Gardner, Jennie Slee, Luis A. Pérez‐Jurado, Alastair H. MacLennan, Jozef Gécz,

Genomics and Rare Diseases

Cerebral 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,