PUBLICATION

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

Authors
Corbett, M.A., van Eyk, C.L., Webber, D.L., Bent, S.J., Newman, M., Harper, K., Berry, J.G., Azmanov, D.N., Woodward, K.J., Gardner, A.E., Slee, J., Pérez-Jurado, L.A., MacLennan, A.H., Gecz, J.
ID
ZDB-PUB-181220-7
Date
2018
Source
NPJ genomic medicine   3: 33 (Journal)
Registered Authors
Newman, Morgan
Keywords
none
MeSH Terms
none
PubMed
30564460 Full text @ NPJ Genom Med
Abstract
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, 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.
Errata / Notes
This article is corrected by ZDB-PUB-220906-158 .
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