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

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. Neurodevelopment: Copy number variants underlie cases of cerebral palsy At least 23% of cerebral palsy has a genetic basis, due to either point mutations or large chromosomal abnormalities. Using sequence data from 186 unrelated patients, a team led by Mark Corbett from the University of Adelaide, Australia, searched the protein-coding portion of the genome for disease-causing duplications or deletions, types of mutations collectively known as copy number variants, or CNVs. The researchers singled out 7 pathogenic CNVs that they corroborated through microarray profiling and gene expression analyses. Using a zebrafish model, the researchers identified a new gene “PDCD6IP” associated with cerebral palsy and epilepsy. They also flagged another 14 CNVs that were likely pathogenic but could not be confirmed. The work highlights the need for comprehensive genetic testing to be considered early in the diagnosis of cerebral palsy.