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.

脑性瘫痪（CP）是儿童期最常见的运动障碍，在发达国家中影响每500例活产中的1例。我们以前通过外显子组测序在14％（14/98）的三重奏中发现了可能的致病性从头或遗传的单核苷酸变体（SNV），而使用RNA测序从异常基因表达的证据中又发现了5％（9/182）。在这里，我们使用CoNIFER算法从186名与CP无关的个体（包括我们最初的98位三重奏）的外显子组中检测到拷贝数变异（CNV）。用Illumina 850 K SNP阵列验证CNV，并与来自淋巴母细胞系（LCL）的RNA-Seq离群基因表达分析进行比较。基因表达与基因剂量效应高度相关。我们用致病性或可能致病性CNV解决了这个队列中的另外3.7％（7/186），而另外7个则解决了。7％（14/186）的CNV意义不确定。我们确定了先前由于2p25.3缺失，22q11.2缺失和重复以及Xp单体性而与CP相关的复发性基因组重排。我们还发现了一个基因的缺失，PDCD6IP，并进行了其他斑马鱼模型研究，以支持其在CP病因学中的单等位基因丢失。SNV和CNV联合分析显示，未选择的CP个体中有22.7％的病原体和可能的病原体变异。