Cerebral palsy (CP) is the most common motor disability in children. To ascertain the role of major genetic variants in the etiology of CP, we conducted exome sequencing on a large-scale cohort with clinical manifestations of CP. The study cohort comprised 505 girls and 1,073 boys. Utilizing the current gold standard in genetic diagnostics, 387 of these 1,578 children (24.5%) received genetic diagnoses. We identified 412 pathogenic and likely pathogenic (P/LP) variants across 219 genes associated with neurodevelopmental disorders, and 59 P/LP copy number variants. The genetic diagnostic rate of children with CP labeled at birth with perinatal asphyxia was higher than the rate in children without asphyxia (P = 0.0033). Also, 33 children with CP manifestations (8.5%, 33 of 387) had findings that were clinically actionable. These results highlight the need for early genetic testing in children with CP, especially those with risk factors like perinatal asphyxia, to enable evidence-based medical decision-making.

脑瘫（CP）是儿童最常见的运动障碍。为了确定主要遗传变异在 CP 病因学中的作用，我们对具有 CP 临床表现的大规模队列进行了外显子组测序。该研究队列由 505 名女孩和 1,073 名男孩组成。利用当前基因诊断的黄金标准，这 1,578 名儿童中的 387 名 (24.5%) 接受了基因诊断。我们在与神经发育障碍相关的 219 个基因中鉴定出了 412 个致病性和可能致病性 (P/LP) 变异，以及 59 个 P/LP 拷贝数变异。出生时标记为CP并伴有围产期窒息的儿童的基因诊断率高于未发生窒息的儿童（P  =0.0033）。此外，33 名有 CP 表现的儿童（8.5%，387 名儿童中的 33 名）的发现具有临床可行性。这些结果强调了对脑瘫儿童进行早期基因检测的必要性，尤其是那些具有围产期窒息等危险因素的儿童，以便做出基于证据的医疗决策。