A growing body of evidence points to a considerable and heterogeneous genetic aetiology of cerebral palsy (CP). To identify recurrently variant CP genes, we designed a custom gene panel of 112 candidate genes. We tested 366 clinically unselected singleton cases with CP, including 271 cases not previously examined using next-generation sequencing technologies. Overall, 5.2% of the naïve cases (14/271) harboured a genetic variant of clinical significance in a known disease gene, with a further 4.8% of individuals (13/271) having a variant in a candidate gene classified as intolerant to variation. In the aggregate cohort of individuals from this study and our previous genomic investigations, six recurrently hit genes contributed at least 4% of disease burden to CP: COL4A1, TUBA1A, AGAP1, L1CAM, MAOB and KIF1A. Significance of Rare VAriants (SORVA) burden analysis identified four genes with a genome-wide significant burden of variants, AGAP1, ERLIN1, ZDHHC9 and PROC, of which we functionally assessed AGAP1 using a zebrafish model. Our investigations reinforce that CP is a heterogeneous neurodevelopmental disorder with known as well as novel genetic determinants.

越来越多的证据表明，大脑性麻痹（CP）的遗传病因很多。为了识别循环变异的CP基因，我们设计了一个由112个候选基因组成的自定义基因组。我们测试了366例未选择CP的临床未选病例，包括271例以前未使用下一代测序技术进行检查的病例。总体而言，有5.2％的单纯病例（14/271）在已知的疾病基因中具有临床意义的遗传变异，另外还有4.8％的个体（13/271）在候选基因中具有变异，该变异被归类为不耐变异。在这项研究和我们先前的基因组研究的总体人群中，六个反复发作的基因至少对CP造成了4％的疾病负担：COL4A1，TUBA1A，AGAP1，L1CAM，MAOB和KIF1A。稀有变异（SORVA）负荷分析的意义确定了四个具有全基因组显着负荷变体的基因，即AGAP1，ERLIN1，ZDHHC9和PROC，我们使用斑马鱼模型对其功能进行了评估。我们的研究进一步证实，CP是一种异质性神经发育障碍，具有已知的遗传决定因素和新颖的遗传决定因素。