Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Laboratory of Human Genetics and Genomics, Rockefeller University, New York, NY, USA.
Nat Genet. 2020 Oct;52(10):1046-1056. doi: 10.1038/s41588-020-0695-1. Epub 2020 Sep 28.
In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
除了常见的环境因素外，基因组因素也可能导致脑瘫。我们对 250 个亲子三核苷酸进行了全外显子组测序，观察到脑瘫病例中存在丰富的新生致病变异。八个基因有多个致病变异；其中两个（TUBA1A 和 CTNNB1）达到全基因组显著水平。我们确定了两种新的单基因病因，FBXO31 和 RHOB，并表明 RHOB 突变增强了活性状态 Rho 效应物结合，而 FBXO31 突变降低了周期蛋白 D 水平。候选脑瘫风险基因与神经发育障碍基因重叠。网络分析确定 Rho GTPase、细胞外基质、焦点黏附和细胞骨架途径富集。在富集途径中的脑瘫风险基因在果蝇反向遗传学筛选中显示出调节神经运动功能。我们估计，14%的病例可能归因于新生或隐性变异过多。这些发现为脑瘫中早期神经元连接的遗传介导失调提供了证据。
