Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
Neuron. 2018 Jul 25;99(2):302-314.e4. doi: 10.1016/j.neuron.2018.06.019. Epub 2018 Jul 5.
Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10), SMARCC1 (p = 8.15 × 10), and PTCH1 (p = 1.06 × 10). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.
先天性脑积水（CH）的特征是大脑脑室明显扩大，被认为是由于脑脊液（CSF）稳态失衡引起的，需要终身进行手术性 CSF 分流，这会带来相当大的发病率。CH 的发病机制尚不清楚。对 125 个 CH 三核苷酸重复序列和 52 个额外的先证者的外显子组测序发现，有三个基因存在显著的罕见有害新生或传递突变负担：TRIM71（p = 2.15×10）、SMARCC1（p = 8.15×10）和 PTCH1（p = 1.06×10）。此外，在 SHH 基因座上还鉴定出两个新生的重复，编码 PTCH1 配体（p = 1.2×10）。这些先证者加起来约占研究病例的 10%。引人注目的是，所有四个基因对于神经管发育都是必需的，并且调节脑室区神经干细胞命运。这些结果表明，一部分 CH 患者的发病机制是神经发生受损（而不是 CSF 主动积聚），这具有潜在的诊断、预后和治疗意义。
