Department of Pediatrics, Washington University, St. Louis, MO 63110, USA.
Department of Neurosurgery, Washington University, St. Louis, MO 63110, USA.
Am J Hum Genet. 2021 Jan 7;108(1):100-114. doi: 10.1016/j.ajhg.2020.12.001. Epub 2020 Dec 21.
Chiari I malformation (CM1), the displacement of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions. Individuals with CM1 can present with neurological symptoms, including severe headaches and sensory or motor deficits, often as a consequence of brainstem compression or syringomyelia (SM). We conducted whole-exome sequencing (WES) on 668 CM1 probands and 232 family members and performed gene-burden and de novo enrichment analyses. A significant enrichment of rare and de novo non-synonymous variants in chromodomain (CHD) genes was observed among individuals with CM1 (combined p = 2.4 × 10), including 3 de novo loss-of-function variants in CHD8 (LOF enrichment p = 1.9 × 10) and a significant burden of rare transmitted variants in CHD3 (p = 1.8 × 10). Overall, individuals with CM1 were found to have significantly increased head circumference (p = 2.6 × 10), with many harboring CHD rare variants having macrocephaly. Finally, haploinsufficiency for chd8 in zebrafish led to macrocephaly and posterior hindbrain displacement reminiscent of CM1. These results implicate chromodomain genes and excessive brain growth in CM1 pathogenesis.
Chiari I 畸形（CM1）是小脑通过枕骨大孔进入椎管的一种常见儿科神经疾病。CM1 患者可能出现神经症状，包括严重头痛以及感觉或运动功能障碍，这通常是由于脑干受压或脊髓空洞症（SM）所致。我们对 668 名 CM1 先证者和 232 名家族成员进行了全外显子组测序（WES），并进行了基因负担和新生变异的富集分析。CM1 患者的 chromodomain（CHD）基因中存在显著富集的罕见和新生非同义变异（合并 p = 2.4×10），包括 3 个 CHD8 的新生无功能变异（LOF 富集 p = 1.9×10）和 CHD3 中罕见传递变异的显著负担（p = 1.8×10）。总体而言，CM1 患者的头围明显增加（p = 2.6×10），许多患者携带 CHD 罕见变异，表现为大头畸形。最后，斑马鱼中 chd8 的杂合不足导致大头畸形和后脑后移位，类似于 CM1。这些结果表明 chromodomain 基因和过度的大脑生长在 CM1 发病机制中起作用。
