Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Am J Hum Genet. 2019 Sep 5;105(3):606-615. doi: 10.1016/j.ajhg.2019.07.019. Epub 2019 Aug 29.
Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.
小脑畸形是多种常伴有发育障碍的先天性异常。虽然已描述了遗传和产前非遗传原因，但尚未进行系统分析。在此，我们报告了 Dandy-Walker 畸形（DWM）和小脑发育不良（CBLH）的大规模外显子组测序研究。我们对 100 个 DWM 或 CBLH 家系的 282 名个体进行了外显子组测序，在 100 个家系中建立了 36 个分子诊断，CBLH 的阳性率（51%）明显高于 DWM（16%）。41 个变异影响 27 个神经发育障碍相关基因，表明 CBLH 和 DWM 通常是单基因神经发育障碍的特征。虽然在超过 1 个个体中仅鉴定出 7 个单基因病因（19%），但对 131 个额外个体的神经影像学回顾确认了 27 种遗传疾病中的 23 种（85%）存在小脑异常。在没有遗传诊断的个体中，经常发现产前危险因素（64 个个体中的 30 个[47%]）。产前人类小脑组织的单细胞 RNA 测序显示，神经元和血管细胞类型存在基因富集；这表明血管生成缺陷可能破坏小脑发育。此外，PDGFRB 中的新生功能获得性变异，一种对血管祖细胞信号传导至关重要的酪氨酸激酶受体，与 CBLH 相关，这一发现将遗传和非遗传病因联系起来。我们的研究结果表明，遗传缺陷影响特定的小脑细胞类型，并暗示异常血管发育是小脑畸形的一种机制。我们还在存在小脑异常的个体中证实了非遗传产前因素的主要贡献，这大大影响了诊断评估以及对复发风险和预后的咨询。
