Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, Antwerp, Belgium.
Department of Biomedical Sciences, University of Antwerp - CDE, Universiteitsplein 1, BE-2610, Antwerp, Belgium.
Genome Med. 2021 Apr 14;13(1):59. doi: 10.1186/s13073-021-00878-y.
Knowledge of the molecular etiology of neurodegenerative brain diseases (NBD) has substantially increased over the past three decades. Early genetic studies of NBD families identified rare and highly penetrant deleterious mutations in causal genes that segregate with disease. Large genome-wide association studies uncovered common genetic variants that influenced disease risk. Major developments in next-generation sequencing (NGS) technologies accelerated gene discoveries at an unprecedented rate and revealed novel pathways underlying NBD pathogenesis. NGS technology exposed large numbers of rare genetic variants of uncertain significance (VUS) in coding regions, highlighting the genetic complexity of NBD. Since experimental studies of these coding rare VUS are largely lacking, the potential contributions of VUS to NBD etiology remain unknown. In this review, we summarize novel findings in NBD genetic etiology driven by NGS and the impact of rare VUS on NBD etiology. We consider different mechanisms by which rare VUS can act and influence NBD pathophysiology and discuss why a better understanding of rare VUS is instrumental for deriving novel insights into the molecular complexity and heterogeneity of NBD. New knowledge might open avenues for effective personalized therapies.
在过去的三十年中，人们对神经退行性脑疾病（NBD）的分子病因学的认识有了很大的提高。对 NBD 家族的早期遗传研究发现了与疾病共分离的、罕见且具有高度外显率的有害突变。全基因组关联研究发现了影响疾病风险的常见遗传变异。下一代测序（NGS）技术的重大发展以前所未有的速度加速了基因的发现，并揭示了 NBD 发病机制的新途径。NGS 技术揭示了编码区大量不确定意义的罕见遗传变异（VUS），突出了 NBD 的遗传复杂性。由于这些编码罕见 VUS 的实验研究在很大程度上仍然缺乏，因此 VUS 对 NBD 病因学的潜在贡献仍然未知。在这篇综述中，我们总结了 NGS 驱动的 NBD 遗传病因学的新发现，以及罕见 VUS 对 NBD 病因学的影响。我们考虑了罕见 VUS 可以发挥作用并影响 NBD 病理生理学的不同机制，并讨论了为什么更好地理解罕见 VUS 对于深入了解 NBD 的分子复杂性和异质性至关重要。新知识可能为有效的个性化治疗开辟道路。
