The ability to sequence entire exomes and genomes has revolutionized molecular testing in rare movement disorders, and genomic sequencing is becoming an integral part of routine diagnostic workflows for these heterogeneous conditions. However, interpretation of the extensive genomic variant information that is being generated presents substantial challenges. In this Perspective, we outline multidimensional strategies for genetic diagnosis in patients with rare movement disorders. We examine bioinformatics tools and computational metrics that have been developed to facilitate accurate prioritization of disease-causing variants. Additionally, we highlight community-driven data-sharing and case-matchmaking platforms, which are designed to foster the discovery of new genotype–phenotype relationships. Finally, we consider how multiomic data integration might optimize diagnostic success by combining genomic, epigenetic, transcriptomic and/or proteomic profiling to enable a more holistic evaluation of variant effects. Together, the approaches that we discuss offer pathways to the improved understanding of the genetic basis of rare movement disorders.

对整个外显子组和基因组进行测序的能力彻底改变了罕见运动障碍的分子测试，并且基因组测序正在成为这些异质性疾病的常规诊断工作流程中不可或缺的一部分。然而，对正在生成的广泛基因组变异信息的解释提出了巨大的挑战。在本视角中，我们概述了罕见运动障碍患者基因诊断的多维策略。我们检查了为促进准确确定致病变异的优先级而开发的生物信息学工具和计算指标。此外，我们还强调社区驱动的数据共享和案例匹配平台，这些平台旨在促进新基因型-表型关系的发现。最后，我们考虑多组学数据集成如何通过结合基因组、表观遗传学、转录组和/或蛋白质组分析来优化诊断成功，从而能够更全面地评估变异效应。总之，我们讨论的方法为加深对罕见运动障碍的遗传基础的理解提供了途径。