Resolving Complex Structural Variants in Undiagnosed Rare Movement Disorders via Multimodal Genomics and Multi-omics.
TL;DR
The findings underscore the diagnostic potential of integrated long-read and multi-omic approaches for complex structural variant characterization, while illustrating persistent limitations of automated pipelines and highlighting unpredictable relationships between genomic, transcriptomic, and proteomic findings.
Abstract
Background
Long-read sequencing and multi-omic analytical frameworks are increasingly being adopted in rare disease diagnostics. However, clinical workflows comprehensively integrating these methodologies remain uncommon.
Objective
This study aimed to assess the potential and limitations of integrating long-read genomic, transcriptomic, and proteomic analyses to characterize complex structural variants.
Methods
Two unrelated patients presenting with dystonia and comorbid neurological features underwent nanopore-based long-read DNA sequencing. In patient 1, complementary transcriptomic and proteomic analyses were performed.
Results
The workflow enabled the identification and characterization of two pathogenic complex structural variants: a homozygous AluY-mediated inversion disrupting PANK2, underlying neurodegeneration with brain iron accumulation (patient 1), and a heterozygous de novo 16p13.3 duplication-triplication event associated with an atypical dystonia-parkinsonism phenotype (patient 2).
Conclusions
Our findings underscore the diagnostic potential of integrated long-read and multi-omic approaches for complex structural variant characterization, while illustrating persistent limitations of automated pipelines and highlighting unpredictable relationships between genomic, transcriptomic, and proteomic findings. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.