Objective: To determine the proportion of other neurological disorders mimicking essential tremor (ET) and investigate the contribution of structural variants (SVs) to ET pathogenesis.

Background: ET is one of the most common movement disorders, with high heritability suggesting a significant genetic component. While previous genetic studies have primarily focused on single-nucleotide variants, SVs remain largely uninvestigated despite accounting for substantial genetic variation.

Method: We performed whole genome sequencing on 204 clinically diagnosed ET patients. Potential causative variants for tremor-related disorders were filtered and validated. A custom SV discovery pipeline combining six computational tools was employed, with validation using long-read sequencing. Novel SVs were annotated and subjected to pathway analysis (Figure 1).

Results: Molecular diagnosis identified 16 patients (7.77%) with other neurological disorders mimicking ET (Table 1). The proportion of gene-positive patients was significantly higher in the ET plus group compared to pure ET (11/30 vs. 5/174, p = 1.22e-06). Using our SV discovery pipeline (91% accuracy), we detected an average of 3481 SVs per patient and identified 31226 novel SVs in real ET patients (Figure 2). Functional enrichment analysis of genes with exonic SVs revealed several biological processes and pathways potentially involved in ET pathogenesis, including the biological processes of axonogenesis and neuron projection development, along with serotonergic and GABAergic synapse pathways (Figure 3).

Conclusion: Our findings highlight the importance of molecular diagnosis in ET patients, particularly those with subtle additional neurological features. The identification of novel SVs affecting axonogenesis and neurotransmitter pathways provides fresh insights into the biological mechanisms underlying ET, with serotonergic and GABAergic pathways emerging as potential therapeutic targets.

Figure 1. Workflow for this study.

Figure 2. SV profiles in ET patients

Figure 3. Novel SV distribution and function in ET

Table1.Clinical and genetic features of ET mimics

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-architecture-of-essential-tremor-clinical-misdiagnosis-and-structural-variant-contributions-to-neurobiological-pathways/