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E. Graf

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Open access Jul 2026

Resolving Complex Structural Variants in Undiagnosed Rare Movement Disorders via Multimodal Genomics and Multi-omics.

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.

Ugo Sorrentino, M. Brugger, A. Saparov et al. · 0 citations
Case report Open access Jan 2026

Splice effect of a synonymous variant in AP4B1: multiomics approach establishes the diagnosis in two sisters with spastic paraplegia

The identification of biallelic causative variants in AP4B1 established the diagnosis of monogenic “Spastic paraplegia 47, autosomal recessive” while the initial hypothesis of digenic inheritance was refuted.

Susann Badmann, A. Saparov, P. Harrer et al. · 0 citations
Open access Aug 2026

Rare genetic variation in adults with surgically treated temporal lobe epilepsy: An exome sequencing study

Abstract Objective To determine the frequency of monogenic variants and pathogenic copy number variants (CNVs) in adults with surgically treated temporal lobe epilepsy (TLE). Methods We performed exome sequencing (ES), including CNV analysis, in 45 adults with TLE who had previously undergone epilepsy surgery. A diagnostic exome‐wide analysis was conducted to identify (likely) pathogenic variants related to epilepsy. In an exploratory approach, we screened a curated list of 45 common epilepsy genes for rare deleterious variants based on AlphaMissense and REVEL in silico predictions. Results No highly penetrant monogenic variants were identified in this cohort. Pathogenic CNVs were detected in two individuals, corresponding to 4.4% of the cohort: a 16p13.11 deletion in a surgery responder and a 22q11.2 duplication in a surgery nonresponder. Both CNVs are characterized by reduced penetrance and broad phenotypic variability. Moreover, we identified two predicted deleterious missense variants in the epilepsy‐associated genes KCNT1 and SLC2A1, both of which were detected in surgery nonresponders. In silico analyses, including structural evidence, suggested a potential impact on protein function; however, their clinical significance remains uncertain. Significance Monogenic causes are exceedingly rare in adults with surgically treated TLE, whereas CNVs may contribute to disease susceptibility in a small subset of patients. Our findings are consistent with previous reports indicating a low diagnostic yield of presurgical genetic testing and further support a predominantly polygenic architecture of TLE. Plain Language Summary Temporal lobe epilepsy (TLE) is a common type of epilepsy in adults, and some patients undergo surgery when medications fail. It is unclear whether genetic testing can help predict surgical success. In this study, we used comprehensive genetic testing in 45 adult TLE patients who had undergone epilepsy surgery. We did not find single‐gene causes of epilepsy. Two patients had structural genetic changes, which increase epilepsy risk but show variable effects. We also identified a few rare variants in epilepsy‐related genes, but their clinical relevance remains uncertain. Overall, our results suggest that single‐gene causes are rare in adults with TLE. Genetic testing may therefore have a low diagnostic rate in this population.

Antonia P. Pirker, Margot Ernst, Matias Wagner et al. · 0 citations