{"doi":"10.1002/mds.30267","title":"Screening of Hidden Pathogenic Structural Variants in <scp><i>PRKN</i></scp>","abstract":"PRKN is the most frequently implicated gene in early-onset Parkinson's disease (EOPD) and autosomal recessive Parkinson's disease (PD). The current standard practice for genetic testing combines short-read sequencing with multiplex ligation-dependent probe amplification (MLPA), which performs well in the majority of cases. However, conventional genetic screening methods sometimes miss pathogenic structural variants (SVs) in PRKN, but advancements in sequencing technologies, like long-read sequencing and optical genome mapping, have improved detection, as we reviewed recently.1 In our recent study, long-read sequencing has identified previously undetected pathogenic SVs in PRKN, revealing hidden variants in over 20% of Japanese EOPD cases.2 This study aimed to explore additional hidden PRKN pathogenic SVs across diverse cohorts from other ancestries. Sixteen PD samples were collected from the Paris Brain Institute (n = 12, “French Cohort”) and the University of Lübeck (n = 4, “German Cohort”) (Table S1). The diagnosis of PD was made in accordance with standard clinical criteria. Prior to this study, a variety of methods had been used to screen these patients for pathogenic variants, including the detection of single nucleotide variations (SNVs) by Sanger sequencing, short-read whole-exome sequencing, or short-read gene panel sequencing. SVs were assessed using MLPA, or digital droplet polymerase chain reaction (ddPCR). Oxford Nanopore Technologies (ONT) whole genome long-read sequencing was conducted in patients with only one identified PRKN variant. Based on ancestral analysis using GenoTools, 13 individuals were annotated as European, together with one each as Ashkenazi Jewish, Middle Eastern, and Complex Admixed History (Table S2).3 ONT-long-read sequencing successfully identified all pathogenic PRKN variants identified previously using other techniques, including six copy number variations (CNVs) and 10 SNVs (Table S3). No additional pathogenic variants were found in other PD-related genes. In the German cohort, a sample previously identified by MLPA as having an exon 4 deletion was further analyzed, revealing a combined exon 3–4 deletion together with an exon 3 duplication (Fig. 1). While MLPA correctly identified the exon 4 deletion, the loss of one exon 3 copy was perfectly offset by the gain of a duplicated exon 3 copy on the same rearranged chromosome. As a result, the total copy number count for exon 3 appeared normal, preventing these CNVs by MLPA. Overall, one of four patients in the German cohort was identified as a biallelic PRKN variant carrier (Lubeck-1), while no such cases were found in the French cohort (Table S3). In the 15 unresolved cases, nine showed age at onset younger than 40 years, presenting strong monogenic indications. Notably, we did not identify any pathogenic complex SVs, like inversion or SVs with multiple breakpoints in the PRKN gene. The age at onset was in the 20s for this male patient (Lubeck-1) with biallelic PRKN variants. The clinical presentation was typical for PRKN-PD, showing a good and sustained response to levodopa with relatively slow progression. The patient gradually developed wearing-off and dyskinesia over the disease course and underwent successful deep brain stimulation approximately 30 years after disease onset. Additionally, none of the promoter or intronic variants of PRKN were predicted to be causative or to affect splicing. Three of our prior studies reported similar overlapping duplications and deletions, highlighting a shared common challenge in genetic testing for EOPD.2, 4, 5 Despite the relatively small cohort size, this study demonstrates the utility of ONT-based long-read sequencing in an independent cohort. To more comprehensively test our overarching hypothesis, we are currently expanding our analysis to a larger and more ancestrally diverse cohort. For this purpose, we are employing adaptive sampling—a real-time, software-based enrichment strategy developed by","journal":"Movement Disorders","year":2025,"id":568885,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9519,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1222658,"name":"Guillaume Cogan","orcid":"0000-0003-3505-7114","position":1,"is_corresponding":false},{"id":295713,"name":"Christelle Tesson","orcid":"0000-0001-7589-3710","position":2,"is_corresponding":false},{"id":17420,"name":"Suzanne Lesage","orcid":"0000-0003-4158-2601","position":3,"is_corresponding":false},{"id":72366,"name":"Susen Schaake","orcid":"0009-0006-6021-3069","position":4,"is_corresponding":false},{"id":249052,"name":"Alexander Balck","orcid":"0000-0003-3967-0282","position":5,"is_corresponding":false},{"id":558553,"name":"Joanne Trinh","orcid":"0000-0001-9863-2070","position":6,"is_corresponding":false},{"id":17495,"name":"Katja Lohmann","orcid":"0000-0002-5121-1460","position":7,"is_corresponding":false},{"id":958501,"name":"Laksh Malik","orcid":"0000-0002-2498-146X","position":8,"is_corresponding":false},{"id":1017521,"name":"Breeana Baker","orcid":null,"position":9,"is_corresponding":false},{"id":1243573,"name":"Kimberly Paquette","orcid":"0000-0003-3989-4614","position":10,"is_corresponding":false},{"id":570985,"name":"Abraham Moller","orcid":"0000-0002-7324-8678","position":11,"is_corresponding":false},{"id":686940,"name":"Carolyn M. Sue","orcid":"0000-0003-1255-3617","position":12,"is_corresponding":false},{"id":17504,"name":"Manabu Funayama","orcid":"0000-0002-7412-3631","position":13,"is_corresponding":false},{"id":17418,"name":"Nobutaka Hattori","orcid":"0000-0002-2034-2556","position":14,"is_corresponding":false},{"id":6986,"name":"Andrew Singleton","orcid":"0000-0001-5606-700X","position":15,"is_corresponding":false},{"id":17492,"name":"Christine Klein","orcid":"0000-0003-2102-3431","position":16,"is_corresponding":false},{"id":17405,"name":"Alexis Brice","orcid":"0000-0002-0941-3990","position":17,"is_corresponding":false},{"id":279270,"name":"Kimberley J. Billingsley","orcid":"0000-0002-8003-4029","position":18,"is_corresponding":false},{"id":252390,"name":"Cornelis Blauwendraat","orcid":"0000-0001-9358-8111","position":19,"is_corresponding":false},{"id":72369,"name":"Kensuke Daida","orcid":"0000-0002-9177-9587","position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":null,"created_at":"2026-07-19T02:56:55.795846Z","pmid":"40546066","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}