{"doi":"10.1002/ana.27155","title":"The Utility of Long‐Read Sequencing in Diagnosing Early Onset Parkinson's Disease","abstract":"OBJECTIVE: Variants in PRKN and PINK1 are the leading cause of early-onset autosomal recessive Parkinson's disease, yet many cases remain genetically unresolved. We previously identified a 7 megabases complex structural variant in a pair of monozygotic twins using Oxford Nanopore Technologies (ONT) long-read sequencing. This study aims to determine if ONT long-read sequencing can detect a second variant in other unresolved early-onset Parkinson's disease (EOPD) cases with 1 heterozygous PRKN or PINK1 variant. METHODS: ONT long-read sequencing was performed on EOPD patients with 1 reported PRKN/PINK1 pathogenic variant, with onset age under 50. Positive controls included EOPD patients with 2 known PRKN pathogenic variants. Initial testing involved short-read targeted panel sequencing for single nucleotide variants and multiplex ligation-dependent probe amplification for copy number variants. RESULTS: A total of 47 patients were studied (PRKN \"one-variant,\" n = 23; PINK1 \"one-variant,\" n = 12; PRKN \"two-variants,\" n = 12). ONT long-read sequencing identified a second pathogenic variant in 26% of PRKN \"one-variant\" patients (6/23), but none in PINK1 \"one-variant\" patients (0/12). Detected variants included 1 complex inversion, 2 structural variant overlaps, and 3 duplications. In the PRKN \"two-variants\" group, both variants were identified in all patients (100%, 12/12). INTERPRETATION: ONT long-read sequencing effectively identifies pathogenic structural variants in the PRKN locus missed by conventional methods. It should be considered for unresolved EOPD cases when a second variant is not detected through conventional approaches. ANN NEUROL 2025;97:753-765.","journal":"Annals of Neurology","year":2024,"id":435943,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":17505,"name":"Hiroyo Yoshino","orcid":null,"position":1,"is_corresponding":false},{"id":958501,"name":"Laksh Malik","orcid":"0000-0002-2498-146X","position":2,"is_corresponding":false},{"id":1017521,"name":"Breeana Baker","orcid":null,"position":3,"is_corresponding":false},{"id":1041147,"name":"Mayu Ishiguro","orcid":null,"position":4,"is_corresponding":false},{"id":1017761,"name":"Rylee M. Genner","orcid":"0009-0004-8251-5960","position":5,"is_corresponding":false},{"id":1243573,"name":"Kimberly Paquette","orcid":"0000-0003-3989-4614","position":6,"is_corresponding":false},{"id":1243574,"name":"Yuanzhe Li","orcid":"0000-0001-7570-3243","position":7,"is_corresponding":false},{"id":644709,"name":"Kenya Nishioka","orcid":"0000-0001-8607-9757","position":8,"is_corresponding":false},{"id":1244067,"name":"Satoshi Masuzugawa","orcid":null,"position":9,"is_corresponding":false},{"id":1243575,"name":"Makito Hirano","orcid":"0000-0003-0759-1627","position":10,"is_corresponding":false},{"id":1243576,"name":"Kenta Takahashi","orcid":"0000-0002-5971-9736","position":11,"is_corresponding":false},{"id":49028,"name":"Mikhail Kolmogorov","orcid":"0000-0002-5489-9045","position":12,"is_corresponding":false},{"id":279270,"name":"Kimberley J. Billingsley","orcid":"0000-0002-8003-4029","position":13,"is_corresponding":false},{"id":17504,"name":"Manabu Funayama","orcid":"0000-0002-7412-3631","position":14,"is_corresponding":false},{"id":252390,"name":"Cornelis Blauwendraat","orcid":"0000-0001-9358-8111","position":15,"is_corresponding":false},{"id":17418,"name":"Nobutaka Hattori","orcid":"0000-0002-2034-2556","position":16,"is_corresponding":false},{"id":72369,"name":"Kensuke Daida","orcid":"0000-0002-9177-9587","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:00:08.103086Z","pmid":"39699073","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":[]}