Annals of neurology · 2024
The Utility of Long-Read Sequencing in Diagnosing Early Onset Parkinson's Disease.
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Daida Kensuke, Yoshino Hiroyo, Malik Laksh, Baker Breeana, Ishiguro Mayu, Genner Rylee, Paquette Kimberly, Li Yuanzhe, Nishioka Kenya, Masuzugawa Satoshi, Hirano Makito, Takahashi Kenta, Kolmogorov Mikhail, Billingsley Kimberley J, Funayama Manabu, Blauwendraat Cornelis, Hattori Nobutaka
Аннотация
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.
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.