Indication for molecular testing by multiplex ligation‐dependent probe amplification in parkinsonism

Mutez, Eugénie; Swiderski, M; Devos, David; Moreau, Caroline; Baille, Guillaume; Degardin, Adrian; Ryckewaert, Gilles; Carrière, Nicolas; Kreisler, Alexandre; Simonin, C.; Rouaix, Nathalie; Tir, Mélissa; Krystkowiak, Pierre; Ramdane, Nassima; Génin, Michaël; Sablonnière, Bernard; Defebvre, Luc; Huin, Vincent

doi:10.1111/ene.15788

Cited by 3 publications

(1 citation statement)

References 39 publications

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“…It is reasonable, therefore, to perform MLPA to screen for SVs first. [39] In our previous study, we combined MLPA with targeted resequencing/Sanger sequencing to analyze EOPD patients (n = 918) with an AAO younger than 50 years in a Japanese cohort. We identified that 6.4% of the patients harbored two variants in the PRKN gene, while 3.9% presented with a single variant.…”

Section: Discussionmentioning

confidence: 99%

The Utility of Long-Read Sequencing in Diagnosing Genetic Autosomal Recessive Parkinson’s Disease: a genetic screening study

Daida,

Yoshino,

Malik

et al. 2024

Preprint

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BackgroundMutations within the genesPRKNandPINK1are the leading cause of early onset autosomal recessive Parkinson’s disease (PD). However, the genetic cause of most early-onset PD (EOPD) cases still remains unresolved. Long-read sequencing has successfully identified many pathogenic structural variants that cause disease, but this technology has not been widely applied to PD. We recently identified the genetic cause of EOPD in a pair of monozygotic twins by uncovering a complex structural variant that spans over 7 Mb, utilizing Oxford Nanopore Technologies (ONT) long-read sequencing. In this study, we aimed to expand on this and assess whether a second variant could be detected with ONT long-read sequencing in other unresolved EOPD cases reported to carry one heterozygous variant inPRKNorPINK1.MethodsONT long-read sequencing was performed on patients with one reportedPRKN/PINK1pathogenic variant. EOPD patients with an age at onset younger than 50 were included in this study. As a positive control, we also included EOPD patients who had already been identified to carry two knownPRKNpathogenic variants. Initial genetic testing was performed using either short-read targeted panel sequencing for single nucleotide variants and multiplex ligation-dependent probe amplification (MLPA) for copy number variants.Results48 patients were included in this study (PRKN“one-variant” n = 24,PINK1“one-variant” n = 12,PRKN“two-variants” n = 12). Using ONT long-read sequencing, we detected a second pathogenic variant in sixPRKN“one-variant” patients (26%, 6/23) but none in thePINK1“one-variant” patients (0%, 0/12). Long-read sequencing identified one case with a complex inversion, two instances of structural variant overlap, and three cases of duplication. In addition, in the positive controlPRKN“two-variants” group, we were able to identify both pathogenic variants inPRKNin all the patients (100%, 12/12).ConclusionsThis data highlights that ONT long-read sequencing is a powerful tool to identify a pathogenic structural variant at thePRKNlocus that is often missed by conventional methods. Therefore, for cases where conventional methods fail to detect a second variant for EOPD, long-read sequencing should be considered as an alternative and complementary approach.

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Section: Discussionmentioning

confidence: 99%

The Utility of Long-Read Sequencing in Diagnosing Genetic Autosomal Recessive Parkinson’s Disease: a genetic screening study

Daida,

Yoshino,

Malik

et al. 2024

Preprint

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The Utility of Long‐Read Sequencing in Diagnosing Early Onset Parkinson's Disease

Daida,

Yoshino,

Malik

et al. 2024

Annals of Neurology

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ObjectiveVariants 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.MethodsONT 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.ResultsA 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).InterpretationONT 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 2024

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Analysis of microbiomes and mycotoxins revealing the importance in the standardized storage of Aesculus wilsonii Rehd fruit

Mo,

Yu,

Shi

et al. 2024

Journal of Applied Research on Medicinal and Aromatic Plants

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Indication for molecular testing by multiplex ligation‐dependent probe amplification in parkinsonism

Cited by 3 publications

References 39 publications

The Utility of Long-Read Sequencing in Diagnosing Genetic Autosomal Recessive Parkinson’s Disease: a genetic screening study

The Utility of Long-Read Sequencing in Diagnosing Genetic Autosomal Recessive Parkinson’s Disease: a genetic screening study

The Utility of Long‐Read Sequencing in Diagnosing Early Onset Parkinson's Disease

Analysis of microbiomes and mycotoxins revealing the importance in the standardized storage of Aesculus wilsonii Rehd fruit

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