Evaluation of the detection of <i>GBA</i> missense mutations and other variants using the Oxford Nanopore MinION

Leija‐Salazar, Melissa; Sedlazeck, Fritz J.; Toffoli, Marco; Mullin, Stephen; Mokretar, Katya; Athanasopoulou, Maria; Donald, Aimee; Sharma, Reena; Hughes, Derralynn; Schapira, Anthony H.V.; Proukakis, Christos

doi:10.1002/mgg3.564

Cited by 67 publications

(48 citation statements)

References 57 publications

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“…Therefore, genetic analysis will have to take this into account and should be performed in a specialized laboratory in order to obtain reliable results. New technologies, such as the long-read sequencer, are on the horizon for even more in-depth identification of possible GBA mutations [64].…”

Section: Pathogenetic Mutations Of the Gba Genementioning

confidence: 99%

GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches

Riboldi

Fonzo

2019

Cells

210

169

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Parkinson’s disease (PD) is the second most common degenerative disorder. Although the disease was described more than 200 years ago, its pathogenetic mechanisms have not yet been fully described. In recent years, the discovery of the association between mutations of the GBA gene (encoding for the lysosomal enzyme glucocerebrosidase) and PD facilitated a better understating of this disorder. GBA mutations are the most common genetic risk factor of the disease. However, mutations of this gene can be found in different phenotypes, such as Gaucher’s disease (GD), PD, dementia with Lewy bodies (DLB) and rapid eye movements (REM) sleep behavior disorders (RBDs). Understanding the pathogenic role of this mutation and its different manifestations is crucial for geneticists and scientists to guide their research and to select proper cohorts of patients. Moreover, knowing the implications of the GBA mutation in the context of PD and the other associated phenotypes is also important for clinicians to properly counsel their patients and to implement their care. With the present review we aim to describe the genetic, clinical, and therapeutic features related to the mutation of the GBA gene.

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Section: Pathogenetic Mutations Of the Gba Genementioning

confidence: 99%

GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches

Riboldi

Fonzo

2019

Cells

210

169

View full text Add to dashboard Cite

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“…This is, for example, the case for mutations in GBA, in which heterozygous mutations increase the risk for PD and that has a neighboring pseudogene complicating the short-read alignment. Long-range PCR amplicons sequenced on the MinION were used for phased detection of SNVs and an exonic deletion [81]. More generally, in a genome-wide evaluation of loci with highly similar copies, it was also suggested that a substantial proportion of variants in genes relevant to neurodegenerative diseases cannot be assessed reliably using short reads due to issues in the alignment [82].…”

Section: Examples Of Svs In Neurodegenerationmentioning

confidence: 99%

Newest Methods for Detecting Structural Variations

Coster

Broeckhoven

2019

Trends in Biotechnology

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A substantial amount of structural variation in the human genome remains uninvestigated due to the limitations of existing technologies, the presence of repetitive sequences, and the complexity of a diploid genome. New technologies have been developed, increasing resolution and appreciation of structural variation and how it affects human diversity and disease. The genetic etiology of most patients with complex disorders such as neurodegenerative brain diseases is not yet elucidated, complicating disease diagnosis, genetic counseling, and understanding of underlying pathological mechanisms needed to develop therapeutic interventions. Here, we focus on innovative progress and opportunities provided by the newest methods such as linked read sequencing, strand-specific sequencing, and long-read sequencing. Finally, we describe a strategy for generating a comprehensive catalog of structural variations across populations. Structural Variation Has Been Systematically Missed Multiple projects have comprehensively cataloged small genetic variants [single nucleotide variants (SNVs)]; however, structural variants (SVs) remain largely underrepresented [1,2]. SVs are defined as regions of DNA larger than 50 bp showing a change in copy number or genomic location including copy number variants (CNVs; deletions and duplications), insertions, inversions, translocations, mobile elements, repetitive sequence expansions, and complex combinations thereof (Figure 1) [3]. SVs contribute $3.4 times more nucleotides to human genetic variation than the far more numerous SNVs [4]. Multiple sequencing technologies (see Glossary), notably longread sequencing and short-read sequencing library preparation methods such as strand-specific sequencing (strand-seq) and linked-read sequencing, have been developed, providing an unprecedented potential and accuracy of genome-wide structural variation. Here, we describe new improvements to SV detection methods, each with different strengths and shortcomings. One landmark study combined several technologies to obtain a complete haplotype-specific characterization in healthy human trios, yielding >30 000 SVs per genome, including >150 inversions and large unbalanced chromosomal rearrangements [5]. This work suggested that previous technologies missed most of the SVs due to technical limitations. The majority of SVs are novel and rare variants, implicating that structural variation databases are not saturated yet [2-7]. Highlights The genetic etiology of complex human diseases is still poorly understood, hampering diagnostics and therapeutic approaches.

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“…While the representative physical long-read platforms such as PacBio and Oxford Nanopore sequencers produce sequences with lower base qualities than those of short-read sequencing platforms such as Illumina sequencers, this shortcoming could be circumvented when genotyping large genome aberrations, such as copy-number variants (CNVs) and SVs. This approach has been taken in various diseases [14], including cancers [15–18]. Moreover, with a careful application of either the long reads alone or in tandem with a more accurate conventional short-read sequencing, single-base-level resolution aberrations such as SNVs and short indels could be genotyped.…”

Section: Cancer Genome Sequencing With Long Readsmentioning

confidence: 99%

A new era of long-read sequencing for cancer genomics

2019

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Cancer is a disease largely caused by genomic aberrations. Utilizing many rapidly emerging sequencing technologies, researchers have studied cancer genomes to understand the molecular statuses of cancer cells and to reveal their vulnerabilities, such as driver mutations or gene expression. Long-read technologies enable us to identify and characterize novel types of cancerous mutations, including complicated structural variants in haplotype resolution. In this review, we introduce three representative platforms for long-read sequencing and research trends of cancer genomics with long-read data. Further, we describe that aberrant transcriptome and epigenome statuses, namely, fusion transcripts, as well as aberrant transcript isoforms and the phase information of DNA methylation, are able to be elucidated by long-read sequencers. Long-read sequencing may shed light on novel types of aberrations in cancer genomics that are being missed by conventional short-read sequencing analyses.

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Evaluation of the detection of GBA missense mutations and other variants using the Oxford Nanopore MinION

Cited by 67 publications

References 57 publications

GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches

GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches

Newest Methods for Detecting Structural Variations

A new era of long-read sequencing for cancer genomics

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