Genetic Mutation Analysis of Parkinson’s Disease Patients Using Multigene Next-Generation Sequencing Panels

Gorostidi, Ana; Martí-Massó, J.F.; Bergareche, Alberto; Rodríguez-Oroz, M.C.; Munáin, Adolfo López de; Ruíz‐Martínez, Javier

doi:10.1007/s40291-016-0216-1

Cited by 17 publications

(21 citation statements)

References 26 publications

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“…Mutations in known genes were previously excluded through custom targeted sequencing. 18 Patients were diagnosed according to the UK PD Brain Bank Society and Gelb criteria. 19,20 Written informed consent, fully approved by the local ethics committee of the Hospital Universitario Donostia, was obtained from all participants.…”

Section: Methodsmentioning

confidence: 99%

“…In this study, we clinically evaluated 2 different families suffering from late-onset PD (LOPD) without mutations in the known genes 18 and performed whole-exome sequencing (WES) analyses in 3 affected family members to identify the genetic causes of disease to enhance our knowledge of the genetic architecture of PD. We identified 2 different mutations in a novel gene, previously reported to be associated with the risk of PD, as possible disease-causing mutations in both unrelated PD families.…”

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confidence: 99%

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Whole-exome sequencing associates novelCSMD1gene mutations with familial Parkinson disease

et al. 2017

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Objective:Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.Methods:In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.Results:Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study.Conclusions:We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Whole-exome sequencing associates novelCSMD1gene mutations with familial Parkinson disease

et al. 2017

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“…At present, diagnosis is usually confirmed by detection of the hemizygous 22q11.2 deletion using chromosomal microarray or fluorescence in situ hybridization . The deletions are too small to be seen using conventional karyotyping methods and are not detectable using currently available PD genetic diagnostic panels …”

Section: Q112 Deletion Syndromementioning

confidence: 99%

“…2 The deletions are too small to be seen using conventional karyotyping methods and are not detectable using currently available PD genetic diagnostic panels. 24…”

Section: Q112 Deletion Syndromementioning

confidence: 99%

22q11.2 Deletion Syndrome–Associated Parkinson's Disease

Boot

Bassett

Marras

2018

Movement Disord Clin Pract

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Background22q11.2 deletion syndrome (22q11.2DS) is a multisystem condition associated with an increased risk of early‐onset Parkinson's disease (PD).MethodsWe review the clinical, neuroimaging, and neuropathological observations, as well as diagnostic challenges, of PD in 22q11.2DS. We conducted a search of PubMed up until June 1, 2018 and personal files to identify relevant publications.Results22q11.2DS‐associated PD is responsible for approximately 0.5% of early‐onset PD. The hallmark motor symptoms and neuropathology of PD, and typical findings of reduced striatal dopamine transporter binding with molecular imaging, are present in 22q11.2DS‐associated PD. Mean age at PD onset in 22q11.2DS is relatively young (∼40 years). Patients with 22q11.2DS‐associated PD show a good response to levodopa.ConclusionsFurther recognition of 22q11.2DS and study of PD in people with 22q11.2DS could provide insights into the mechanisms that cause PD in the general population. 22q11.2DS may serve as an identifiable PD model to study prodromal PD and disease‐modifying treatments.

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“…Next-Generation Sequencing (NGS) provides a way to explore the genetic basis of diseases, and has resulted in the discovery of a large number of disease-associated mutations [20]. In contrast to whole-genome or wholeexome sequencing [21,22], targeted sequencing panels [23] focus the analysis on specific genes of interest. The Ion AmpliSeq™ Neurological Research Panel is a commercially available panel designed to screen genes linked to neurological disorders as well as genes involved in brain function.…”

Section: Introductionmentioning

confidence: 99%

Targeted next-generation sequencing identifies novel variants in candidate genes for Parkinson’s disease in Black South African and Nigerian patients

et al. 2020

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Background: The prevalence of Parkinson's disease (PD) is increasing in sub-Saharan Africa, but little is known about the genetics of PD in these populations. Due to their unique ancestry and diversity, sub-Saharan African populations have the potential to reveal novel insights into the pathobiology of PD. In this study, we aimed to characterise the genetic variation in known and novel PD genes in a group of Black South African and Nigerian patients. Methods: We recruited 33 Black South African and 14 Nigerian PD patients, and screened them for sequence variants in 751 genes using an Ion AmpliSeq™ Neurological Research panel. We used bcftools to filter variants and annovar software for the annotation. Rare variants were prioritised using MetaLR and MetaSVM prediction scores. The effect of a variant on ATP13A2's protein structure was investigated by molecular modelling. Results: We identified 14,655 rare variants with a minor allele frequency ≤ 0.01, which included 2448 missense variants. Notably, no common pathogenic mutations were identified in these patients. Also, none of the known PD-associated mutations were found highlighting the need for more studies in African populations. Altogether, 54 rare variants in 42 genes were considered deleterious and were prioritized, based on MetaLR and MetaSVM scores, for follow-up studies. Protein modelling showed that the S1004R variant in ATP13A2 possibly alters the conformation of the protein. Conclusions: We identified several rare variants predicted to be deleterious in sub-Saharan Africa PD patients; however, further studies are required to determine the biological effects of these variants and their possible role in PD. Studies such as these are important to elucidate the genetic aetiology of this disorder in patients of African ancestry.

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Genetic Mutation Analysis of Parkinson’s Disease Patients Using Multigene Next-Generation Sequencing Panels

Abstract: Benchtop next-generation sequencing is a powerful method for genetic screening for PD. Our results indicated that it yielded a high frequency of discovery (66 %; n = 92) of variants in carriers from an enriched Spanish PD sample.

Cited by 17 publications

References 26 publications

Whole-exome sequencing associates novelCSMD1gene mutations with familial Parkinson disease

Whole-exome sequencing associates novelCSMD1gene mutations with familial Parkinson disease

22q11.2 Deletion Syndrome–Associated Parkinson's Disease

Targeted next-generation sequencing identifies novel variants in candidate genes for Parkinson’s disease in Black South African and Nigerian patients

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