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Current Status of Next-Generation Sequencing Approaches for Candidate Gene Discovery in Familial Parkinson´s Disease

Parkinson’s disease is a neurodegenerative disorder with a heterogeneous genetic etiology. The advent of next-generation sequencing (NGS) technologies has aided novel gene discovery in several complex diseases, including PD. This Perspective article aimed to explore the use of NGS approaches to iden...

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Autores principales: Pillay, Nikita Simone, Ross, Owen A., Christoffels, Alan, Bardien, Soraya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921601/
https://www.ncbi.nlm.nih.gov/pubmed/35299952
http://dx.doi.org/10.3389/fgene.2022.781816
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author Pillay, Nikita Simone
Ross, Owen A.
Christoffels, Alan
Bardien, Soraya
author_facet Pillay, Nikita Simone
Ross, Owen A.
Christoffels, Alan
Bardien, Soraya
author_sort Pillay, Nikita Simone
collection PubMed
description Parkinson’s disease is a neurodegenerative disorder with a heterogeneous genetic etiology. The advent of next-generation sequencing (NGS) technologies has aided novel gene discovery in several complex diseases, including PD. This Perspective article aimed to explore the use of NGS approaches to identify novel loci in familial PD, and to consider their current relevance. A total of 17 studies, spanning various populations (including Asian, Middle Eastern and European ancestry), were identified. All the studies used whole-exome sequencing (WES), with only one study incorporating both WES and whole-genome sequencing. It is worth noting how additional genetic analyses (including linkage analysis, haplotyping and homozygosity mapping) were incorporated to enhance the efficacy of some studies. Also, the use of consanguineous families and the specific search for de novo mutations appeared to facilitate the finding of causal mutations. Across the studies, similarities and differences in downstream analysis methods and the types of bioinformatic tools used, were observed. Although these studies serve as a practical guide for novel gene discovery in familial PD, these approaches have not significantly resolved the “missing heritability” of PD. We speculate that what is needed is the use of third-generation sequencing technologies to identify complex genomic rearrangements and new sequence variation, missed with existing methods. Additionally, the study of ancestrally diverse populations (in particular those of Black African ancestry), with the concomitant optimization and tailoring of sequencing and analytic workflows to these populations, are critical. Only then, will this pave the way for exciting new discoveries in the field.
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spelling pubmed-89216012022-03-16 Current Status of Next-Generation Sequencing Approaches for Candidate Gene Discovery in Familial Parkinson´s Disease Pillay, Nikita Simone Ross, Owen A. Christoffels, Alan Bardien, Soraya Front Genet Genetics Parkinson’s disease is a neurodegenerative disorder with a heterogeneous genetic etiology. The advent of next-generation sequencing (NGS) technologies has aided novel gene discovery in several complex diseases, including PD. This Perspective article aimed to explore the use of NGS approaches to identify novel loci in familial PD, and to consider their current relevance. A total of 17 studies, spanning various populations (including Asian, Middle Eastern and European ancestry), were identified. All the studies used whole-exome sequencing (WES), with only one study incorporating both WES and whole-genome sequencing. It is worth noting how additional genetic analyses (including linkage analysis, haplotyping and homozygosity mapping) were incorporated to enhance the efficacy of some studies. Also, the use of consanguineous families and the specific search for de novo mutations appeared to facilitate the finding of causal mutations. Across the studies, similarities and differences in downstream analysis methods and the types of bioinformatic tools used, were observed. Although these studies serve as a practical guide for novel gene discovery in familial PD, these approaches have not significantly resolved the “missing heritability” of PD. We speculate that what is needed is the use of third-generation sequencing technologies to identify complex genomic rearrangements and new sequence variation, missed with existing methods. Additionally, the study of ancestrally diverse populations (in particular those of Black African ancestry), with the concomitant optimization and tailoring of sequencing and analytic workflows to these populations, are critical. Only then, will this pave the way for exciting new discoveries in the field. Frontiers Media S.A. 2022-03-01 /pmc/articles/PMC8921601/ /pubmed/35299952 http://dx.doi.org/10.3389/fgene.2022.781816 Text en Copyright © 2022 Pillay, Ross, Christoffels and Bardien. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Pillay, Nikita Simone
Ross, Owen A.
Christoffels, Alan
Bardien, Soraya
Current Status of Next-Generation Sequencing Approaches for Candidate Gene Discovery in Familial Parkinson´s Disease
title Current Status of Next-Generation Sequencing Approaches for Candidate Gene Discovery in Familial Parkinson´s Disease
title_full Current Status of Next-Generation Sequencing Approaches for Candidate Gene Discovery in Familial Parkinson´s Disease
title_fullStr Current Status of Next-Generation Sequencing Approaches for Candidate Gene Discovery in Familial Parkinson´s Disease
title_full_unstemmed Current Status of Next-Generation Sequencing Approaches for Candidate Gene Discovery in Familial Parkinson´s Disease
title_short Current Status of Next-Generation Sequencing Approaches for Candidate Gene Discovery in Familial Parkinson´s Disease
title_sort current status of next-generation sequencing approaches for candidate gene discovery in familial parkinson´s disease
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921601/
https://www.ncbi.nlm.nih.gov/pubmed/35299952
http://dx.doi.org/10.3389/fgene.2022.781816
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