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

Nikita Simone Pillay,Alan Christoffels,Soraya Bardien,Owen A Ross

doi:10.3389/fgene.2022.781816

Abstract

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.

Highlights

Over the past almost 2 decades, next-generation sequencing (NGS) approaches, with their high-throughput and rapid output, have accelerated novel gene discovery for several human diseases. In this Perspective article, we summarize, analyze and highlight the studies that identified new loci for Parkinson’s disease (PD) using NGS strategies
That initial hope has not been realized with most of the genes identified through NGS, only being found in a single family
This may be due to the complexity of PD etiology, with either, each family having its own rare genetic cause, or that the more common genetic causes underlying PD have not yet been identified

Summary

Introduction

Over the past almost 2 decades, next-generation sequencing (NGS) approaches, with their high-throughput and rapid output, have accelerated novel gene discovery for several human diseases. In this Perspective article, we summarize, analyze and highlight the studies that identified new loci for Parkinson’s disease (PD) using NGS strategies. The remaining 5–10% of cases are accounted for by familial PD, usually displaying a Mendelian mode of inheritance (Lesage and Brice, 2012; Hernandez et al, 2016). PD genes identified using this approach have demonstrated autosomal dominant (AD-PD) (SNCA, LRRK2), autosomal recessive (AR-PD) (PRKN, PINK1, DJ1) and X-linked (RAB39B) inheritance patterns (Bras and Singleton., 2011; Gasser, 2013; Bandres-Ciga et al, 2020)

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