Integrated Analysis of Whole Exome Sequencing and Copy Number Evaluation in Parkinson's Disease

Abstract

Genetic studies of the familial forms of Parkinson's disease (PD) have identified a number of causative genes with an established role in its pathogenesis. These genes only explain a fraction of the diagnosed cases. The emergence of Next Generation Sequencing (NGS) expanded the scope of rare variants identification in novel PD related genes. In this study we describe whole exome sequencing (WES) genetic findings of 60 PD patients with 125 variants validated in 51 of these cases. We used strict criteria for variant categorization that generated a list of variants in 20 genes. These variants included loss of function and missense changes in 18 genes that were never previously linked to PD (NOTCH4, BCOR, ITM2B, HRH4, CELSR1, SNAP91, FAM174A, BSN, SPG7, MAGI2, HEPHL1, EPRS, PUM1, CLSTN1, PLCB3, CLSTN3, DNAJB9 and NEFH) and 2 genes that were previously associated with PD (EIF4G1 and ATP13A2). These genes either play a critical role in neuronal function and/or have mouse models with disease related phenotypes. We highlight NOTCH4 as an interesting candidate in which we identified a deleterious truncating and a splice variant in 2 patients. Our combined molecular approach provides a comprehensive strategy applicable for complex genetic disorders.

Figure 1

Summary of the 3-stage analysis approach applied in this study. (a) Pre-WES mutation screening of reported genes. (b) WES filtering and validation. (c) Criteria for gene prioritization.

Figure 2

Breakdown of genetic alterations identified in this study. Pie chart illustrating the type and the number of all the validated genetic alterations (SNVs and CNVs) identified in this study.

Figure 3

Distribution of variants harbouring genes across the genome. Distribution of the identified genes with validated variants across chromosomes.