Whole-genome sequencing suggests mechanisms for 22q11.2 deletion-associated Parkinson’s disease

Abstract

ObjectivesTo investigate disease risk mechanisms of early-onset Parkinson’s disease (PD) associated with the recurrent 22q11.2 deletion, a genetic risk factor for early-onset PD.MethodsIn a proof-of-principle study, we used whole-genome sequencing (WGS) to investigate sequence variants in nine adults with 22q11.2DS, three with neuropathologically confirmed early-onset PD and six without PD. Adopting an approach used recently to study schizophrenia in 22q11.2DS, here we tested candidate gene-sets relevant to PD.ResultsNo mutations common to the cases with PD were found in the intact 22q11.2 region. While all were negative for rare mutations in a gene-set comprising PD disease-causing and risk genes, another candidate gene-set of 1000 genes functionally relevant to PD presented a nominally significant (P = 0.03) enrichment of rare putatively damaging missense variants in the PD cases. Polygenic score results, based on common variants associated with PD risk, were non-significantly greater in those with PD.ConclusionsThe results of this first-ever pilot study of WGS in PD suggest that the cumulative burden of genome-wide sequence variants may contribute to expression of early-onset PD in the presence of threshold-lowering dosage effects of a 22q11.2 deletion. We found no evidence that expression of PD in 22q11.2DS is mediated by a recessive locus on the intact 22q11.2 chromosome or mutations in known PD genes. These findings offer initial evidence of the potential effects of multiple within-individual rare variants on the expression of PD and the utility of next generation sequencing for studying the etiology of PD.

Parkinson’s disease with hypocalcaemia: adult presentation of 22q11.2 deletion syndrome

“…In another recent article, the authors searched for genetic variants linking 22q11.2DS and PD using whole-genome sequencing analysis. The results provided preliminary evidence that the genome-wide burden of rare deleterious variants in genes functionally relevant to PD may collectively increase the likelihood of PD expression in the presence of the 22q11.2 deletion 9. Furthermore, in a few case reports, parkinsonism or EOPD preceded the diagnosis of 22q11.2DS 10 11…”

Use of Array Comparative Genomic Hybridization for the Diagnosis of DiGeorge Syndrome in Saudi Arabian Population

“…This could be explained by smaller deletions, SNPs and/or translocations in this region that were not detected by any of the 3 techniques. Therefore, we recommend refining the diagnosis of those samples by whole-genome sequencing as suggested elsewhere [Guo et al, 2016;Butcher et al, 2017]. We believe that the integration of NGS alongside with aCGH in routine clinical genomic practice will allow more accurate and comprehensive clinical diagnosis.…”

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

“…Additional genetic and environmental factors that contribute to the increased PD risk in this group of patients are yet to be determined. A whole‐genome sequencing pilot study in patients with 22q11.2DS showed nominal enrichment in the PD cases of additional rare putatively damaging missense variants involving genome‐wide candidate genes with functional relevance to PD . Larger longitudinal studies are needed to improve prevalence estimates, and to evaluate how the interaction of lifestyle and additional environmental and genetic factors may contribute to lifetime risk of developing PD in 22q11.2DS …”

“…22q11.2DS-ASSOCIATED PD additional rare putatively damaging missense variants involving genome-wide candidate genes with functional relevance to PD. 25 Larger longitudinal studies are needed to improve prevalence estimates, and to evaluate how the interaction of lifestyle and additional environmental and genetic factors may contribute to lifetime risk of developing PD in 22q11.2DS. 1 Natural History of PD in 22q11.2 Deletion Syndrome PD in 22q11.2DS appears largely indistinguishable from idiopathic PD with respect to major clinical PD features.…”