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Abstract
Objective: Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes.
Methods: We performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with <5% frequency in the exome variant server database and our own control data were considered for analysis. We performed joint gene-based tests for association using RVASSOC and SKAT (Sequence Kernel Association Test) as well as single-variant test statistics.
Results: We identified 3 novel VPS35 variations that changed the coded amino acid (nonsynonymous) in 3 cases. Two variations were in multiplex families and neither segregated with PD. In EIF4G1, we identified 11 (9 nonsynonymous and 2 small indels) RVs including the reported pathogenic mutation p.R1205H, which segregated in all affected members of a large family, but also in 1 unaffected 86-year-old family member. Two additional RVs were found in isolated patients only. Whereas initial association studies suggested an association (p = 0.04) with all RVs in EIF4G1, subsequent testing in a second dataset for the driving variant (p.F1461) suggested no association between RVs in the gene and PD.
Conclusions: We confirm that the specific EIF4G1 variation p.R1205H seems to be a strong PD risk factor, but is nonpenetrant in at least one 86-year-old. A few other select RVs in both genes could not be ruled out as causal. However, there was no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development in our dataset.
GLOSSARY
- AAO=
- age at onset;
- EIF4G1=
- eukaryotic translation initiation factor 4 gamma 1;
- EVS=
- Exome Variant Server;
- ICD=
- internal control database;
- nsRV=
- nonsynonymous rare variant;
- PD=
- Parkinson disease;
- RV=
- rare variant;
- SKAT=
- Sequence Kernel Association Test;
- SNP=
- single-nucleotide polymorphism;
- sRV=
- synonymous rare variant;
- VPS35=
- vacuolar protein sorting 35;
- WES=
- whole exome sequencing
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of this article.
Editorial, page 974
- Received July 9, 2012.
- Accepted October 8, 2012.
- © 2013 American Academy of Neurology
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