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Original Investigation |

Whole-Exome Sequencing in Familial Parkinson Disease

Janice L. Farlow, PhD1; Laurie A. Robak, MD, PhD2,3,4,5; Kurt Hetrick, MS6; Kevin Bowling, PhD7; Eric Boerwinkle, PhD8,9; Zeynep H. Coban-Akdemir, PhD2; Tomasz Gambin, PhD2; Richard A. Gibbs, PhD8; Shen Gu, PhD2; Preti Jain, PhD7,10; Joseph Jankovic, MD11; Shalini Jhangiani, MS8; Kaveeta Kaw, BS2,5; Dongbing Lai, PhD1; Hai Lin, BS12; Hua Ling, PhD6; Yunlong Liu, PhD1; James R. Lupski, MD, PhD, DSc2,3,4,8; Donna Muzny, MS8; Paula Porter, MPhil2,5; Elizabeth Pugh, PhD6; Janson White, BS2; Kimberly Doheny, PhD6; Richard M. Myers, PhD7; Joshua M. Shulman, MD, PhD2,5,11,13; Tatiana Foroud, PhD1
[+] Author Affiliations
1Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis
2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
3Department of Pediatrics, Baylor College of Medicine, Houston, Texas
4Department of Pediatrics, Texas Children’s Hospital, Houston
5Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston
6Center for Inherited Disease Research, The Johns Hopkins University, Baltimore, Maryland
7HudsonAlpha Institute for Biotechnology, Huntsville, Alabama
8Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas
9Human Genetics Center, University of Texas Health Science Center, Houston
10Department of Pediatrics, Columbia University Medical Center, New York, New York
11Department of Neurology, Baylor College of Medicine, Houston, Texas
12Department of BioHealth Informatics, Indiana University School of Informatics and Computing, Indianapolis
13Department of Neuroscience, Baylor College of Medicine, Houston, Texas
JAMA Neurol. 2016;73(1):68-75. doi:10.1001/jamaneurol.2015.3266.
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Importance  Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.

Objective  To identify genetic variants contributing to disease risk in familial PD.

Design, Setting, and Participants  A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD.

Main Outcomes and Measures  Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design.

Results  The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing.

Conclusions and Relevance  TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

Figures in this Article


Place holder to copy figure label and caption
Figure 1.
Study Design and Discovery Cohort Variant Filtering

Shown is the overall design for the 2-stage study and variant counts at each stage of filtering. GO indicates Gene Ontology (annotations listed in the Filtering subsection of the Methods section); Indels, insertions or deletions; MAF, minor allele frequency; and SNVs, single-nucleotide variants.

Graphic Jump Location
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Figure 2.
Pedigrees Segregating TNK2 and TNR Variants

PD indicates Parkinson disease. A square indicates a male individual; a circle, a female individual. Below each symbol is a subject number. For sequenced, affected individuals, the age at disease onset is below the subject number. A question mark indicates an unknown age at onset.

Graphic Jump Location




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