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JAMA Neurol. 2016 Jan;73(1):68-75. doi: 10.1001/jamaneurol.2015.3266.

Whole-Exome Sequencing in Familial Parkinson Disease.

Author information

1
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3Department of Pediatrics, Baylor College of Medicine, Houston, Texas4Department of Pediatrics, Texas Children's Hospital, Houston5Jan and Dan Duncan Neurological Resear.
3
Center for Inherited Disease Research, The Johns Hopkins University, Baltimore, Maryland.
4
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama.
5
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas9Human Genetics Center, University of Texas Health Science Center, Houston.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
7
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
8
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama10Department of Pediatrics, Columbia University Medical Center, New York, New York.
9
Department of Neurology, Baylor College of Medicine, Houston, Texas.
10
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas5Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston.
11
Department of BioHealth Informatics, Indiana University School of Informatics and Computing, Indianapolis.
12
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3Department of Pediatrics, Baylor College of Medicine, Houston, Texas4Department of Pediatrics, Texas Children's Hospital, Houston8Human Genome Sequencing Center, Baylor.
13
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas5Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston11Department of Neurology, Baylor College of Medicine, Houston, Texas13Department.

Abstract

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.

PMID:
26595808
PMCID:
PMC4946647
DOI:
10.1001/jamaneurol.2015.3266
[Indexed for MEDLINE]
Free PMC Article

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