title: Whole-Exome Sequencing in Familial Parkinson Disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Farlow
authors.affiliation: 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.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Robak
authors.affiliation: Center for Inherited Disease Research, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Kurt
authors.initials: K
authors.lastname: Hetrick
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bowling
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas9Human Genetics Center, University of Texas Health Science Center, Houston.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Zeynep H
authors.initials: ZH
authors.lastname: Coban-Akdemir
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Shen
authors.initials: S
authors.lastname: Gu
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama10Department of Pediatrics, Columbia University Medical Center, New York, New York.
authors.forename: Preti
authors.initials: P
authors.lastname: Jain
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, Texas.
authors.forename: Joseph
authors.initials: J
authors.lastname: Jankovic
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jhangiani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas5Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston.
authors.forename: Kaveeta
authors.initials: K
authors.lastname: Kaw
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
authors.forename: Dongbing
authors.initials: D
authors.lastname: Lai
authors.affiliation: Department of BioHealth Informatics, Indiana University School of Informatics and Computing, Indianapolis.
authors.forename: Hai
authors.initials: H
authors.lastname: Lin
authors.affiliation: Center for Inherited Disease Research, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Hua
authors.initials: H
authors.lastname: Ling
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas5Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston.
authors.forename: Paula
authors.initials: P
authors.lastname: Porter
authors.affiliation: Center for Inherited Disease Research, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pugh
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Janson
authors.initials: J
authors.lastname: White
authors.affiliation: Center for Inherited Disease Research, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Doheny
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: 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.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020734:Parkinsonian Disorders / Q000175:diagnosis* / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*; D019063:Tenascin / Q000235:genetics*
chemical_list: D019063:Tenascin; C074638:tenascin R; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human