title: Disease penetrance of late-onset parkinsonism: a meta-analysis.
abstract: OBJECTIVE
  Mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13 have been implicated in late-onset familial parkinsonism. However, the estimated disease penetrance of these mutations varies widely.
  
  
  OBJECTIVE
  To compare penetrance of various mutations reported in published genetic studies to improve the understanding of late-onset parkinsonism.
  
  
  METHODS
  Forty-nine previously published studies, including 709 participants, were included for all original and subsequent articles in ISI Web of Science, PubMed electronic databases, and extracted information about number of mutation carriers within families and sporadic cases worldwide for pathogenic mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13. The end-of-search date was January 31, 2014.
  
  
  METHODS
  Published studies were included if there was information on the ethnicity of the patient or unaffected individual, confirmation of mutation, age of patient or unaffected individual, age at onset, and first motor symptom of patient. Autosomal recessive parkinsonism and genes implicated without significant genetic linkage were excluded from this study.
  
  
  METHODS
  The age-associated cumulative incidence was estimated using the Kaplan-Meier method with age at onset as the time variable; asymptomatic carriers were right censored at the age at last contact or age at death.
  
  
  METHODS
  Comparative measures were obtained with log-rank tests, and each penetrance estimate was given separately with 95% confidence intervals.
  
  
  RESULTS
  All the assessed autosomal dominant Parkinson disease mutations have significantly different age-dependent cumulative incidences (P < .001). In particular, penetrance of SNCA duplications was comparable to point mutations (log-rank P = .97) and driven by inclusion of SNCA p.A53T (mean age at onset, 45.9 years; 95% CI, 43-49 years). In addition, Israeli Ashkenazi Jewish LRRK2 p.G2019S carriers (mean age at onset, 57.9 years; 95% CI, 54-63 years) were comparable to Tunisian Arab Berbers (mean age at onset, 57.1 years; 95% CI, 45.5-68.7 years) (P = .58), whereas Norwegian carriers (mean age at onset, 63 years; 95% CI, 51.4-74.6 years) were significantly different from the other groups (P < .001).
  
  
  CONCLUSIONS
  Parkinson disease pathogenic mutations have an age-dependent penetrance that could be ameliorated or exacerbated by modifier genes or environmental factors in different populations.
authors.affiliation: Djavad Mowafaghian Centre for Brain Health, Centre of Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver.
authors.forename: Joanne
authors.initials: J
authors.lastname: Trinh
authors.affiliation: Djavad Mowafaghian Centre for Brain Health, Centre of Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Guella
authors.affiliation: Djavad Mowafaghian Centre for Brain Health, Centre of Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver.
authors.forename: Matthew James
authors.initials: MJ
authors.lastname: Farrer
mesh_terms: D017668:Age of Onset; D006801:Humans; D020734:Parkinsonian Disorders / Q000235:genetics*; D019683:Penetrance