title: Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension.
abstract: BACKGROUND
  Analysis of the age of onset in heritable pulmonary arterial hypertension (HPAH) has led to the hypothesis that genetic anticipation causes younger age of onset and death in subsequent generations. With accrual of pedigree data over multiple decades, we retested this hypothesis using analyses that eliminate the truncation of data that exists with shorter duration of follow-up.
  
  
  OBJECTIVE
  To analyze the pedigrees of families with mutations in bone morphogenetic protein receptor type 2 (BMPR2), afflicted in two or more generations with HPAH, eliminating time truncation bias by including families for whom we have at least 57 years of data.
  
  
  METHODS
  We analyzed 355 individuals with BMPR2 mutations from 53 families in the Vanderbilt Pulmonary Hypertension Registry. We compared age at diagnosis or death in affected individuals (n = 249) by generation within families with multigenerational disease. We performed linear mixed effects models and we limited time-truncation bias by restricting date of birth to before 1955. This allowed for 57 years of follow-up (1955-2012) for mutation carriers to develop disease. We also conducted Kaplan-Meier analysis to include currently unaffected mutation carriers (n = 106).
  
  
  RESULTS
  Differences in age at diagnosis by generation were found in a biased analysis that included all birth years to the present, but this finding was eliminated when the 57-year observation limit was imposed. By Kaplan-Meier analysis, inclusion of currently unaffected mutation carriers strengthens the observation that bias of ascertainment exists when recent generations are included.
  
  
  CONCLUSIONS
  Genetic anticipation is likely an artifact of incomplete time of observation of kindreds with HPAH due to BMPR2 mutations.
authors.affiliation: Vanderbilt University Institute for Medicine and Public Health, Vanderbilt Medical Center North, Nashville, TN 37232-2650, USA.
authors.forename: Emma K
authors.initials: EK
authors.lastname: Larkin
authors.forename: John H
authors.initials: JH
authors.lastname: Newman
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
authors.forename: Lisa
authors.initials: L
authors.lastname: Wheeler
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Robbins
authors.forename: James D
authors.initials: JD
authors.lastname: West
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips
authors.forename: Rizwan
authors.initials: R
authors.lastname: Hamid
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D020132:Anticipation, Genetic; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D012042:Registries
chemical_list: C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II