Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension

Abstract

Rationale: 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.

Objectives: 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).

Measurements and main 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.

Figure 1.

Age at diagnosis of 115 patients from 30 families with two to four generations of members affected with heritable pulmonary arterial hypertension, born in or before 1955. The Tukey plots show median (bar within box), mean (bold star), interquartile range (boxes), the 10th and 90st percentile (whiskers), and outliers (beyond whiskers). There are no differences among generations 1-2-3-4 in any combination.

Figure 2.

Age at diagnosis of 249 patients from 53 families with two to four generations of members with heritable pulmonary arterial hypertension born in or before 2011. Inclusion of recent generations without sufficient time for all at-risk members to express disease results in statistical lowering of the age at diagnosis (P < 0.0001), especially in the recent two generations.

Figure 3.

A Kaplan-Meier plot of disease-free status of all 355 patients in the 53-family cohort, including known mutation carriers who are disease free and therefore censored (open circles) at the most recent age of query. Adding the censored members reverses the statistically significant differences by generation noted in the time biased analysis in Figure 2. FPAH = familial pulmonary arterial hypertension.