Calendar | For Your Patients | PHA Main Site | Contact Us | About Us | Not a registered user? Sign up here.

Resource Library

Longitudinal Analysis Casts Doubt on the Presence of Genetic Anticipation in Heritable Pulmonary Arterial Hypertension (HPAH)

Lisa Wheeler

Emma Larkin

James E. Loyd

Eric Austin

Anna Hemnes

Ivan Robbins

James West

John Phillips III

Rizwan Hamid

John Newman


  Sign in to add a review

Leave a Comment

Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

Lisa Wheeler, Emma K Larkin, James E Loyd, Eric D Austin, Anna Hemnes, Ivan M Robbins, James D West, John A Phillips III, Rizwan Hamid, John H Newman

Vanderbilt University Medical Center, USA

BACKGROUNDGenetic anticipation (GA) is a phenomenon whereby the symptoms of disease tend to appear at an earlier age as the disorder is passed from one generation to the next. In 1995, we reported that GA appeared likely in our family cohort of PAH patients, as earlier reports also suggested. However, this observation is complicated by many potential biases, in particular, incomplete time of follow-up for younger generations of at risk individuals to develop disease.

METHODSWe analyzed data from 54 (BMPR2 mutation positive) families including 251 affected subjects. We made comparisons of age at diagnosis by generation starting with the first generation exhibiting an affected family member. In order to study the impact of time truncation bias, we replicated truncated analyses that compared the mean ages of affected parents and offspring, using linear mixed effect models to account for correlated family data. To reduce truncation bias, we then conducted analyses by limiting generations to those offspring who have at least 47 years of follow-up (born on or before 1965), a number that was selected to be higher than the mean age of onset of HPAH (>85% by age 45). This action eliminates parent offspring pairs from later generations that include only affected offspring diagnosed at young ages without allowing for older affected siblings.

RESULTSHPAH families do not exhibit genetic anticipation when time truncation bias is taken into account. This observation is illustrated in the figures below.


 Longitudinal Analysis Casts Doubt on the Presence of Genetic Anticipation in Heritable Pulmonary Art         












The biased ascertainment by age at diagnosis of 155 family members with HPAH born 2012 or earlier by generation of affected family members. There is a significant decrease in the age at diagnosis by generation, amounting to almost 15 year difference in the range where most patients are diagnosed, ages 30-45, p < 0.05. Late onset cases in youngest generations in the future cannot be included, creating a false impression of genetic anticipation.

Longitudinal Analysis Casts Doubt on the Presence of Genetic Anticipation in Heritable Pulmonary Art










Age at diagnosis of 121 family members born in 1965 or earlier with HPAH over two or more successive generations (4 generations). There are no differences in age at death by generation number, p = 0.85.

CONCLUSIONSGenetic anticipation is likely an artifact of incomplete time of observation of kindreds with BMPR2 associated HPAH.