|
Overview of Genetics as presented
at the PAH Symposium in Venice
C. Gregory Elliott, MD
LDS Hospital, University of Utah School of Medicine, Salt
Lake City, Utah
Medical scientists have achieved three major goals proposed
by the 1998 Evian task force on the genetics of pulmonary
hypertension. First, mutations in the gene that codes
for bone morphogenetic protein receptor 2 (BMPR2) are
linked to familial primary pulmonary hypertension. BMPR2
mutations are detectable in approximately half of the
families affected by primary pulmonary hypertension. The
gene that codes for BMPR2 is large (13 exons) and already
more than 26 mutations are described. Second, many patients
with apparently sporadic primary pulmonary hypertension
have mutations of the gene that codes for BMPR2. This
observation, combined with observations of common ancestors
among patients with apparently sporadic primary pulmonary
hypertension, indicates that an inherited basis underlies
many cases of primary pulmonary hypertension. However,
the relatively low penetrance of these mutations (only
15% to 20% of persons carrying a BMPR2 mutation develop
clinically evident disease in their lifetime) makes identification
of familial disease difficult. Third, BMPR2 mutations
are rare in other classifications of pulmonary arterial
hypertension, eg, pulmonary arterial hypertension associated
with CREST, HIV infection, or fenfluramine exposure. Rare
cases of pulmonary arterial hypertension with BMPR2 mutations
and fenfluramine exposure raise the possibility of disease
triggered by genetic predisposition and an environmental
trigger.
The exact pathogenesis of familial primary pulmonary
hypertension remains elusive in spite of the identification
of BMPR2 mutations. The identification of abnormalities
in other TGF beta receptors [ALK-1; TGF beta R2, and BMPR1A
(ALK3)] suggests that dysfunctional TGF beta receptors
are important in the pathogenesis of familial primary
pulmonary hypertension. Indeed, TGFB represents a classic
pleiotropic mediator to the vascular system by modifying
growth, differentiation, and death of vascular cells.
Nevertheless, other genes and/or environmental factors
must also be important in order to explain the reduced
penetrance of BMPR2 mutations. Genes that control nitric
oxide synthesis, serotonin transport, or prostacyclin
may prove important to the expression of disease. Animal
models (eg, mice) allow study of genetic alterations of
BMPR2 as well as other pathways, eg, serotonin. Inactivation
of BMPR2 in mice leads to preand perinatal mortality because
of abnormal mesoderm formation, illustrating the potential
of BMPR2 mutations to cause vascular disease. To date,
scientists have not been able to reproduce primary pulmonary
hypertension in mouse models, but this remains an important
goal for future research.
The discovery of mutations in the gene that codes for
BMPR2 makes genetic testing and counseling possible. In
the future such tests may corroborate diagnostic impressions
and provide estimates of an individual’s risk to develop
primary pulmonary hypertension. The use of such tests
requires an understanding of the meaning of the test results,
as well as the risks and benefits of this knowledge to
those who are tested and to other family members. Before
and after the tests, education and counseling will be
necessary, especially because the penetrance of known
BMRP2 mutations is low and because the results may prove
psychologically (eg, depression, anxiety) or socially
(eg, employment barriers and effects on insurability)
harmful.
For these reasons genetic testing for BMPR2 mutations
will require adherence to basic rules. Informed consent
is essential when a test can be linked to an individual.
The consent should be voluntary, without coercion or intimidation;
and patients should be assured that their care is unaffected
by decisions to forego genetic tests. In addition confidentiality
of results must be assured.
Genetic tests for mutations associated with primary pulmonary
hypertension are not available in the United States. The
BMPR2 gene is large, making tests expensive unless the
test is directed at a known mutation. For these reasons
the task force concluded that genetic testing needs development
and is not ready for widespread implementation.
|
