BMPR2 for Hereditary Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is characterized by widespread obliteration of the smallest pulmonary arteries. When a sufficient number of vessels are occluded, the resistance to blood flow through the lungs increases, and the right ventricle attempts to compensate by generating higher pressure to maintain pulmonary blood flow. When the right ventricle can no longer compensate for the increased resistance, progressive heart failure occurs. All ages are affected, but the mean age at diagnosis is 36 years. Mean survival after diagnosis is 2.8 years. PAH may be inherited and is then classified as familial PAH. Familial PAH is inherited as an autosomal dominant trait, but the average penetrance is only 20%. Each child of an affected individual has a 50% chance of inheriting the mutant allele; however, because of reduced penetrance the risk of the child actually developing PAH is only 10% (50% x 20%). Most PAH is caused by a mutation in the gene for bone morphogenetic receptor type-2 (BMPR2). Bone morphogenetic protein receptor type-2 (BMPR-2) is a member of the transforming growth factor ? (TGF-?) superfamily of cell-signaling molecules. The majority of BMPR2 mutations leads to a truncated BMPR-2 protein that cannot carry out its normal cell signaling function. Loss of signal transduction may result in the abnormal smooth muscle proliferation that occurs in the pulmonary arterioles of patients with PAH. The diagnosis of familial PAH is confirmed by the presence of two or more family members with PAH or the identification of a responsible BMPR2 mutation in a single family member. BMPR2 mutations are detected in about 75% of individuals with familial PAH. In about 25% of families the responsible mutation has not yet been discovered. BMPR2 mutations have been identified in 25% of individuals who represent simplex cases (i.e., a single occurrence in a family). Of those mutations detected, 37% have been point mutations and 48% have been larger deletions or duplications in the coding region of the BMPR2 gene . Unfortunately, no single method detects all of these mutations. DNA sequencing detects small intragenic deletions, insertions, missense, nonsense, and splice site mutations, but does not detect larger deletion/duplications. To detect the latter, multiplex ligation-dependent probe amplification is required. To achieve maximum sensitivity both deletion/ duplication analysis and DNA sequencing need to be performed. Deletion/duplication analysis has a clinical sensitivity of only 34% for familial PAH, while the combination of deletion/duplication analysis and DNA sequencing has a higher clinical sensitivity of 70% for familial PAH and 15% for idiopathic PAH. Unfortunately, the addition of DNA sequencing more than triples the cost of testing.
