Mutation in the gene for bone morphogenetic protein receptor II as a causeof primary pulmonary hypertension in a large kindred

Background: Most patients with primary pulmonary hypertension are thought t o have sporadic, not inherited, disease. Because clinical disease develops in only 10 to 20 percent of persons carrying the gene for familial primary pulmonary hypertension, we hypothesized that many patients with apparently sporadic primary pulmonary hypertension may actually have familial primary pulmonary hypertension. Methods: In a study conducted over 20 years, we developed a registry of 67 families affected by familial primary pulmonary hypertension. Through patie nt referrals, extensive family histories, and correlation of family pedigre es, we discovered shared ancestry among five subfamilies. We assessed some family members for mutations in the gene encoding bone morphogenetic protei n receptor II (BMPR2), which has recently been found to cause familial prim ary pulmonary hypertension. Results: We linked five separately identified subfamilies that included 394 known members spanning seven generations, which were traced back to a foun ding couple in the mid-1800s. Familial primary pulmonary hypertension has b een diagnosed in 18 family members, 12 of whom were first thought to have s poradic disease. The conditions of 7 of the 18 were initially misdiagnosed as other cardiopulmonary diseases. Six members affected with familial prima ry pulmonary hypertension and 6 of 10 at risk for carriage have undergone g enotype analysis, and they have the same mutation in BMPR2, a transversion of thymine to guanine at position 354 in exon 3. Conclusions: Many cases of apparently sporadic primary pulmonary hypertensi on may be familial. The recent discovery of mutations in BMPR2 should make it possible to identify those with susceptibility to the disease.