Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32

Primary pulmonary hypertension (PPH), an often fatal disease, is characterized by elevated pulmonary artery pressures in the absence of a secondary cause. Endovascular occlusion in the smallest pulmonary arteries occurs by proliferation of cells and matrix, with thrombus and vasospasm. Diagnosis is often delayed because the initial symptoms of fatigue and dyspnea on exertion are nonspacific and definitive diagnosis requires invasive procedures. The average life expectancy after diagnosis is two to three years with death usually due to progressive right heart failure. The aetiology of the disease is unknown. Although most cases appear to be sporadic, ~6% of cases recorded in the NIH Primary Pulmonary Hypertension Registry are inherited in an autosomal dominant manner with reduced penetrance. Following a genome-wide search using a set of highly polymorphic short tandem repeat (STR) markers and 19 affected individuals from six families, initial evidence for linkage was obtained with two chromosome 2q markers. We subsequently genotyped patients and all available family members for 19 additional markers spanning ~40 centiMorgans (CM) on the long arm of chromosome 2. We obtained a maximum two-point lod score of 6.97 at θ=0 with the marker D2S389; multipoint linkage analysis yielded a maximum lod score of 7.86 with the marker D2S311. Haplotype analysis established a minimum candidate interval of ~25 cM.