Familial Primary Pulmonary Hypertension Locus Mapped to Chromosome 2q31-q32

The pathogenesis of primary pulmonary hypertension (PPH) is unknown, although families with several affected members suggest a genetic etiology for the familial form. We used microsatellite markers and linkage analyses to map the chromosomal locus linked to PPH in two families with three or more affected members. Previously reported, family 1 (of European ancestry) was known to have nine affected members over five generations. Family 2 (Hispanic) had an unaffected father with three unaffected children and three affected children by different wives. Two autosomal dominant (AD) models of inheritance were used in the analyses. AD1 considered only affected members in the families, whereas AD2 used disease penetrances assigned according to age- and gender-related incidence data (literature). The genomic screen of family 1 analyzed data from the use of 260 evenly distributed autosomal markers on 22 living, initially available members (3 affected and 19 unaffected; later, autopsies from 2 affected members became available). Only autosomes were screened because of male-to-male transmission in both families. Multipoint analysis eliminated 40% of the genome (AD1). The use of additional markers eliminated all but one region. The final analyses included both families, with additional genotypes obtained from autopsies of two affected members of family 1, and analyzed only the markers in the region of interest (D2S1776, D2S324, D2S350, D2S364, D2S1391, D2S152, D2S318, D2S311, and D2S1384). Saturating the candidate region with closely spaced markers mapped the disease locus, PPH1 (GBD/HUGO designation), to a 27 cM region on chromosome 2q31-q32 flanked by recombination events at D2S1776 and D2S1384. Analysis under the AD2 led to a maximal pairwise lod score of 3.21 at D2S1391 and multipoint lod score of 3.87 at D2S350 and D2S364. The lod scores for family 2, although not significant in themselves, indicated cosegregation of PPH with markers for this region and added to the evidence for linkage. Since submission of these findings, the addition of a third large PPH family and of an affected sibling in family 2, previously thought to be asymptomatic, increased the multipoint lod score to >4.5.