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* From the Institute of Human Genetics (Drs. Janssen, Barth, Miltenberger-Miltenyi, and Bartram and Mr. \E Rindermann), University of Heidelberg, Heidelberg; Department of Cardiology (Drs. Mereles, Abushi, Kübler, and Grünig), University of Heidelberg, Heidelberg; and Department of Pneumonology (Dr. Seeger), University of Giessen, Giessen, Germany.
Correspondence to: Bart Janssen, PhD, Institute of Human Genetics, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany; e-mail: Bart_Janssen{at}med.uni-heidelberg.de
Primary pulmonary hypertension (PPH) is an autosomal dominant disorder with an estimated incidence of about one to two cases per million. The disease is characterized by increased resistance of precapillary pulmonary arteries and leads to sustained elevation of pulmonary arterial pressure (mean pressure > 25 mm Hg at rest or > 30 mm Hg during exercise).1 The disease can occur at any stage throughout life from infancy onwards. The mean age at onset is 36 years, and the median length of survival without treatment is < 3 years after diagnosis.2 Therefore, even in large families, there will never be a high number of living family members with manifest PPH at any one time point. As a consequence, linkage studies are hampered by low numbers of living patients. Despite these problems, American and British investigators managed to find the gene locus and to identify the trait-causing gene: the bone morphogenetic protein receptor type II (BMPR2) gene on chromosome 2q33.3 4 The BMPR2 gene is mutated in a significant proportion of PPH patients, and studies on large cohorts have shown mutation detection rates ranging from 26% in sporadic PPH to 48% in familial cases.5 6 Nevertheless, it appears to be impossible to find all or almost all mutations in a cohort of patients. Several plausible explanations for this problem can be mentioned, like a mutational hot spot in a regulatory element or undetected locus heterogeneity. So far, it was not possible to investigate the latter explanation due to the limited number of living patients.
Our echocardiographic studies have demonstrated that a predisposition to PPH can be diagnosed at an early stage of disease using stress Doppler echocardiography.7 A pathologic rise of pulmonary artery systolic pressure (PASP) during supine bicycle exercise (> 40 mm Hg) was observed only in those family members who shared the risk haplotype with the index patients. To investigate the genetic cause in BMPR2-negative PPH patients, we analyzed a large family with PPH and a normal BMPR2 gene using linkage analysis, stress Doppler echocardiography and, in some family members, right-heart catheterization.
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Methods and Results |
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 TOP Methods and Results ConclusionReferences |
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45
mm Hg) during supine bicycle exercise. Family members with a maximum
PASP of 
35 mm Hg were classified as normal. All family members with
intermediate PASP values (> 35 mm Hg and < 45 mm Hg) and family
members suspected as having pulmonary hypertension due to secondary
causes were classified as status unknown. The intermediate PASP range
corresponds to the SD at high heart rates and was introduced to avoid
the occurrence of false recombinations. In total, we studied 57 family
members. A manifest PPH was diagnosed in two family members. A PPH
carrier status was found by Doppler echocardiography in 12 individuals;
in another 12 family members, the PASP values were normal. The
remaining family members had secondary pulmonary hypertension, were not
available for clinical investigation, revealed inadequate Doppler
echocardiographic signals, or revealed intermediate PASP values and
were therefore classified as status unknown. All adult cases with
manifest PPH or a PPH carrier status were reinvestigated by right-heart
catheterization. In each case, the stress echocardiographic data were
confirmed.
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The multipoint analysis showed high LOD scores in the proximal part of the PPH candidate region, whereas insignificant LOD scores (Z < 0.1) were obtained for the more distal markers linked to BMPR2 (locus PPH1). The haplotypes indicated that recombinations with the PPH1 locus occurred in one unaffected family member (V-7) and in two members who showed a pathologic increase of PASP (51 mm Hg and 47 mm Hg, respectively) during supine bicycle exercise (IV-2 and IV-7) [Fig 1 ]. The maximum LOD score for this family was found at the position of marker D2S2307 (Z maximum, 4.54). At the BMPR2-linked marker D2S307, the LOD score was 0.07.
A PASP of 40 mm Hg during supine bicycle exercise is generally accepted as maximal for normal individuals.8 9 Based on these findings, we had to consider the individuals with pathologic PASP as genuine PPH carriers, despite the recombinant haplotypes.
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Conclusion |
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TOPMethods and ResultsConclusionReferences |
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The genetic classification of our families would not have been possible without the novel diagnostic procedure involving stress Doppler echocardiography. Although we studied a PPH-related phenotype rather than PPH itself, the haplotype information demonstrates that the PPH2 locus is not the site of a modifier gene, modifying the PPH phenotype toward a trait detectable by stress Doppler echocardiography, but the site of a mutation that is the direct cause of PPH. We conclude that stress Doppler echocardiography enables the investigators to identify carriers of the disease, nearly independent of the state of the disease process. Although the use of an intermediate range ensures that we only counted genuine recombinations, we noticed that 15 noncarriers and only 2 carriers were excluded from the study due to intermediate PASP values. Therefore, the use of an intermediate range and the exact cutoff value needs further evaluation.
Our data indicate that a second PPH gene maps to 2q31–32. This map position is supported by a highly significant LOD score. We realize that more conclusive evidence should come from studies on larger numbers of families. Such a study is currently in progress in our institutions.
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Footnotes |
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TOPMethods and ResultsConclusionReferences |
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This article has been cited by other articles:
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  J. E. Loyd Genetics and Pulmonary Hypertension Chest, December 1, 2002; 122(6_suppl): 284S - 286S. [Abstract] [Full Text] [PDF]
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