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Linkage Analysis in a Large Family With Primary Pulmonary Hypertension*: Genetic Heterogeneity and a Second Primary Pulmonary Hypertension Locus on 2q31–32

Bart Janssen, PhD; Matthias Rindermann; Ulrike Barth, PhD; Gabriel Miltenberger-Miltenyi, MD; Derliz Mereles, MD; Adel Abushi, MD; Werner Seeger, MD; Wolfgang Kübler, MD; Claus R. Bartram, MD; Ekkehard Grünig, MD
Author and Funding Information

*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@med.uni-heidelberg.de



Chest. 2002;121(3_suppl):54S-56S. doi:10.1378/chest.121.3_suppl.54S
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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 2q33.34 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.56 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.

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