05 February 2018 by Christina Eichstaedt

Identification of genetic defects in pulmonary arterial hypertension by a new panel diagnostic


Pulmonary arterial hypertension (PAH) is a rare autosomal dominant lung disease with reduced penetrance. In this study we developed a new PAH specific gene panel including major disease genes and further candidates. This next generation based diagnostic approach provides more comprehensive data than the current diagnostic procedure of Sanger sequencing of the three major genes (BMPR2, ACVRL1, ENG).


We aimed to investigate the frequency of mutations in all known PAH and further candidate genes using a novel PAH specific gene panel.


We included 37 patients with invasively confirmed PAH by right heart catheterisation and 5 relatives of further affected patients for genetic testing. A new PAH-specific gene panel was designed to enrich genes of interest. We used next generation sequencing to assess the coding sequence and intron/exon boundaries of 12 known disease genes and 17 candidate genes. Any potential pathogenic variants were reassessed by direct Sanger sequencing.


Twenty-two of the 37 patients (59%) had a mutation in the gene BMPR2, ACVRL1, ENG or EIF2AK4 identified by panel and Sanger sequencing. In addition, 12 unclassified variants were identified in 7 genes (known and candidate genes). A sensitivity of 100% was met after quality parameters were adjusted. The positive predictive value for all newly investigated genes based on panel results increased to 100% when Sanger technique was additionally applied.


This new PAH-specific gene panel allowed for the first time the assessment of all known PAH genes and further candidates at once and markedly reduced overall sequencing time and cost. The technique enables the identification of mutations in different genes within the same patient, which might act as modifiers increasing disease penetrance and accelerating PAH manifestation. Thus, this approach is about to change the routine diagnostic genetic testing in PAH patients.

Key Contributors

Christina A. Eichstaedt, PhD1,2,3*, Jie Song, MD1,2,3*, Rebecca Rodríguez Viales, PhD4, Nicola Benjamin, MSc1,3, Satenik Harutyunova, MD1,3, Christine Fischer, PhD2, Ekkehard Grünig, MD1,3and Katrin Hinderhofer, PhD2 1 Centre for Pulmonary Hypertension at Thoraxclinic, University Hospital Heidelberg, Röntgenstraße 1, 69126 Heidelberg, Germany 2 Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany 3 Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany 4 European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany * These authors contributed equally to this work.

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