Identification of genetic defects in pulmonary arterial hypertension by a new gene panel diagnostic tool.
In the present study we developed a new specific gene panel for pulmonary arterial hypertension (PAH) including major disease genes and further candidates. We assessed 37 patients with invasively confirmed PAH and five relatives of affected patients for genetic testing. A new PAH-specific gene panel was designed using next generation sequencing (NGS) including 12 known disease genes and 17 further candidates. Any potential pathogenic variants were reassessed by Sanger sequencing. Twenty-two of the 37 patients (59%) had a mutation in BMPR2, ALK1, ENG or EIF2AK4 genes identified by panel and Sanger sequencing. In addition, 12 unclassified variants were identified in seven genes (known and candidate genes). A sensitivity of 100% was met after quality parameters were adjusted. Specificity increased to 100% when Sanger technique was added as a routine validation. The new PAH-specific gene panel developed in the present study allowed for the first time the assessment of all known PAH genes and further candidates at once and markedly reduced overall sequencing time and costs. Sensitivity and specificity reached 100% when Sanger sequencing was additionally applied. Thus, this technique will potentially change the routine diagnostic genetic testing in PAH patients.
Centre for Pulmonary Hypertension at Thoraxclinic, University Hospital Heidelberg, Röntgenstraße 1, 69126 Heidelberg, Germany Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
Jie
J
Song
Centre for Pulmonary Hypertension at Thoraxclinic, University Hospital Heidelberg, Röntgenstraße 1, 69126 Heidelberg, Germany Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
Christina A
CA
Eichstaedt
Research Unit for Genome Biology, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.
Rebecca Rodríguez
RR
Viales
Centre for Pulmonary Hypertension at Thoraxclinic, University Hospital Heidelberg, Röntgenstraße 1, 69126 Heidelberg, Germany Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
Nicola
N
Benjamin
Centre for Pulmonary Hypertension at Thoraxclinic, University Hospital Heidelberg, Röntgenstraße 1, 69126 Heidelberg, Germany Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
Satenik
S
Harutyunova
Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Christine
C
Fischer
Centre for Pulmonary Hypertension at Thoraxclinic, University Hospital Heidelberg, Röntgenstraße 1, 69126 Heidelberg, Germany Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
Ekkehard
E
Grünig
Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany katrin.hinderhofer@med.uni-heidelberg.de.
Katrin
K
Hinderhofer
D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D000328:Adult; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
genetics; mutation analysis; panel diagnostic; pulmonary hypertension