Abstract
Background: Mutations in the bone morphogenic protein receptor 2 (BMRP2), ALK1 and endoglin have previously been identified as main disease causing genes in pulmonary arterial hypertension (PAH). In clinical practice genetic assessment is performed by Sanger sequencing including these 3 genes only although 7 further PAH-genes have previously been identified. In this study we developed a new PAH-specific gene panel.
Methods: We included 37 patients with invasively confirmed PAH for genetic testing and 5 relatives of affected PAH-patients. A new PAH-specific gene panel was developed using next generation sequencing. The panel included the 10 known PAH-genes and 22 further candidates within the BMPR2/Alk1 pathway. Any potential pathogenic variants were reassessed by Sanger sequencing. Within repeated runs quality parameters have been adjusted.
Results: Twenty-five of the 42 subjects (60%) had a mutation in BMPR2, ALK1 or endoglin genes identified by panel and Sanger sequencing. In addition, 3 new mutations and 13 unclassified variants were identified in 9 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.
Conclusion: The new PAH-specific gene panel developed in this study allowed for the first time the assessment of all known 10 PAH-genes and further 22 candidates at once and reduced markedly overall sequencing costs and time. Sensitivity and positive predictive value reached 100% when Sanger technique was additionally applied. Thus, this technique might revolutionize the routine diagnostic genetic testing in PAH-patients.
- Copyright ©the authors 2016