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.