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Here we applied a multistep approach to extend identification of the genetic bases of such a disease by searching for novel candidate genes\/pathways. Twenty-eight patients belonging to 18 families were screened for <jats:italic>BMPR2<\/jats:italic> mutations and <jats:italic>BMPR2<\/jats:italic>-negative samples were tested for 12 additional candidate genes by means of a specific massive parallel sequencing-based assay. Finally, whole exome sequencing was performed on four patients showing no mutations at known disease genes, as well as on their unaffected parents. In addition to <jats:italic>EIF2AK4<\/jats:italic>, which has been already suggested to be associated with pulmonary veno-occlusive disease, we identified the novel candidate genes <jats:italic>ATP13A3<\/jats:italic>, <jats:italic>CD248<\/jats:italic>, <jats:italic>EFCAB4B<\/jats:italic>, involved in lung vascular remodeling that represent reliable drivers contributing to the disease according to their biological functions\/inheritance patterns. Therefore, our results suggest that combining gene panel and whole exome sequencing provides new insights useful for the genetic diagnosis of familial and idiopathic pulmonary arterial hypertension, as well as for the identification of biological pathways that will be potentially targeted by new therapeutic strategies.<\/jats:p>","DOI":"10.1038\/s41598-018-37277-0","type":"journal-article","created":{"date-parts":[[2019,1,24]],"date-time":"2019-01-24T11:04:17Z","timestamp":1548327857000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["A Combined Targeted and Whole Exome Sequencing Approach Identified Novel Candidate Genes Involved in Heritable Pulmonary Arterial Hypertension"],"prefix":"10.1038","volume":"9","author":[{"given":"Chiara","family":"Barozzi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Galletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Tomasi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"De Fanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Palazzini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Manes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5382-7827","authenticated-orcid":false,"given":"Marco","family":"Sazzini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazzareno","family":"Gali\u00e8","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,1,24]]},"reference":[{"key":"37277_CR1","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1056\/NEJMra040291","volume":"351","author":"M Humbert","year":"2004","unstructured":"Humbert, M., Sitbon, O. & Simonneau, G. 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